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Perspective

Neuronal and Non-Neuronal GABA in COVID-19: Relevance for Psychiatry

by
Adonis Sfera
1,2,*,
Karina G. Thomas
1,
Sarvin Sasannia
3,
Jonathan J. Anton
1,4,
Christina V. Andronescu
5,
Michael Garcia
2,
Dan O. Sfera
1,
Michael A. Cummings
1 and
Zisis Kozlakidis
6
1
Patton State Hospital, University of California, Riverside, CA 92521, USA
2
Department of Psychiatry, University of California, Riverside, CA 92521, USA
3
Department of Medicine, Shiraz University of Medical Sciences, Shiraz 14336-71348, Iran
4
College of Health Science, California Baptist University, Riverside, CA 92504, USA
5
Medical Anthropology Department, Stanford University, Stanford, CA 94305, USA
6
International Agency for Research on Cancer (IARC), 69372 Lyon, France
*
Author to whom correspondence should be addressed.
Reports 2022, 5(2), 22; https://doi.org/10.3390/reports5020022
Submission received: 20 May 2022 / Revised: 3 June 2022 / Accepted: 6 June 2022 / Published: 8 June 2022
(This article belongs to the Special Issue Novel Aspects of COVID-19 after a Two-Year Pandemic)
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Review Reports Versions Notes

Abstract

:
Infection with SARS-CoV-2, the causative agent of the COVID-19 pandemic, originated in China and quickly spread across the globe. Despite tremendous economic and healthcare devastation, research on this virus has contributed to a better understanding of numerous molecular pathways, including those involving γ-aminobutyric acid (GABA), that will positively impact medical science, including neuropsychiatry, in the post-pandemic era. SARS-CoV-2 primarily enters the host cells through the renin–angiotensin system’s component named angiotensin-converting enzyme-2 (ACE-2). Among its many functions, this protein upregulates GABA, protecting not only the central nervous system but also the endothelia, the pancreas, and the gut microbiota. SARS-CoV-2 binding to ACE-2 usurps the neuronal and non-neuronal GABAergic systems, contributing to the high comorbidity of neuropsychiatric illness with gut dysbiosis and endothelial and metabolic dysfunctions. In this perspective article, we take a closer look at the pathology emerging from the viral hijacking of non-neuronal GABA and summarize potential interventions for restoring these systems.

1. Introduction

The infection with SARS-CoV-2 became a pandemic on 11 March 2020, ushering in immeasurable economic and healthcare catastrophes. Up until 14 May 2022, more than 517 million people had been afflicted by COVID-19, and more than 6 million had died (https://covid19.who.int/ (26 May 2022)). However, the extensive research conducted on this virus in a short period of time has broadened our understanding of its numerous pathogenetic mechanisms, leading to novel paradigms that will likely bear fruit in the post-pandemic era. For example, local renin–angiotensin systems (RAS) expressed in the brain and gastro-intestinal (GI) tract, although previously acknowledged, were poorly defined prior to the COVID-19 pandemic. Likewise, the crosstalk between host RAS and microbial γ-aminobutyric acid (mGABA) was seldom considered when explaining the high comorbidity of inflammatory bowel disease (IBD) and neuropsychiatric conditions, including anxiety, depression, psychosis, and seizure disorder [1,2,3,4]. By the same token, endothelial GABA (eGABA) and its role in blood pressure homeostasis and neuropsychiatric pathology began to be examined only after the appearance of COVID-19 [5].
Although neuronal GABA (nGABA) has been studied for several decades, also within the context of viral infections, its non-neurotransmitter functions were poorly understood until very recently [6,7]. For example, the antiviral and anti-inflammatory properties of GABA were highlighted by recent preclinical studies showing that GABA supplementation decreased COVID-19 death rates [8,9,10]. Along this line, a novel study has demonstrated that Limosilactobacillus fermentum, a GABA-producing gut microbe, thwarts Norovirus infection, further attesting to the antiviral actions of this biomolecule [11]. In addition, mGABA was demonstrated to augment host autophagy, including that of pathogen-infected cells, indicating participation in antimicrobial defenses [12]. Interestingly, gut angiotensin-converting enzyme-2 (ACE-2), the SARS-CoV-2 entry portal, upregulates mGABA by increasing its release from the gut flora [13]. This is significant, as earlier studies have demonstrated that angiotensin receptor blockers (ARBs) possess antiepileptic, anti-depressant, and anti-anxiety properties, suggesting that the functions of RAS and GABA are highly intertwined [14,15,16]. Indeed, blood–brain barrier (BBB)-crossing ARBs were reported to lower CNS inflammation, highlighting the role of RAS in neuropsychiatric pathology and placing this system on an equal footing with serotonin (5-HT) and dopamine (DA) [17,18]. Furthermore, in the CNS and pancreas, ACE2–GABA crosstalk was reported to optimize glucose metabolism, probably accounting for the anti-diabetic properties of ARBs [19,20]. As many psychotropic drugs are associated with metabolic dysfunction, using centrally acting ARBs, such as candesartan, for hypertension may bring additional benefits to psychiatric patients [21].
SARS-CoV-2 depletes host GABA by several mechanisms:
  • The viral spike (S) protein contains a GABA-mimicking sequence or short linear motif that can directly usurp host GABAergic signaling [22,23].
  • The SARS-CoV-2 proteins nonstructural protein 6 (NSP6), open reading frame 8 (ORF8), and open reading frame 3 (ORF3a) interact directly with host mammalian target of rapamycin complex 1 (mTORC-1), interleukin 17 (IL-17), and transmembrane protein 16F (TMEM16F), inducing premature EC senescence, a phenotype characterized by low GABA [24,25,26,27,28,29] (Figure 1).
  • SARS-CoV-2/ACE-2 binding disrupts the function of the protective renin–angiotensin system (RAS) branch, including Mas receptor (MasR) signaling, lowering GABA [14,30].
  • The viral protein ORF3a interacts with toll-like receptor 4(TLR4), triggering EC senescence and lowering GABA [31].
  • The SARS-CoV-2 viral proteins nonstructural protein 4 (NSP4), nonstructural protein 8 (NSP8), and open reading frame 9c (ORF9c) decrease GABA by disrupting the mitochondria, triggering vascular senescence [32] (Figure 1).
SARS-CoV-2-mediated GABA depletion likely explains the neuropsychiatric manifestations of COVID-19, including anxiety, depression, posttraumatic stress disorder (PTSD), cognitive impairment, and seizure disorder [33,34,35,36,37].
In this perspective article, we take a closer look at the viral hijacking of endothelial, pancreatic, and gut GABA and the associated pathology. We also discuss potential interventions for GABAergic system restoration.

2. Two Senescence Mechanisms in SARS-CoV-2 Infection

SARS-CoV-2 is a single-stranded, enveloped RNA virus that contains four structural proteins: spike (S), nucleocapsid (N), membrane (M), and envelope (E). The S protein is composed of two subunits, S1 and S2. The former engages ACE-2, while the latter (FCS) interacts with furin, merging viral envelope and host plasma membrane as well as cells, thus forming syncytia [38]. The viral attachment to ACE-2 disrupts the physiological function of this protein, leading to the unchecked accumulation of angiotensin II (ANG II), a mitochondrial toxin linked to premature EC senescence [39,40].

2.1. S1/ACE-2 Attachment and ANG II-Induced Senescence

The SARS-CoV-2 envelope protein S1 binds ACE-2, contributing to the loss of this enzyme’s biological function as well as to the shutting down of the anti-inflammatory/antioxidant (protective) RAS (Figure 2). The unchecked accumulation of ANG II enhances the proinflammatory/prooxidative RAS branch, which, under normal circumstances is counterbalanced by the protective axis. The imbalance between the two RAS arms results in ANG II-driven hyperinflammation or “cytokine storm” [41,42] (Figure 2). Depletion of ACE-2 and loss of anti-inflammatory/antioxidant RAS induce premature cellular senescence, lowering eGABA, which in return may trigger a neuropsychiatric pathology [43,44,45,46].

2.2. S2/Furin Attachment and Syncytia-Induced Senescence

Enveloped viruses are known for generating multinuclear giant cells by inducing cell–cell fusion or syncytia formation. Cell–cell fusion is a physiological or pathological process in which neighboring cells merge their plasma membranes, sharing intracellular organelles, including cytoplasm and nuclei [47,48].
SARS-CoV-2 entry into host cells requires furin cleavage of the S antigen at the S1/S2 site to initiate membrane fusion [49]. The insertion of the polybasic PRRAR motif at FCS is crucial for fusing viral envelopes with host plasma membrane, as well as the host cells with each other [50]. PRRAR is a triple-arginine motif that forms cell membrane pores via its guanidinium side chains, compelling the cells to fuse for protection [51,52].
Taken together, the SARS-CoV-2 virus induces cellular senescence via ANG II and/or syncytia formation, downregulating the antiviral amino acid GABA [53,54].

2.3. Molecular Mechanisms of Syncytia Formation

The subunit β3 of GABA-A receptors contains a triple-arginine motif (RRR) that interacts with the endocytic pathway (EP) protein AP2, likely disrupting SARS-CoV-2 endocytosis [55]. On the other hand, the triple arginine (PRRAR) in the S antigen of SARS-CoV-2 may counteract this GABA action, usurping the EP and opening it for viral ingress.
A human endogenous retrovirus W (HERV-W) was identified in the regulatory region of GABA-B receptor subunit 1 gene, suggesting that this ancestral retrovirus can be activated by exogenous viruses, including SARS-CoV-2 [56]. HERV-W activation and increased GABA-B expression likely depresses the antiviral GABA-A, facilitating SARS-CoV-2 replication [57]. We surmise that the triple-arginine FCS of SARS-CoV-2 has retrovirus-activating properties, switching on HERVs and human immunodeficiency virus-1 (HIV-1) [58,59] (please see section Ancient and modern viruses disrupt GABAergic signaling).
The SARS-CoV-2 proteins ORF3a and S activate TMEM16F, a calcium-dependent phospholipid scramblase that executes the fusion of both viral envelope with plasma membrane and host cells with each other [60]. In addition, SARS-CoV-2 can deplete GABA by disrupting the mitochondria, which in turn activate the cellular senescence program [24,61] (Figure 1). Furthermore, ORF3a stimulation of TLR4 can induce EC senescence and TMEM16F activation, forming syncytia [31,60,62].

2.4. Biological Barrier Dysfunction

Senescent endothelia may disrupt the BBB and the gut barrier, facilitating the translocation of GI tract microbes and/or their molecules, including LPS, into the systemic circulation, as reported in COVID-19 critically ill patients [63,64] (Figure 1). In addition, the S protein of SARS-CoV-2 can bind directly to circulating LPS, triggering a hyperinflammatory pathology [65]. Interestingly, ANG II upregulates TLR4, the main LPS sensor, augmenting inflammation and neuropsychiatric pathology [43,66,67,68]. As GABA is a negative regulator of TLR4, it likely inhibits both cell–cell fusion and premature senescence, counteracting not only the “cytokine storm” but also neuroinflammation [62,69]. Indeed, low GABA and elevated LPS were demonstrated in the brains of patients with Alzheimer’s disease (AD), suggesting BBB dysfunction and poor LPS suppression [70,71]. Moreover, several studies have demonstrated that LPS can induce pathology by fusing cells into multinuclear structures [72]. For example, brain cells can merge, forming physiological or pathological syncytia that alter both neuronal networks and information processing [73,74] (Figure 3). For example, neuron–neuron fusion occurs during normal aging as well as in the presence of viral infections, multiple sclerosis (MS), AD, and following radiation exposure and chemotherapy [75].
Cell–cell fusion is a major cause of genome destabilization and generation of aneuploidy, somatic mosaicism, and reactivation of the cell cycle in postmitotic cells [61,75,76,77,78] (Figure 3).
Taken together, SARS-CoV-2 may precipitate premature vascular aging via ACE-2 depletion and syncytia formation. Senescent ECs downregulate eGABA, predisposing to neuropsychiatric disorders.

3. Cellular Senescence in Psychopathology

Psychiatric disorders have been associated with shorter-than-average patient lifespan and high comorbidity with age-related diseases, suggesting that premature cellular senescence plays a major role in the pathogenesis of these conditions [79,80]. SARS-CoV-2, like many other viruses, induces premature tissue aging, a phenomenon also demonstrated in depression, anxiety, schizophrenia, and seizure disorder, indicating that GABA depletion may be the common denominator of these pathologies [81,82,83,84]. On the other hand, GABA supplementation was associated with less inflammaging and improved sleep and mood, pointing to a potential therapeutic modality [85,86]. In addition, as GABA promotes autophagic elimination of damaged and virus-infected cells, GABA supplementation may benefit not only COVID-19-affected patients but also those with age-related diseases [5,12].

Adult Neurogenesis and SARS-CoV-2 Infection

The COVID-19 pandemic has highlighted the role of RAS dysfunction, especially ANG II, in the pathogenesis of neuropsychiatric disorders [87]. On the other hand, ARBs and ACEi showed promising results in the treatment of these conditions, emphasizing the pathological role of dysregulated ANG II [88,89]. Moreover, recent epidemiological studies found that COVID-19 survivors may be at increased risk of several neuropsychiatric disorders, further emphasizing the role of RAS in this pathology [30,90,91].
COVID-19-induced premature cellular senescence may engender neuropathology by suppressing adult neurogenesis in the hippocampal subgranular zone (SGZ) and cerebral subventricular zone (SVZ) [92,93]. Unlike in the adult CNS, GABA is an excitatory neurotransmitter in immature neurons; therefore, the loss of GABAergic signaling may disrupt adult neurogenesis [92,94,95,96]. Interestingly, TLR4 was reported to play a key role in the conversion of immature into mature neuronal cells, linking viral exploitation of this protein to dysfunctional neurogenesis [97,98].
Taken together, virus-induced senescence lowers eGABA, contributing to neuropsychiatric pathology by precipitating premature vascular aging and disrupting neurogenesis.

4. GABA, Neuronal and Non-Neuronal Information Processing

GABA is a non-protein amino acid present in almost all life forms, including plants, bacteria, and gut microbes. In the central nervous system (CNS), GABA, signaling via inotropic (GABA-A) and metabotropic (GABA-B) receptors, functions as an inhibitory neurotransmitter and participates in numerous physiological processes, including cognition, wakefulness, and self-awareness [99,100,101].
Neuronal and non-neuronal GABA are synthesized from glutamate via glutamic acid decarboxylase (GAD), an enzyme located in all GABA-generating cells, including the gut microbes [102,103]. This is significant, as autoantibodies against GAD were documented in COVID-19 patients, suggesting molecular mimicry between this enzyme and SARS-CoV-2 proteins [104,105]. Dysfunctional GABAergic systems were associated with neuropsychiatric illness and disorders of consciousness [106,107,108,109,110,111]. For example, the GABAergic system was linked to gamma oscillations on electroencephalogram (EEG), a self-awareness pattern, disrupted in many neuropsychiatric disorders, including epilepsy, schizophrenia, autism, anxiety, and depression [112,113,114]. The EEG gamma-band (25–90 Hz) was positively correlated with resting GABA concentration as well as with the cerebral blood flow, emphasizing the potential of eGABA as a biomarker [115,116].
During development and early life, GABA is an excitatory neurotransmitter that matures gradually throughout childhood and early adolescence [117]. During this time, the partial or total loss of GABA causes circulatory abnormalities and inhibits the migration and placement of cortical interneurons [118]. In adolescence, GABA reaches sufficient levels to initiate microglia-mediated synapse elimination and axonal pruning, characteristic of mature cognition [119]. Indeed, recent studies have shown that GABA-sensing microglia are required for synapse remodeling in adolescence and the installment of adult information processing [120]. On the other hand, dysfunctional GABA signaling may contribute to the pathological reactivation of microglia known to eliminate healthy neurons and synapses, a phenomenon documented in both psychopathology and neurodegeneration [121]. These microglial functions can be hijacked by intracellular pathogens, especially those linked to mental illness [122,123,124].

4.1. Non-Neuronal Information Processing

Recent studies have shown that EC can form cellular networks and communicate via Ca2+ waves, suggesting that information processing may take place at the vascular level [125,126]. Likewise, astrocytes form physiological syncytia, a finding consistent with the Ca2+ wave hypothesis of information processing [127]. In addition, the dysfunctional eGABA association with altered cortical circuits and behavior likely highlights the role of ECs in cognition [118]. Indeed, ECs communicate with and shadow neurons throughout the brain, likely participating in cognitive processes mediated by Ca2+. Moreover, as Ca2+ drives the rudimentary memory of plants and unicellular organisms, an ancient modality of non-neuronal information processing is emphasized [128,129,130]. Along this line, the antidepressant action of ketamine, based, at least in part, on its impact on calcium/calmodulin-dependent protein kinase II (CaMKII), likely implicates Ca2+ in emotional intelligence and cognition [131]. This is important, as virtual screening studies documented the existence of a CaMKII system in the S protein of SARS-CoV-2, linking this pathogen to affective disorders [132]. Moreover, non-neuronal information processing was reported in skeletal muscle, heart, and fascia, indicating that neuronal cells do not hold the exclusive monopoly on cognitive processes [133,134]. Along this line, the acquisition of donor personality characteristics following heart transplantation, documented by numerous studies, may reflect EC-mediated cognition [135,136,137]. This is in line with the hemo-neural hypothesis that connects information processing to endothelial blood flow [138].
In the following sections, we take a closer look at the COVID-19 influence on non-neuronal GABAergic systems, especially the endothelial, microbial, and pancreatic pathways, emphasizing their potential participation in neuropsychiatric pathology.

4.2. eGABA

ECs line the inner layer of the circulatory system and regulate the vascular function via membrane-bound receptors that interact with various neurotransmitters, hormones, and metabolites. While previously conceptualized as passive components of membranes and biological barriers, ECs are now known to play an essential role in vascular homeostasis and the pathogenesis of thrombosis and inflammation [139]. Under normal circumstances, ECs synthesize and secrete eGABA, a molecule depleted in the virus-induced cellular senescence phenotype [118,140,141]. Aside from viral infections, EC senescence and low eGABA were associated with PTSD, anxiety, depression, autism, schizophrenia, and epilepsy, suggesting that the viral manipulation of this neurotransmitter may initiate or exacerbate neuropsychiatric pathology [35,142,143,144,145,146]. Moreover, as human ECs express abundant ACE-2, a positive regulator of eGABA, SARS-CoV-2 could disrupt the GABAergic signaling directly [20]. Indeed, ACE-2 variants with depleted GABA were linked to major depressive disorder, schizophrenia, bipolar disorder, and epilepsy, emphasizing the importance of RAS/GABA crosstalk for central nervous system (CNS) homeostasis [14,87,91,147].

4.3. pGABA

Recent studies have identified another GABA pool in pancreatic β cells that may be altered by SARS-CoV-2 infection, promoting metabolic dysfunction [148,149]. On the other hand, the administration of exogenous GABA was demonstrated to improve glucose tolerance in rodents, indicating that this biomolecule may play a key role in β cell homeostasis [150,151].
Excessive ANG II was associated with diabetes mellitus type 2 (DMT2), indicating that SARS-CoV-2 can trigger dysmetabolism by disrupting RAS [152]. In addition, the S and ORF3a antigens of SARS-CoV-2 were shown to activate TMEM16F, promoting cell–cell fusion, a phenotype associated with premature cellular senescence and low GABA [53,54,153]. Moreover, premature senescence of β cells and depleted pGABA may drive DMT2 and the neuropsychiatric pathology-linked dysmetabolism [154,155]. So far, several neuropsychiatric disorders and psychotropic drugs have been associated with impaired metabolism, suggesting that exogenous GABA may benefit individuals with these conditions [82]. Indeed, in a previous article, we discussed the relationship between obesity and impulsivity in psychiatric patients, emphasizing that attaining optimal results requires the concomitant treatment of both conditions [156].

4.4. mGABA

SARS-CoV-2 affinity for ACE-2 suggests that tissues with high expression of this protein, such as intestinal epithelial cells (IECs), are more vulnerable to infection [157]. As ACE-2 protects the beneficial GI tract microbes, many of which generate mGABA, the viral exploitation of this protein may trigger intestinal dysbiosis [158,159]. Interestingly, gut ACE-2 is co-expressed with L-dopa decarboxylase (DDC), an enzyme required for microbial DA generation; thus, the viral exploitation of ACE-2 likely affects the brain dopaminergic system (DAS) [160]. As elevated DDC was demonstrated in patients with schizophrenia, the importance of RAS and DAS crosstalk is further emphasized [161].
In the GI tract, ACE-2 heterodimerizes with broad neutral amino acid transporter 1 (B0AT1) that participates in tryptophan (Trp) absorption, indicating that SARS-CoV-2 infection may deplete this amino acid [162] (Figure 4). For example, ACE2-deficient mice display low Trp blood levels, emphasizing the role of this protein in Trp homeostasis [163,164]. As Trp is crucial for serotonin biosynthesis, the viral exploitation of this essential amino acid may trigger neuropsychiatric symptoms, including depression [165]. Moreover, the gut microbes involved in tryptophan (Trp) metabolism are also implicated in adult neurogenesis via aryl hydrocarbon receptor (Ahr), a protein usurped by COVID-19 [166,167]. Ahr is a cytoplasmic ligand and xenobiotic sensor that regulates the microbiota population and the host–microbe crosstalk [168,169]. In our earlier work, we discussed the role of Ahr in psychotropic drugs-induced metabolic dysfunction and suggested that various microbial products, including indole-3-propionic acid, could ameliorate glucose tolerance [170]. As recent studies have linked Ahr to cellular senescence, it is likely that impaired Trp absorption may predispose to this low mGABA phenotype [171,172]. Moreover, mGABA enhances the expression of T helper 17 cells (Th17) characterized by the release of IL-17, an mTORC1-activating antiviral biomolecule [173,174,175]. Interestingly, SARS-CoV-2 exploits mTORC-1 and IL-17, disrupting both host antiviral defenses and the gut barrier [176,177] (Figure 1).

5. Ancient and Modern Viruses Disrupt GABAergic Signaling

The syncytia-forming S2 protein of SARS-CoV-2 is crucial for infectivity, as highlighted by its presence in several highly contagious viruses [178,179]. Indeed, FCS, absent in other SARS-linked coronaviruses, usurps host furin, enhancing COVID-19 transmissibility [180]. On the other hand, loss of FCS was shown to attenuate SARS-CoV-2 virulence and pathogenicity, emphasizing the utmost importance of S2 for the pandemic spread of this viral infection [181].
Aside from SARS-CoV-2, arginine-rich FCSs were identified in HIV-1 protein GP160 ENV, as well as in syncytin-1, a physiological placental fusogen encoded by HERV-W, suggesting that COVID-19 can activate dormant viral fossils [58,182,183]. This is significant, as it connects COVID-19 to retroviruses as well as to the reproductive pathology [184,185].
HERVs are ancient viruses, comprising about 8% of the human DNA, that under normal circumstances are not transcribed. However, various pathologies, including exogenous viral infections, can reactivate HERVs, and translate their DNA into proteins, such as syncytin-1, a molecule that generates trophoblast syncytia during placentation [186]. Pathologically, syncytin-1 promotes cell–cell fusion, hyperinflammation, and autoimmunity, as well as the psychopathology linked to defective GABA [187].
Posttranslational cleavage of syncytin-1 is executed by furin, a host protein usurped by viral FCS, disrupting both CNS and placental GABA [188]. Indeed, a recent meta-analysis connected SARS-CoV-2 infection during pregnancy to preeclampsia, linking this condition to usurped syncytin-1 [189]. Dysregulated GABA was previously reported in patients with preeclampsia, implicating the furin–syncytin-1 axis in reproductive pathologies [190,191]. Moreover, in the first trimester of pregnancy, GABA upregulates human chorionic gonadotropin (hCG), a key hormone for prenatal brain development, suggesting that the viral exploitation of GABA may trigger a developmental pathology [192,193].

5.1. Syncytia Inhibitors

Over the past decade, a considerable effort was devoted to the development of syncytia-blocking agents, including furin inhibitors [194]. The finding that arginine repeats play a major role in virus-induced cell–cell fusion, contributed to the development of FCS-attached arginine mimetics, including phenylacetyl-Arg-Val-Arg-4-amidinobenzylamide, to inhibit the formation of syncytia [195,196]. As furin is highly expressed in ECs and involved in vascular aging and dysmetabolism, furin inhibitors may be capable of averting premature EC senescence and disrupt viral replication [197,198] (Table 1).
Aside from inhibiting furin, syncytia formation can be blocked by lowering the expression of TMEM16F. TMEM16F is a Ca2+-driven phospholipid scramblase that maintains phosphatidylserine (PS) in the inner leaflet of the cell membrane, allowing its externalization only when the cell is ready for apoptosis or fusion [199,200]. Since externalized PS (ePS) is indispensable for syncytia formation, TMEM16F inhibitors may block pathological cell–cell fusion [201]. For example, niclosamide, a TMEM16F-targeting drug, was reported to inhibit both SARS-CoV-2 syncytia and viral transmissibility [202]. Niclosamide is an anthelmintic compound with demonstrated antiviral properties that is currently being evaluated for the treatment of COVID-19 [203]. Several recent studies show that TMEM16F interacts with inositol 1,4,5-triphosphate receptor 1 (IP3R1) in many cell types, including the GABAergic interneurons, implicating this protein in cell–cell fusion [204,205]. Interestingly, IP3R1 was associated with psychopathology, including schizophrenia, neurodegenerative disorders, and epilepsy, suggesting that niclosamide may have a therapeutic value in the treatment of these conditions [206,207,208]. Indeed, lithium and valproic acid, drugs routinely utilized in the treatment of bipolar disorder, alter IP3R1 expression, indicating that TMEM16F inhibitors could have a place in neuropsychiatry [209]. As lithium, valproate, and niclosamide alter the Wnt/β-catenin signaling, the latter may possess mood-stabilizing properties. Interestingly, a valproic acid/niclosamide combination was found therapeutic in some cancers, emphasizing the pleotropic role of the Wnt/β-catenin pathway [210,211]. Furthermore, dysfunctional TMEM16F–IP3R1–GABA signaling was found to pathologically activate the microglia, probably leading to aberrant phagocytosis of healthy neurons and synapses, documented in neuropsychiatric pathologies [212].
It has been known for several decades that diazepam displays anti-syncytial properties, as it inhibits the fusion of myoblasts during musculoskeletal system development [213]. In contrast, as arginine enhances myoblast fusion and abolishes the anxiolytic effects of diazepam, benzodiazepines may be able to counteract FCS-mediated cell–cell fusion [214,215]. Interestingly, ivermectin binds GABA-A receptors at the diazepam site, highlighting this drug’s anti-syncytial mechanism of action [216].
Taken together, the TMEM16F–IP3R1–GABA axis comprises a signaling hub involved in viral infections, cancer, and neuropsychiatric illness. GABA upregulation may inhibit TMEM16F and the formation of pathological syncytia.

5.2. GABA, Autophagy, and Blood Pressure

The antiviral properties of GABA—the elimination of virus-infected cells—highlight the autophagy-activating role of this amino acid [217,218]. Indeed, GABA interferes with host EP that many viruses, including SARS-CoV-2, exploit to enter host cells [12,219]. Viral FCS usurps GABA-mediated autophagy by inhibiting subunit β3 interaction with the clathrin endocytosis AP2 protein [55].
Autophagy modulation may account for the other beneficial properties of GABA, including anti-hypertension, anti-diabetes, antioxidant, and anti-inflammatory actions, suggesting that supplementation with this amino acid may be salutary for patients with these disorders [220,221]. Exogenous GABA may or may not cross the BBB, as conflicting results were reported by different studies. However, CNS-reaching GABA ligands are routinely utilized for the treatment of neuropsychiatric diseases [222,223]. For example, GABA-enhancing anticonvulsants, including tiagabine, gabapentin, and topiramate not only increase neuronal GABA but also augment the non-neuronal GABAergic pathways [224]. For example, gabapentin and tiagabine lower blood pressure in patients with hypertension, while topiramate decreases intracranial pressure, connecting eGABA to the homeostasis of extracellular compartments [225,226]. Interestingly, diazepam displays both antihypertensive and antiretroviral properties (against HIV-1), further emphasizing the beneficial effects of GABA signaling [227,228]. Furthermore, due to their antiretroviral function, benzodiazepines may suppress HERV activation by exogenous viral infections, including SARS-CoV-2 [228,229].
Table
Table 1. Potential syncytia-inhibiting drugs and mechanisms of action.
Table 1. Potential syncytia-inhibiting drugs and mechanisms of action.
DrugMechanismReferences
Arginine mimeticsFurin inhibition[195,196]
NiclosamideTMEM16F inhibition[202]
IvermectinGABA upregulation[36,37]
ARBs/ACEiGABA upregulation[14,15,16]
BenzodiazepinesGABA upregulation[213]
Taken together, the syncytia-inducing FCS of SARS-CoV-2 activates HERV-W and lowers retrovirus-inhibiting GABA. GABA and its agonists likely inhibit S2-mediated HERV activation.

6. Conclusions

The COVID-19 pandemic has stimulated research highlighting numerous molecular pathways that were poorly defined prior to the arrival of this virus. The viral predilection for ACE-2 has shed light on RAS and the importance of balancing its two branches to prevent pathology, including neuropsychiatric diseases. As SARS-CoV-2 has been extensively studied in a relatively short period of time, several cellular mechanisms relevant for psychiatry have been highlighted, including:
  • ACE-2 is protective for the GABAergic signaling in both neuronal and non-neuronal pathways.
  • Inhibition of protective RAS promotes cellular senescence, lowering neuronal and non-neuronal GABA.
  • Virus-induced syncytia formation is a major trigger of premature cellular senescence and related pathology.
  • Aside from functioning as a neurotransmitter, GABA displays anti-hypertension, anti-senescence, anti-diabetes, antioxidant, and anti-inflammatory properties.
  • ARBs and ACEi upregulate GABA, promoting adult neurogenesis that prevents senescence-mediated psychopathologies.
  • The S2 protein of SARS-CoV-2 contains a triple-arginine insert that activates HERVs, promoting hyperinflammatory pathologies.
  • SARS-CoV-2 alters Trp catabolism and the GABA-producing gut flora, facilitating microbial translocation from the GI tract into various tissues and organs, including the brain.
  • Furin and TMEM16F inhibitors suppress syncytia formation, while ARBs and ACEi upregulate GABA, lowering ANG II-induced senescence.

Author Contributions

Conceptualization, A.S.; Methodology, K.G.T.; Formal analysis, investigation, S.S.; data curation, J.J.A.; writing, M.G.; original draft preparation, C.V.A.; review and editing, M.A.C.; supervision, Z.K.; project administration, D.O.S. All authors have read and agreed to the published version of the manuscript.

Funding

This research received no external funding.

Institutional Review Board Statement

Not applicable.

Informed Consent Statement

Not applicable.

Data Availability Statement

The study did not report any data.

Conflicts of Interest

The authors declare no conflict of interest.

Disclaimer

Where authors are identified as personnel of the International Agency for Research on Cancer/WHO, the authors alone are responsible for the views expressed in this article and they do not necessarily represent the decisions, policy or views of the International Agency for Research on Cancer/WHO.

Abbreviations

eGABAendothelial GABA
mGABAmicrobial GABA
pGABApancreatic GABA
nGABAneuronal GABA
TLR4toll-like receptor 4
ANG IIangiotensin converting enzyme 2

References

  1. Benavente, L.; Morís, G. Neurologic disorders associated with inflammatory bowel disease. Eur. J. Neurol. 2010, 18, 138–143. [Google Scholar] [CrossRef] [PubMed]
  2. Abautret-Daly, Á.; Dempsey, E.; Parra-Blanco, A.; Medina, C.; Harkin, A. Gut–brain actions underlying comorbid anxiety and depression associated with inflammatory bowel disease. Acta Neuropsychiatr. 2017, 30, 275–296. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  3. Nowakowski, J.; Chrobak, A.; Dudek, D. Psychiatry Illness in Inflammatory Bowel Diseases-Psychiatric Comorbidity and Biological Underpinnings. Psychiatr. Polska 2016, 50, 1157–1166. [Google Scholar] [CrossRef] [PubMed]
  4. Fernández-Rodríguez, E.; Camarero-González, E. Paciente con enfermedad de Crohn y convulsiones por hipomagnesemia [Patient with Crohn’s disease and seizures due to hypomagnesemia]. Nutr. Hosp. 2007, 22, 720–722. [Google Scholar]
  5. Ma, P.; Li, T.; Ji, F.; Wang, H.; Pang, J. Effect of GABA on blood pressure and blood dynamics of anesthetic rats. Int. J. Clin. Exp. Med. 2015, 8, 14296–14302. [Google Scholar] [PubMed]
  6. Buzhdygan, T.; Lisinicchia, J.; Patel, V.; Johnson, K.; Neugebauer, V.; Paessler, S.; Jennings, K.; Gelman, B. Neuropsychological, Neurovirological and Neuroimmune Aspects of Abnormal GABAergic Transmission in HIV Infection. J. Neuroimmune Pharmacol. 2016, 11, 279–293. [Google Scholar] [CrossRef] [Green Version]
  7. Jehmlich, U.; Ritzer, J.; Grosche, J.; Härtig, W.; Liebert, U.G. Experimental measles encephalitis in Lewis rats: Dissemination of infected neuronal cell subtypes. J. Neurovirol. 2013, 19, 461–470. [Google Scholar] [CrossRef]
  8. Tian, J.; Middleton, B.; Kaufman, D.L. GABA administration prevents severe illness and death following coronavirus infection in mice. Preprint. bioRxiv 2020. [CrossRef]
  9. Bhat, R.; Axtell, R.; Mitra, A.; Miranda, M.; Lock, C.; Tsien, R.W.; Steinman, L. Inhibitory role for GABA in autoimmune inflammation. Proc. Natl. Acad. Sci. USA 2010, 107, 2580–2585. [Google Scholar] [CrossRef] [Green Version]
  10. Prud’Homme, G.J.; Glinka, Y.; Wang, Q. Immunological GABAergic interactions and therapeutic applications in autoimmune diseases. Autoimmun. Rev. 2015, 14, 1048–1056. [Google Scholar] [CrossRef]
  11. Li, Y.; Gao, J.; Xue, L.; Shang, Y.; Cai, W.; Xie, X.; Jiang, T.; Chen, H.; Zhang, J.; Wang, J.; et al. Determination of Antiviral Mechanism of Centenarian Gut-Derived Limosilactobacillus fermentum Against Norovirus. Front. Nutr. 2022, 9, 812623. [Google Scholar] [CrossRef] [PubMed]
  12. Kim, J.K.; Kim, Y.S.; Lee, H.-M.; Jin, H.S.; Neupane, C.; Kim, S.; Lee, S.-H.; Min, J.-J.; Sasai, M.; Jeong, J.-H.; et al. GABAergic signaling linked to autophagy enhances host protection against intracellular bacterial infections. Nat. Commun. 2018, 9, 4184. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  13. Otaru, N.; Ye, K.; Mujezinovic, D.; Berchtold, L.; Constancias, F.; Cornejo, F.A.; Krzystek, A.; de Wouters, T.; Braegger, C.; Lacroix, C.; et al. GABA Production by Human Intestinal Bacteroides spp.: Prevalence, Regulation, and Role in Acid Stress Tolerance. Front. Microbiol. 2021, 12, 656895. [Google Scholar] [CrossRef]
  14. Krasniqi, S.; Daci, A. Role of the Angiotensin Pathway and its Target Therapy in Epilepsy Management. Int. J. Mol. Sci. 2019, 20, 726. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  15. Liu, F.; Havens, J.; Yu, Q.; Wang, G.; Davisson, R.L.; Pickel, V.M.; Iadecola, C. The link between angiotensin II-mediated anxiety and mood disorders with NADPH oxi-dase-induced oxidative stress. Int. J. Physiol. Pathophysiol. Pharmacol. 2012, 4, 28–35. [Google Scholar] [PubMed]
  16. Pereira, M.G.; Becari, C.; Oliveira, J.A.; Salgado, M.C.O.; Garcia-Cairasco, N.; Costa-Neto, C.M. Inhibition of the renin–angiotensin system prevents seizures in a rat model of epilepsy. Clin. Sci. 2010, 119, 477–482. [Google Scholar] [CrossRef] [Green Version]
  17. Jo, Y.; Kim, S.; Ye, B.S.; Lee, E.; Yu, Y.M. Protective Effect of Renin-Angiotensin System Inhibitors on Parkinson’s Disease: A Nationwide Cohort Study. Front. Pharmacol. 2022, 13, 837890. [Google Scholar] [CrossRef] [PubMed]
  18. Saavedra, J.M. Angiotensin II AT1 receptor blockers as treatments for inflammatory brain disorders. Clin. Sci. 2012, 123, 567–590. [Google Scholar] [CrossRef] [Green Version]
  19. Chang, C.-H.; Chang, Y.-C.; Wu, L.-C.; Lin, J.-W.; Chuang, L.-M.; Lai, M.-S. Different angiotensin receptor blockers and incidence of diabetes: A nationwide population-based cohort study. Cardiovasc. Diabetol. 2014, 13, 91. [Google Scholar] [CrossRef] [Green Version]
  20. Ma, X.; Gao, F.; Chen, Q.; Xuan, X.; Wang, Y.; Deng, H.; Yang, F.; Yuan, L. ACE2 modulates glucose homeostasis through GABA signaling during metabolic stress. J. Endocrinol. 2020, 246, 223–236. [Google Scholar] [CrossRef]
  21. Sánchez-Lemus, E.; Honda, M.; Saavedra, J.M. Angiotensin II AT1 receptor blocker candesartan prevents the fast up-regulation of cerebrocortical benzodiazepine-1 receptors induced by acute inflammatory and restraint stress. Behav. Brain Res. 2012, 232, 84–92. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  22. Beaudoin, C.A.; Jamasb, A.R.; Alsulami, A.F.; Copoiu, L.; van Tonder, A.J.; Hala, S.; Bannerman, B.P.; Thomas, S.E.; Vedithi, S.C.; Torres, P.H.; et al. Predicted structural mimicry of spike receptor-binding motifs from highly pathogenic human coronaviruses. Comput. Struct. Biotechnol. J. 2021, 19, 3938–3953. [Google Scholar] [CrossRef] [PubMed]
  23. Yapici-Eser, H.; Koroglu, Y.E.; Oztop-Cakmak, O.; Keskin, O.; Gursoy, A.; Gursoy-Ozdemir, Y. Neuropsychiatric Symptoms of COVID-19 Explained by SARS-CoV-2 Proteins’ Mimicry of Human Protein Interactions. Front. Hum. Neurosci. 2021, 15, 656313. [Google Scholar] [CrossRef]
  24. Porges, E.C.; Jensen, G.; Foster, B.; Edden, R.A.; Puts, N.A. The trajectory of cortical GABA across the lifespan, an individual participant data meta-analysis of edited MRS studies. eLife 2021, 10, e62575. [Google Scholar] [CrossRef] [PubMed]
  25. Ethiraj, J.; Palpagama, T.H.; Turner, C.; van der Werf, B.; Waldvogel, H.J.; Faull, R.L.M.; Kwakowsky, A. The effect of age and sex on the expression of GABA signaling components in the human hippocampus and entorhinal cortex. Sci. Rep. 2021, 11, 21470. [Google Scholar] [CrossRef] [PubMed]
  26. Lin, L.; Li, Q.; Wang, Y.; Shi, Y. Syncytia formation during SARS-CoV-2 lung infection: A disastrous unity to eliminate lymphocytes. Cell Death Differ. 2021, 28, 2019–2021. [Google Scholar] [CrossRef] [PubMed]
  27. Gordon, D.E.; Jang, G.M.; Bouhaddou, M.; Xu, J.; Obernier, K.; White, K.M.; O’Meara, M.J.; Rezelj, V.V.; Guo, J.Z.; Swaney, D.L.; et al. A SARS-CoV-2 protein interaction map reveals targets for drug repurposing. Nature 2020, 583, 459–468. [Google Scholar] [CrossRef]
  28. Mao, L.-Y.; Ding, J.; Peng, W.-F.; Ma, Y.; Zhang, Y.-H.; Fan, W.; Wang, X. Interictal interleukin-17A levels are elevated and correlate with seizure severity of epilepsy patients. Epilepsia 2013, 54, e142–e145. [Google Scholar] [CrossRef]
  29. Griffith, J.L.; Wong, M. The mTOR pathway in treatment of epilepsy: A clinical update. Futur. Neurol. 2018, 13, 49–58. [Google Scholar] [CrossRef]
  30. Wang, L.; de Kloet, A.; Pati, D.; Hiller, H.; Smith, J.A.; Pioquinto, D.J.; Ludin, J.A.; Oh, S.P.; Katovich, M.J.; Frazier, C.J.; et al. Increasing brain angiotensin converting enzyme 2 activity decreases anxiety-like behavior in male mice by activating central Mas receptors. Neuropharmacology 2016, 105, 114–123. [Google Scholar] [CrossRef] [Green Version]
  31. Zhang, J.; Li, Q.; Cosme, R.S.C.; Gerzanich, V.; Tang, Q.; Simard, J.M.; Zhao, R.Y. Genome-Wide Characterization of SARS-CoV-2 Cytopathogenic Proteins in the Search of Antiviral Targets. mBio 2022, 13. [Google Scholar] [CrossRef] [PubMed]
  32. Targhetta, V.P.; Amaral, M.A.; Camara, N.O.S. Through DNA sensors and hidden mitochondrial effects of SARS-CoV-2. J. Venom. Anim. Toxins Incl. Trop. Dis. 2021, 27, e20200183. [Google Scholar] [CrossRef] [PubMed]
  33. Han, Y.; Yuan, K.; Wang, Z.; Liu, W.-J.; Lu, Z.-A.; Liu, L.; Shi, L.; Yan, W.; Yuan, J.-L.; Li, J.-L.; et al. Neuropsychiatric manifestations of COVID-19, potential neurotropic mechanisms, and therapeutic interventions. Transl. Psychiatry 2021, 11, 499. [Google Scholar] [CrossRef] [PubMed]
  34. Emami, A.; Fadakar, N.; Akbari, A.; Lotfi, M.; Farazdaghi, M.; Javanmardi, F.; Rezaei, T.; Asadi-Pooya, A.A. Seizure in patients with COVID-19. Neurol. Sci. 2020, 41, 3057–3061. [Google Scholar] [CrossRef] [PubMed]
  35. Sfera, A.; Osorio, C.; Rahman, L.; del Campo, C.M.Z.-M.; Maldonado, J.C.; Jafri, N.; Cummings, M.A.; Maurer, S.; Kozlakidis, Z. PTSD as an Endothelial Disease: Insights from COVID-19. Front. Cell. Neurosci. 2021, 15, 770387. [Google Scholar] [CrossRef] [PubMed]
  36. Krusek, J.; Zemkova´, H. Effect of ivermectin on γ-aminobutyric acid-induced chloride currents in mouse hippocampal embryonic neurones. Eur. J. Pharmacol. 1994, 259, 121–128. [Google Scholar] [CrossRef]
  37. Li, M.P.; Eaton, M.M.M.; Steinbach, J.H.; Akk, G. The Benzodiazepine Diazepam Potentiates Responses of α1β2γ2L γ-Aminobutyric Acid Type A Receptors Activated by either γ-Aminobutyric Acid or Allosteric Agonists. Anesthesiology 2013, 118, 1417–1425. [Google Scholar] [CrossRef] [Green Version]
  38. Chan, Y.A.; Zhan, S.H. The Emergence of the Spike Furin Cleavage Site in SARS-CoV-2. Mol. Biol. Evol. 2021, 39, msab327. [Google Scholar] [CrossRef]
  39. Hu, Y.; Liu, L.; Lu, X. Regulation of Angiotensin-Converting Enzyme 2: A Potential Target to Prevent COVID-19? Front. Endocrinol. 2021, 12, 725967. [Google Scholar] [CrossRef]
  40. Doughan, A.K.; Harrison, D.G.; Dikalov, S.I. Molecular Mechanisms of Angiotensin II–Mediated Mitochondrial Dysfunction. Circ. Res. 2008, 102, 488–496. [Google Scholar] [CrossRef] [Green Version]
  41. Bobkova, N.V. The Balance between Two Branches of RAS Can Protect from Severe COVID-19 Course. Biochem. (Moscow) Suppl. Ser. A Membr. Cell Biol. 2021, 15, 36–51. [Google Scholar] [CrossRef] [PubMed]
  42. Mahmudpour, M.; Roozbeh, J.; Keshavarz, M.; Farrokhi, S.; Nabipour, I. COVID-19 cytokine storm: The anger of inflammation. Cytokine 2020, 133, 155151. [Google Scholar] [CrossRef] [PubMed]
  43. Romero, E.; Guaza, C.; Castellano, B.; I Borrell, J. Ontogeny of sensorimotor gating and immune impairment induced by prenatal immune challenge in rats: Implications for the etiopathology of schizophrenia. Mol. Psychiatry 2008, 15, 372–383. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  44. Sen, S.; Roy, S.; Bandyopadhyay, G.; Scott, B.; Xiao, D.; Ramadoss, S.; Mahata, S.K.; Chaudhuri, G. γ-Aminobutyric Acid Is Synthesized and Released by the Endothelium. Circ. Res. 2016, 119, 621–634. [Google Scholar] [CrossRef] [PubMed]
  45. Chen, Y.; Wang, J.; Liu, C.; Su, L.; Zhang, D.; Fan, J.; Yang, Y.; Xiao, M.; Xie, J.; Xu, Y.; et al. IP-10 and MCP-1 as biomarkers associated with disease severity of COVID-19. Mol. Med. 2020, 26, 97. [Google Scholar] [CrossRef] [PubMed]
  46. Stragier, B.; Hristova, I.; Sarre, S.; Ebinger, G.; Michotte, Y. In vivo characterization of the angiotensin-(1-7)-induced dopamine and γ-aminobutyric acid release in the striatum of the rat. Eur. J. Neurosci. 2005, 22, 658–664. [Google Scholar] [CrossRef]
  47. Brukman, N.G.; Uygur, B.; Podbilewicz, B.; Chernomordik, L.V. How cells fuse. J. Cell Biol. 2019, 218, 1436–1451. [Google Scholar] [CrossRef] [Green Version]
  48. Zhang, Y.; Le, T.; Grabau, R.; Mohseni, Z.; Kim, H.; Natale, D.R.; Feng, L.; Pan, H.; Yang, H. TMEM16F phospholipid scramblase mediates trophoblast fusion and placental development. Sci. Adv. 2020, 6, eaba0310. [Google Scholar] [CrossRef]
  49. Peacock, T.P.; Goldhill, D.H.; Zhou, J.; Baillon, L.; Frise, R.; Swann, O.C.; Kugathasan, R.; Penn, R.; Brown, J.C.; Sanchez-David, R.Y.; et al. The furin cleavage site in the SARS-CoV-2 spike protein is required for transmission in ferrets. Nat. Microbiol. 2021, 6, 899–909. [Google Scholar] [CrossRef]
  50. Leroy, H.; Han, M.; Woottum, M.; Bracq, L.; Bouchet, J.; Xie, M.; Benichou, S. Virus-Mediated Cell-Cell Fusion. Int. J. Mol. Sci. 2020, 21, 9644. [Google Scholar] [CrossRef]
  51. Armstrong, C.T.; Mason, P.; Anderson, R.; Dempsey, C.E. Arginine side chain interactions and the role of arginine as a gating charge carrier in voltage sensitive ion channels. Sci. Rep. 2016, 6, 21759. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  52. Osorio, C.; Sfera, A.; Anton, J.J.; Thomas, K.G.; Andronescu, C.V.; Li, E.; Yahia, R.W.; Avalos, A.G.; Kozlakidis, Z. Virus-Induced Membrane Fusion in Neurodegenerative Disorders. Front. Cell. Infect. Microbiol. 2022, 12, 845580. [Google Scholar] [CrossRef] [PubMed]
  53. Chuprin, A.; Gal, H.; Biron-Shental, T.; Biran, A.; Amiel, A.; Rozenblatt, S.; Krizhanovsky, V. Cell fusion induced by ERVWE1 or measles virus causes cellular senescence. Genes Dev. 2013, 27, 2356–2366. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  54. Berndt, B.; Zanker, K.S.; Dittmar, T. Cell fusion is a potent inducer of aneuploidy and drug resistance in tumor cell/ normal cell hybrids. Crit. Rev. Oncog. 2013, 18, 97–113. [Google Scholar] [CrossRef] [PubMed]
  55. Smith, K.R.; Muir, J.; Rao, Y.; Browarski, M.; Gruenig, M.C.; Sheehan, D.F.; Haucke, V.; Kittler, J.T. Stabilization of GABAA Receptors at Endocytic Zones Is Mediated by an AP2 Binding Motif within the GABAA Receptor β3 Subunit. J. Neurosci. 2012, 32, 2485–2498. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  56. Hegyi, H. GABBR1 has a HERV-W LTR in its regulatory region—A possible implication for schizophrenia. Biol. Direct 2013, 8, 5. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  57. Obrietan, K.; Pol, A.N.V.D. GABAB receptor-mediated inhibition of GABAA receptor calcium elevations in developing hypothalamic neurons. J. Neurophysiol. 1998, 79, 1360–1370. [Google Scholar] [CrossRef] [Green Version]
  58. Hallenberger, S.; Bosch, V.; Angliker, H.; Shaw, E.; Klenk, H.-D.; Garten, W. Inhibition of furin-mediated cleavage activation of HIV-1 glycoprotein gpl60. Nature 1992, 360, 358–361. [Google Scholar] [CrossRef]
  59. Charvet, B.; Brunel, J.; Pierquin, J.; Iampietro, M.; Decimo, D.; Queruel, N.; Lucas, A.; Encabo-Berzosa, M.d.M.; Arenaz, I.; Marmolejo, T.P.; et al. SARS-CoV-2 induces human endogenous retrovirus type W envelope protein expression in blood lym-phocytes and in tissues of COVID-19 patients. medRxiv 2022. Available online: https://www.medrxiv.org/content/10.1101/2022.01.18.21266111v2 (accessed on 15 May 2022). [CrossRef]
  60. Schleiss, M.R. Letermovir and HCT: Too much of a good thing? Blood 2021, 138, 1–2. [Google Scholar] [CrossRef]
  61. Sikora, E.; Bielak-Zmijewska, A.; Dudkowska, M.; Krzystyniak, A.; Mosieniak, G.; Wesierska, M.; Wlodarczyk, J. Cellular Senescence in Brain Aging. Front. Aging Neurosci. 2021, 13, 646924. [Google Scholar] [CrossRef] [PubMed]
  62. Kim, S.; Shan, P.; Hwangbo, C.; Zhang, Y.; Min, J.; Zhang, X.; Ardito, T.; Li, A.; Peng, T.; Sauler, M.; et al. Endothelial toll-like receptor 4 maintains lung integrity via epigenetic suppression of p16 INK4a. Aging Cell 2019, 18, e12914. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  63. Sun, Z.; Song, Z.-G.; Liu, C.; Tan, S.; Lin, S.; Zhu, J.; Dai, F.-H.; Gao, J.; She, J.-L.; Mei, Z.; et al. Gut microbiome alterations and gut barrier dysfunction are associated with host immune homeostasis in COVID-19 patients. BMC Med. 2022, 20, 24. [Google Scholar] [CrossRef] [PubMed]
  64. Peerapornratana, S.; Sirivongrangson, P.; Tungsanga, S.; Tiankanon, K.; Kulvichit, W.; Putcharoen, O.; Kellum, J.A.; Srisawat, N. Endotoxin Adsorbent Therapy in Severe COVID-19 Pneumonia. Blood Purif. 2021, 51, 47–54. [Google Scholar] [CrossRef]
  65. Petruk, G.; Puthia, M.; Petrlova, J.; Samsudin, F.; Strömdahl, A.-C.; Cerps, S.; Uller, L.; Kjellström, S.; Bond, P.J.; Schmidtchen, A. SARS-CoV-2 Spike protein binds to bacterial lipopolysaccharide and boosts proinflammatory activity. J. Mol. Cell Biol. 2020, 12, 916–932. [Google Scholar] [CrossRef]
  66. Wolf, G.; Bohlender, J.; Bondeva, T.; Roger, T.; Thaiss, F.; Wenzel, U.O. Angiotensin II Upregulates Toll-Like Receptor 4 on Mesangial Cells. J. Am. Soc. Nephrol. 2006, 17, 1585–1593. [Google Scholar] [CrossRef] [Green Version]
  67. Lu, Y.-C.; Yeh, W.-C.; Ohashi, P.S. LPS/TLR4 signal transduction pathway. Cytokine 2008, 42, 145–151. [Google Scholar] [CrossRef]
  68. O’Connor, J.C.; A Lawson, M.; André, C.; Moreau, M.; Lestage, J.; Castanon, N.; Kelley, K.W.; Dantzer, R. Lipopolysaccharide-induced depressive-like behavior is mediated by indoleamine 2,3-dioxygenase activation in mice. Mol. Psychiatry 2008, 14, 511–522. [Google Scholar] [CrossRef] [Green Version]
  69. Wang, Y.-Y.; Sun, S.-P.; Zhu, H.-S.; Jiao, X.-Q.; Zhong, K.; Guo, Y.-J.; Zha, G.-M.; Han, L.-Q.; Yang, G.-Y.; Li, H.-P. GABA regulates the proliferation and apoptosis of MAC-T cells through the LPS-induced TLR4 signaling pathway. Res. Veter. Sci. 2018, 118, 395–402. [Google Scholar] [CrossRef]
  70. Zhao, Y.; Cong, L.; Lukiw, W.J. Lipopolysaccharide (LPS) Accumulates in Neocortical Neurons of Alzheimer’s Disease (AD) Brain and Impairs Transcription in Human Neuronal-Glial Primary Co-cultures. Front. Aging Neurosci. 2017, 9, 407. [Google Scholar] [CrossRef]
  71. Solas, M.; Puerta, E.; Ramirez, M. Treatment Options in Alzheimer´s Disease: The GABA Story. Curr. Pharm. Des. 2015, 21, 4960–4971. [Google Scholar] [CrossRef] [PubMed]
  72. Nakanishi-Matsui, M.; Yano, S.; Matsumoto, N.; Futai, M. Lipopolysaccharide induces multinuclear cell from RAW264.7 line with increased phagocytosis activity. Biochem. Biophys. Res. Commun. 2012, 425, 144–149. [Google Scholar] [CrossRef] [PubMed]
  73. Giordano-Santini, R.; Kaulich, E.; Galbraith, K.M.; Ritchie, F.K.; Wang, W.; Li, Z.; Hilliard, M.A. Fusogen-mediated neuron−neuron fusion disrupts neural circuit connectivity and alters animal behavior. Proc. Natl. Acad. Sci. USA 2020, 117, 23054–23065. [Google Scholar] [CrossRef] [PubMed]
  74. Kemp, K.; Wilkins, A.; Scolding, N. Cell fusion in the brain: Two cells forward, one cell back. Acta Neuropathol. 2014, 128, 629–638. [Google Scholar] [CrossRef] [Green Version]
  75. Arendt, T.; Mosch, B.; Morawski, M. Neuronal Aneuploidy in Health and Disease:A Cytomic Approach to Understand the Molecular Individuality of Neurons. Int. J. Mol. Sci. 2009, 10, 1609–1627. [Google Scholar] [CrossRef] [Green Version]
  76. Kemp, K.; Gray, E.; Wilkins, A.; Scolding, N. Purkinje cell fusion and binucleate heterokaryon formation in multiple sclerosis cerebellum. Brain 2012, 135, 2962–2972. [Google Scholar] [CrossRef]
  77. Potter, H.; Chial, H.J.; Caneus, J.; Elos, M.; Elder, N.; Borysov, S.; Granic, A. Chromosome Instability and Mosaic Aneuploidy in Neurodegenerative and Neurodevelopmental Disorders. Front. Genet. 2019, 10, 1092. [Google Scholar] [CrossRef] [Green Version]
  78. Paquola, A.C.; Erwin, J.; Gage, F.H. Insights into the role of somatic mosaicism in the brain. Curr. Opin. Syst. Biol. 2016, 1, 90–94. [Google Scholar] [CrossRef] [Green Version]
  79. Lindqvist, D.; Epel, E.S.; Mellon, S.H.; Penninx, B.W.; Révész, D.; Verhoeven, J.E.; Reus, V.I.; Lin, J.; Mahan, L.; Hough, C.M.; et al. Psychiatric disorders and leukocyte telomere length: Underlying mechanisms linking mental illness with cellular aging. Neurosci. Biobehav. Rev. 2015, 55, 333–364. [Google Scholar] [CrossRef] [Green Version]
  80. Pousa, P.; Souza, R.; Melo, P.; Correa, B.; Mendonça, T.; Simões-E-Silva, A.; Miranda, D. Telomere Shortening and Psychiatric Disorders: A Systematic Review. Cells 2021, 10, 1423. [Google Scholar] [CrossRef]
  81. E Verhoeven, J.; Révész, D.; Epel, E.S.; Lin, J.; Wolkowitz, O.M.; Penninx, B.W.J.H. Major depressive disorder and accelerated cellular aging: Results from a large psychiatric cohort study. Mol. Psychiatry 2013, 19, 895–901. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  82. Papanastasiou, E.; Gaughran, F.; Smith, S. Schizophrenia as segmental progeria. J. R. Soc. Med. 2011, 104, 475–484. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  83. Huang, W.-Y.; Lai, Y.-L.; Liu, K.-H.; Lin, S.; Chen, H.-Y.; Liang, C.-H.; Wu, H.-M.; Hsu, K.-S. TNFα-mediated necroptosis in brain endothelial cells as a potential mechanism of increased seizure susceptibility in mice following systemic inflammation. J. Neuroinflammation 2022, 19, 29. [Google Scholar] [CrossRef] [PubMed]
  84. Ogrodnik, M.; Zhu, Y.; Langhi, L.G.; Tchkonia, T.; Krüger, P.; Fielder, E.; Victorelli, S.; Ruswhandi, R.A.; Giorgadze, N.; Pirtskhalava, T.; et al. Obesity-Induced Cellular Senescence Drives Anxiety and Impairs Neurogenesis. Cell Metab. 2019, 29, 1061–1077. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  85. Sekiguchi, F.; Tsubota, M.; Kawabata, A. Involvement of voltage-gated calcium channels in inflammation and inflam-matory pain. Biol. Pharm. Bull. 2018, 41, 1127–1134. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  86. Gilbert, N. The science of tea’s mood-altering magic. Nature 2019, 566, S8. [Google Scholar] [CrossRef] [PubMed]
  87. Sanches, M.; Colpo, G.D.; Cuellar, V.A.; Bockmann, T.; Rogith, D.; Soares, J.C.; Teixeira, A.L. Decreased Plasma Levels of Angiotensin-Converting Enzyme Among Patients with Bipolar Disorder. Front. Neurosci. 2021, 15, 617888. [Google Scholar] [CrossRef]
  88. Colbourne, L.; Luciano, S.; Harrison, P.J. Onset and recurrence of psychiatric disorders associated with anti-hypertensive drug classes. Transl. Psychiatry 2021, 11, 319. [Google Scholar] [CrossRef]
  89. Vian, J.; Pereira, C.; Chavarria, V.; Köhler, C.; Stubbs, B.; Quevedo, J.; Kim, S.-W.; Carvalho, A.F.; Berk, M.; Fernandes, B.S. The renin–angiotensin system: A possible new target for depression. BMC Med. 2017, 15, 144. [Google Scholar] [CrossRef]
  90. Xie, Y.; Xu, E.; Al-Aly, Z. Risks of mental health outcomes in people with covid-19: Cohort study. BMJ 2022, 376, e068993. [Google Scholar] [CrossRef]
  91. Firouzabadi, N.; Farshadfar, P.; Haghnegahdar, M.; Alavi-Shoushtari, A.; Ghanbarinezhad, V. Impact of ACE2 genetic variant on antidepressant efficacy of SSRIs. Acta Neuropsychiatr. 2021, 34, 30–36. [Google Scholar] [CrossRef] [PubMed]
  92. Apple, D.M.; Fonseca, R.S.; Kokovay, E. The role of adult neurogenesis in psychiatric and cognitive disorders. Brain Res. 2017, 1655, 270–276. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  93. Klein, R.; Soung, A.; Sissoko, C.; Nordvig, A.; Canoll, P.; Mariani, M.; Jiang, X.; Bricker, T.; Goldman, J.; Rosoklija, G.; et al. COVID-19 induces neuroinflammation and loss of hippocampal neurogenesis. Preprint Res. Sq. 2021, 1, rs.3.rs-1031824. [Google Scholar] [CrossRef]
  94. Ge, S.; Pradhan, D.A.; Ming, G.-L.; Song, H. GABA sets the tempo for activity-dependent adult neurogenesis. Trends Neurosci. 2007, 30, 1–8. [Google Scholar] [CrossRef]
  95. Mu, Y.; Lee, S.W.; Gage, F.H. Signaling in adult neurogenesis. Curr. Opin. Neurobiol. 2010, 20, 416–423. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  96. Owens, D.F.; Kriegstein, A.R. Is there more to GABA than synaptic inhibition? Nat. Rev. Neurosci. 2002, 3, 715–727. [Google Scholar] [CrossRef]
  97. Grasselli, C.; Ferrari, D.; Zalfa, C.; Soncini, M.; Mazzoccoli, G.; Facchini, F.A.; Marongiu, L.; Granucci, F.; Copetti, M.; Vescovi, A.L.; et al. Toll-like receptor 4 modulation influences human neural stem cell proliferation and differentiation. Cell Death Dis. 2018, 9, 280. [Google Scholar] [CrossRef] [Green Version]
  98. Kase, Y.; Okano, H. Expression of ACE2 and a viral virulence-regulating factor CCN family member 1 in human iPSC-derived neural cells: Implications for COVID-19-related CNS disorders. Inflamm. Regen. 2020, 40, 32. [Google Scholar] [CrossRef]
  99. Yu, X.; Ye, Z.; Houston, C.M.; Zecharia, A.Y.; Ma, Y.; Zhang, Z.; Uygun, D.S.; Parker, S.; Vyssotski, A.L.; Yustos, R.; et al. Wakefulness Is Governed by GABA and Histamine Cotransmission. Neuron 2015, 87, 164–178. [Google Scholar] [CrossRef] [Green Version]
  100. Möhler, H. Role of GABAA receptors in cognition. Biochem. Soc. Trans. 2009, 37, 1328–1333. [Google Scholar] [CrossRef]
  101. Lou, H.C.; Thomsen, K.R.; Changeux, J.-P. The Molecular Organization of Self-awareness: Paralimbic Dopamine-GABA Interaction. Front. Syst. Neurosci. 2020, 14, 3. [Google Scholar] [CrossRef] [PubMed]
  102. Lyu, C.; Zhao, W.; Peng, C.; Hu, S.; Fang, H.; Hua, Y.; Yao, S.; Huang, J.; Mei, L. Exploring the contributions of two glutamate decarboxylase isozymes in Lactobacillus brevis to acid resistance and γ-aminobutyric acid production. Microb. Cell Fact. 2018, 17, 180. [Google Scholar] [CrossRef] [PubMed]
  103. Bak, L.K.; Schousboe, A.; Waagepetersen, H.S. The glutamate/GABA-glutamine cycle: Aspects of transport, neurotransmitter homeostasis and ammonia transfer. J. Neurochem. 2006, 98, 641–653. [Google Scholar] [CrossRef] [PubMed]
  104. Omotosho, Y.B.; Ying, G.W.; Stolar, M.; Mallari, A.J.P. COVID-19-Induced Diabetic Ketoacidosis in an Adult with Latent Autoimmune Diabetes. Cureus 2021, 13, e12690. [Google Scholar] [CrossRef]
  105. Emekli, A.S.; Parlak, A.; Göcen, N.Y.; Kürtüncü, M. Anti-GAD associated post-infectious cerebellitis after COVID-19 infection. Neurol. Sci. 2021, 42, 3995–4002. [Google Scholar] [CrossRef]
  106. Jin, Z.; Mendu, S.K.; Birnir, B. GABA is an effective immunomodulatory molecule. Amino Acids 2013, 45, 87–94. [Google Scholar] [CrossRef] [Green Version]
  107. Qin, P.; Wu, X.; Duncan, N.W.; Bao, W.; Tang, W.; Zhang, Z.; Hu, J.; Jin, Y.; Wu, X.; Gao, L.; et al. GABAA receptor deficits predict recovery in patients with disorders of consciousness: A preliminary multimodal [11C]Flumazenil PET and fMRI study. Hum. Brain Mapp. 2015, 36, 3867–3877. [Google Scholar] [CrossRef] [Green Version]
  108. Fujimori, S.; Yoneda, Y. [Neuropsychiatric disorders and GABA]. Nihon Shinkei Seishin Yakurigaku Zasshi 2004, 24, 265–271. (In Japanese) [Google Scholar]
  109. Clauss, R. Disorders of consciousness and pharmaceuticals that act on oxygen based amino acid and monoamine neuro-transmitter pathways of the brain. Curr. Pharm. Des. 2014, 20, 4053–4140. [Google Scholar]
  110. Tsubomoto, M.; Kawabata, R.; Zhu, X.; Minabe, Y.; Chen, K.; A Lewis, D.; Hashimoto, T. Expression of Transcripts Selective for GABA Neuron Subpopulations across the Cortical Visuospatial Working Memory Network in the Healthy State and Schizophrenia. Cereb. Cortex 2018, 29, 3540–3550. [Google Scholar] [CrossRef]
  111. Sakimoto, Y.; Oo, P.M.-T.; Goshima, M.; Kanehisa, I.; Tsukada, Y.; Mitsushima, D. Significance of GABAA Receptor for Cognitive Function and Hippocampal Pathology. Int. J. Mol. Sci. 2021, 22, 12456. [Google Scholar] [CrossRef] [PubMed]
  112. Wyss, C.; Tse, D.H.Y.; Kometer, M.; Dammers, J.; Achermann, R.; Shah, N.J.; Kawohl, W.; Neuner, I. GABA metabolism and its role in gamma-band oscillatory activity during auditory processing: An MRS and EEG study. Hum. Brain Mapp. 2017, 38, 3975–3987. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  113. Herrmann, C.S.; Demiralp, T. Human EEG gamma oscillations in neuropsychiatric disorders. Clin. Neurophysiol. 2005, 116, 2719–2733. [Google Scholar] [CrossRef] [PubMed]
  114. Coghlan, S.; Horder, J.; Inkster, B.; Mendez, M.A.; Murphy, D.; Nutt, D. GABA system dysfunction in autism and related disorders: From synapse to symptoms. Neurosci. Biobehav. Rev. 2012, 36, 2044–2055. [Google Scholar] [CrossRef] [Green Version]
  115. Harris, S.; Ma, H.; Zhao, M.; Boorman, L.; Zheng, Y.; Kennerley, A.; Bruyns-Haylett, M.; Overton, P.G.; Berwick, J.; Schwartz, T.H. Coupling between gamma-band power and cerebral blood volume during recurrent acute neocortical seizures. NeuroImage 2014, 97, 62–70. [Google Scholar] [CrossRef] [Green Version]
  116. Muthukumaraswamy, S.D.; Edden, R.A.; Jones, D.K.; Swettenham, J.B.; Singh, K.D. Resting GABA concentration predicts peak gamma frequency and fMRI amplitude in response to visual stimulation in humans. Proc. Natl. Acad. Sci. USA 2009, 106, 8356–8361. [Google Scholar] [CrossRef] [Green Version]
  117. Kilb, W. Development of the GABAergic System from Birth to Adolescence. Neuroscience 2011, 18, 613–630. [Google Scholar] [CrossRef]
  118. Li, S.; Kumar T, P.; Joshee, S.; Kirschstein, T.; Subburaju, S.; Khalili, J.S.; Kloepper, J.; Du, C.; Elkhal, A.; Szabó, G.; et al. Endothelial cell-derived GABA signaling modulates neuronal migration and postnatal behavior. Cell Res. 2017, 28, 221–248. [Google Scholar] [CrossRef]
  119. Wu, X.; Fu, Y.; Knott, G.W.; Lu, J.; Di Cristo, G.; Huang, Z.J. GABA Signaling Promotes Synapse Elimination and Axon Pruning in Developing Cortical Inhibitory Interneurons. J. Neurosci. 2012, 32, 331–343. [Google Scholar] [CrossRef] [Green Version]
  120. Favuzzi, E.; Huang, S.; Saldi, G.A.; Binan, L.; Ibrahim, L.A.; Fernández-Otero, M.; Cao, Y.; Zeine, A.; Sefah, A.; Zheng, K.; et al. GABA-receptive microglia selectively sculpt developing inhibitory circuits. Cell 2021, 184, 4048–4063.e32. [Google Scholar] [CrossRef]
  121. Whitelaw, B. Microglia-mediated synaptic elimination in neuronal development and disease. J. Neurophysiol. 2018, 119, 1–4. [Google Scholar] [CrossRef] [PubMed]
  122. Fuks, J.; Arrighi, R.B.G.; Weidner, J.M.; Mendu, S.K.; Jin, Z.; Wallin, R.P.A.; Rethi, B.; Birnir, B.; Barragan, A. GABAergic Signaling Is Linked to a Hypermigratory Phenotype in Dendritic Cells Infected by Toxoplasma gondii. PLoS Pathog. 2012, 8, e1003051. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  123. Fruntes, V.; Limosin, F. Schizophrenia and viral infection during neurodevelopment: A pathogenesis model? Med. Sci. Monit. 2008, 14, RA71–RA77. [Google Scholar] [PubMed]
  124. Scordel, C.; Huttin, A.; Cochet-Bernoin, M.; Szelechowski, M.; Poulet, A.; Richardson, J.; Benchoua, A.; Gonzalez-Dunia, D.; Eloit, M.; Coulpier, M. Borna Disease Virus Phosphoprotein Impairs the Developmental Program Controlling Neurogenesis and Reduces Human GABAergic Neurogenesis. PLoS Pathog. 2015, 11, e1004859. [Google Scholar] [CrossRef] [PubMed]
  125. McCarron, J.G.; Lee, M.D.; Wilson, C. The Endothelium Solves Problems That Endothelial Cells Do Not Know Exist. Trends Pharmacol. Sci. 2017, 38, 322–338. [Google Scholar] [CrossRef] [Green Version]
  126. Lee, M.D.; Buckley, C.; Zhang, X.; Louhivuori, L.; Uhlén, P.; Wilson, C.; McCarron, J.G. Small-world connectivity dictates collective endothelial cell signaling. Proc. Natl. Acad. Sci. USA 2022, 119, e2118927119. [Google Scholar] [CrossRef] [PubMed]
  127. Junior, A.P.; Dos Santos, R.P.; Barrros, R.F. The Calcium Wave Model of the Perception-Action Cycle: Evidence from Semantic Relevance in Memory Experiments. Front. Psychol. 2013, 4, 252. [Google Scholar] [CrossRef] [Green Version]
  128. Carafoli, E.; Krebs, J. Why Calcium? How Calcium Became the Best Communicator. J. Biol. Chem. 2016, 291, 20849–20857. [Google Scholar] [CrossRef] [Green Version]
  129. Knight, H.; Brandt, S.; Knight, M.R. A history of stress alters drought calcium signalling pathways in Arabidopsis. Plant J. 1998, 16, 681–687. [Google Scholar] [CrossRef] [Green Version]
  130. Kawamoto, E.M.; Vivar, C.; Camandola, S. Physiology and Pathology of Calcium Signaling in the Brain. Front. Pharmacol. 2012, 3, 61. [Google Scholar] [CrossRef] [Green Version]
  131. Adaikkan, C.; Taha, E.; Barrera, I.; David, O.; Rosenblum, K. Calcium/Calmodulin-Dependent Protein Kinase II and Eukaryotic Elongation Factor 2 Kinase Pathways Mediate the Antidepressant Action of Ketamine. Biol. Psychiatry 2018, 84, 65–75. [Google Scholar] [CrossRef] [PubMed]
  132. Wenzhong, L.; Hualan, L. COVID-19: The CaMKII-like system of S protein drives membrane fusion and induces syncytial multinucleated giant cells. Immunol. Res. 2021, 69, 496–519. [Google Scholar] [CrossRef] [PubMed]
  133. Baluška, F.; Levin, M. On Having No Head: Cognition throughout Biological Systems. Front. Psychol. 2016, 7, 902. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  134. Snijders, T.; Aussieker, T.; Holwerda, A.; Parise, G.; Van Loon, L.J.C.; Verdijk, L.B. The concept of skeletal muscle memory: Evidence from animal and human studies. Acta Physiol. 2020, 229, e13465. [Google Scholar] [CrossRef]
  135. Pearsall, P.; Schwartz, G.E.; Russek, L.G. Changes in heart transplant recipients that parallel the personalities of their donors. Integr. Med. 2000, 2, 65–72. [Google Scholar] [CrossRef] [Green Version]
  136. Bunzel, B.; Schmidl-Mohl, B.; Wollenek, G. Does changing the heart mean changing personality? A retrospective inquiry on 47 heart transplant patients. Qual. Life Res. 1992, 1, 251–256. [Google Scholar] [CrossRef]
  137. Liester, M.B. Personality changes following heart transplantation: The role of cellular memory. Med. Hypotheses 2019, 135, 109468. [Google Scholar] [CrossRef]
  138. Moore, C.I.; Cao, R. The Hemo-Neural Hypothesis: On The Role of Blood Flow in Information Processing. J. Neurophysiol. 2008, 99, 2035–2047. [Google Scholar] [CrossRef] [Green Version]
  139. Cines, D.B.; Pollak, E.S.; A Buck, C.; Loscalzo, J.; A Zimmerman, G.; McEver, R.P.; Pober, J.S.; Wick, T.; A Konkle, B.; Schwartz, B.S.; et al. Endothelial cells in physiology and in the pathophysiology of vascular disorders. Blood 1998, 91, 3527–3561. [Google Scholar]
  140. Datta, D.; Subburaju, S.; Kaye, S.; Baruah, J.; Choi, Y.K.; Nian, Y.; Khalili, J.S.; Chung, S.; Elkhal, A.; Vasudevan, A. Human forebrain endothelial cell therapy for psychiatric disorders. Mol. Psychiatry 2020, 26, 4864–4883. [Google Scholar] [CrossRef]
  141. Choi, Y.K.; Vasudevan, A. Endothelial GABA signaling: A phoenix awakened. Aging 2018, 10, 859–860. [Google Scholar] [CrossRef] [PubMed]
  142. Do, D.P.; Dowd, J.; Ranjit, N.; House, J.S.; Kaplan, G.A. Hopelessness, Depression, and Early Markers of Endothelial Dysfunction in U.S. Adults. Psychosom. Med. 2010, 72, 613–619. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  143. Vetter, M.W.; Martin, B.-J.; Fung, M.; Pajevic, M.; Anderson, T.J.; Raedler, T.J. Microvascular dysfunction in schizophrenia: A case–control study. Schizophrenia 2015, 1, 15023. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  144. Azmitia, E.C.; Saccomano, Z.T.; Alzoobaee, M.F.; Boldrini, M.; Whitakerazmitia, P.M. Persistent Angiogenesis in the Autism Brain: An Immunocytochemical Study of Postmortem Cortex, Brainstem and Cerebellum. J. Autism Dev. Disord. 2015, 46, 1307–1318. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  145. Sara, J.D.S.; Ahmad, A.; Toya, T.; Pardo, L.S.; Lerman, L.O.; Lerman, A. Anxiety Disorders Are Associated With Coronary Endothelial Dysfunction in Women With Chest Pain and Nonobstructive Coronary Artery Disease. J. Am. Heart Assoc. 2021, 10, e021722. [Google Scholar] [CrossRef]
  146. Ogaki, A.; Ikegaya, Y.; Koyama, R. Vascular Abnormalities and the Role of Vascular Endothelial Growth Factor in the Epileptic Brain. Front. Pharmacol. 2020, 11, 20. [Google Scholar] [CrossRef] [Green Version]
  147. Mohite, S.; de Campos-Carli, S.M.; Rocha, N.P.; Sharma, S.; Miranda, A.S.; Barbosa, I.G.; Salgado, J.V.; Simoes-E-Silva, A.C.; Teixeira, A.L. Lower circulating levels of angiotensin-converting enzyme (ACE) in patients with schizophrenia. Schizophr. Res. 2018, 202, 50–54. [Google Scholar] [CrossRef]
  148. Braun, M.; Ramracheya, R.; Bengtsson, M.; Clark, A.; Walker, J.N.; Johnson, P.R.; Rorsman, P. γ-Aminobutyric Acid (GABA) Is an Autocrine Excitatory Transmitter in Human Pancreatic β-Cells. Diabetes 2010, 59, 1694–1701. [Google Scholar] [CrossRef] [Green Version]
  149. Wu, C.-T.; Lidsky, P.V.; Xiao, Y.; Lee, I.T.; Cheng, R.; Nakayama, T.; Jiang, S.; Demeter, J.; Bevacqua, R.J.; Chang, C.A.; et al. SARS-CoV-2 infects human pancreatic β cells and elicits β cell impairment. Cell Metab. 2021, 33, 1565–1576.e5. [Google Scholar] [CrossRef]
  150. Sohrabipour, S.; Sharifi, M.R.; Talebi, A.; Soltani, N. GABA dramatically improves glucose tolerance in streptozotocin-induced diabetic rats fed with high-fat diet. Eur. J. Pharmacol. 2018, 826, 75–84. [Google Scholar] [CrossRef]
  151. Soltani, N.; Qiu, H.; Aleksic, M.; Glinka, Y.; Zhao, F.; Liu, R.; Li, Y.; Zhang, N.; Chakrabarti, R.; Ng, T.; et al. GABA exerts protective and regenerative effects on islet beta cells and reverses diabetes. Proc. Natl. Acad. Sci. USA 2011, 108, 11692–11697. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  152. Chu, K.Y.; Leung, P.S. Angiotensin II in Type 2 Diabetes Mellitus. Curr. Protein Pept. Sci. 2009, 10, 75–84. [Google Scholar] [CrossRef] [PubMed]
  153. Gal, H.; Krizhanovsky, V. Cell fusion induced senescence. Aging 2014, 6, 353–354. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  154. Menegaz, D.; Hagan, D.W.; Almaça, J.; Cianciaruso, C.; Rodriguez-Diaz, R.; Molina, J.; Dolan, R.M.; Becker, M.W.; Schwalie, P.C.; Nano, R.; et al. Mechanism and effects of pulsatile GABA secretion from cytosolic pools in the human beta cell. Nat. Metab. 2019, 1, 1110–1126. [Google Scholar] [CrossRef] [PubMed]
  155. Aguayo-Mazzucato, C.; Midha, A. β-cell senescence in type 2 diabetes. Aging 2019, 11, 9967–9968. [Google Scholar] [CrossRef] [PubMed]
  156. Sfera, A.; Osorio, C.; Inderias, L.A.; Parker, V.; Price, A.I.; Cummings, M. The Obesity–Impulsivity Axis: Potential Metabolic Interventions in Chronic Psychiatric Patients. Front. Psychiatry 2017, 8, 20. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  157. Xu, J.; Chu, M.; Zhong, F.; Tan, X.; Tang, G.; Mai, J.; Lai, N.; Guan, C.; Liang, Y.; Liao, G. Digestive symptoms of COVID-19 and expression of ACE2 in digestive tract organs. Cell Death Discov. 2020, 6, 76. [Google Scholar] [CrossRef]
  158. Yu, W.; Ou, X.; Liu, X.; Zhang, S.; Gao, X.; Cheng, H.; Zhu, B.; Yan, J. ACE2 contributes to the maintenance of mouse epithelial barrier function. Biochem. Biophys. Res. Commun. 2020, 533, 1276–1282. [Google Scholar] [CrossRef]
  159. Koester, S.T.; Li, N.; Lachance, D.M.; Morella, N.M.; Dey, N. Variability in digestive and respiratory tract Ace2 expression is associated with the microbiome. PLoS ONE 2021, 16, e0248730. [Google Scholar] [CrossRef]
  160. Mpekoulis, G.; Frakolaki, E.; Taka, S.; Ioannidis, A.; Vassiliou, A.G.; Kalliampakou, K.I.; Patas, K.; Karakasiliotis, I.; Aidinis, V.; Chatzipanagiotou, S.; et al. Alteration of L-Dopa decarboxylase expression in SARS-CoV-2 infection and its association with the interferon-inducible ACE2 isoform. PLoS ONE 2021, 16, e0253458. [Google Scholar] [CrossRef]
  161. Reith, J.; Benkelfat, C.; Sherwin, A.; Yasuhara, Y.; Kuwabara, H.; Andermann, F.; Bachneff, S.; Cumming, P.; Diksic, M.; E Dyve, S. Elevated dopa decarboxylase activity in living brain of patients with psychosis. Proc. Natl. Acad. Sci. USA 1994, 91, 11651–11654. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  162. Stevens, B.R.; Ellory, J.C.; Preston, R.L. B0AT1 Amino Acid Transporter Complexed With SARS-CoV-2 Receptor ACE2 Forms a Heterodimer Functional Unit: In Situ Conformation Using Radiation Inactivation Analysis. Function 2021, 2, zqab027. [Google Scholar] [CrossRef] [PubMed]
  163. Eroğlu, I.; Eroğlu, B.; Güven, G.S. Altered tryptophan absorption and metabolism could underlie long-term symptoms in survivors of coronavirus disease 2019 (COVID-19). Nutrition 2021, 90, 111308. [Google Scholar] [CrossRef] [PubMed]
  164. Singer, D.; Camargo, S.; Ramadan, T.; Schäfer, M.; Mariotta, L.; Herzog, B.; Huggel, K.; Wolfer, D.; Werner, S.; Penninger, J.; et al. Defective intestinal amino acid absorption in Ace2 null mice. Am. J. Physiol. Liver Physiol. 2012, 303, G686–G695. [Google Scholar] [CrossRef]
  165. Deng, J.; Zhou, F.; Hou, W.; Silver, Z.; Wong, C.Y.; Chang, O.; Huang, E.; Zuo, Q.K. The prevalence of depression, anxiety, and sleep disturbances in COVID-19 patients: A meta-analysis. Ann. N. Y. Acad. Sci. 2020, 1486, 90–111. [Google Scholar] [CrossRef]
  166. Giovannoni, F.; Li, Z.; Remes-Lenicov, F.; Dávola, M.E.; Elizalde, M.; Paletta, A.; Ashkar, A.A.; Mossman, K.L.; Dugour, A.V.; Figueroa, J.M.; et al. AHR signaling is induced by infection with coronaviruses. Nat. Commun. 2021, 12, 5148. [Google Scholar] [CrossRef]
  167. Wei, G.Z.; Martin, K.A.; Xing, P.Y.; Agrawal, R.; Whiley, L.; Wood, T.K.; Hejndorf, S.; Ng, Y.Z.; Low, J.Z.Y.; Rossant, J.; et al. Tryptophan-metabolizing gut microbes regulate adult neurogenesis via the aryl hydrocarbon receptor. Proc. Natl. Acad. Sci. USA 2021, 118, e2021091118. [Google Scholar] [CrossRef]
  168. Ji, J.; Qu, H. Cross-regulatory Circuit Between AHR and Microbiota. Curr. Drug Metab. 2019, 20, 4–8. [Google Scholar] [CrossRef]
  169. Lindén, J.; Lensu, S.; Tuomisto, J.; Pohjanvirta, R. Dioxins, the aryl hydrocarbon receptor and the central regulation of energy balance. Front. Neuroendocr. 2010, 31, 452–478. [Google Scholar] [CrossRef]
  170. Sfera, A.; Osorio, C.; Diaz, E.L.; Maguire, G.; Cummings, M. The Other Obesity Epidemic—Of Drugs and Bugs. Front. Endocrinol. 2020, 11, 488. [Google Scholar] [CrossRef]
  171. Sabbatinelli, J.; Prattichizzo, F.; Olivieri, F.; Procopio, A.D.; Rippo, M.R.; Giuliani, A. Where Metabolism Meets Senescence: Focus on Endothelial Cells. Front. Physiol. 2019, 10, 1523. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  172. Brinkmann, V.; Ale-Agha, N.; Haendeler, J.; Ventura, N. The Aryl Hydrocarbon Receptor (AhR) in the Aging Process: Another Puzzling Role for This Highly Conserved Transcription Factor. Front. Physiol. 2020, 10, 1561. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  173. Ren, W.; Liao, Y.; Ding, X.; Jiang, Y.; Yan, J.; Xia, Y.; Tan, B.; Lin, Z.; Duan, J.; Jia, X.; et al. Slc6a13 deficiency promotes Th17 responses during intestinal bacterial infection. Mucosal Immunol. 2018, 12, 531–544. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  174. Brevi, A.; Cogrossi, L.L.; Grazia, G.; Masciovecchio, D.; Impellizzieri, D.; Lacanfora, L.; Grioni, M.; Bellone, M. Much More Than IL-17A: Cytokines of the IL-17 Family Between Microbiota and Cancer. Front. Immunol. 2020, 11, 565470. [Google Scholar] [CrossRef]
  175. Hamada, H.; Garcia-Hernandez, M.D.L.L.; Reome, J.B.; Misra, S.K.; Strutt, T.M.; McKinstry, K.K.; Cooper, A.; Swain, S.L.; Dutton, R.W. Tc17, a Unique Subset of CD8 T Cells That Can Protect against Lethal Influenza Challenge. J. Immunol. 2009, 182, 3469–3481. [Google Scholar] [CrossRef] [Green Version]
  176. Zhang, L.; Liu, M.; Liu, W.; Hu, C.; Li, H.; Deng, J.; Cao, Q.; Wang, Y.; Hu, W.; Li, Q. Th17/IL-17 induces endothelial cell senescence via activation of NF-κB/p53/Rb signaling pathway. Lab. Investig. 2021, 101, 1418–1426. [Google Scholar] [CrossRef]
  177. Ming, X.-F.; Montani, J.-P.; Yang, Z. Perspectives of Targeting mTORC1–S6K1 in Cardiovascular Aging. Front. Physiol. 2012, 3, 5. [Google Scholar] [CrossRef] [Green Version]
  178. Fuentes-Prior, P. Priming of SARS-CoV-2 S protein by several membrane-bound serine proteinases could explain enhanced viral infectivity and systemic COVID-19 infection. J. Biol. Chem. 2021, 296, 100135. [Google Scholar] [CrossRef]
  179. Zhang, Z.; Zheng, Y.; Niu, Z.; Zhang, B.; Wang, C.; Yao, X.; Peng, H.; Franca, D.N.; Wang, Y.; Zhu, Y.; et al. SARS-CoV-2 spike protein dictates syncytium-mediated lymphocyte elimination. Cell Death Differ. 2021, 28, 2765–2777. [Google Scholar] [CrossRef]
  180. Winstone, H.; Lista, M.J.; Reid, A.C.; Bouton, C.; Pickering, S.; Galao, R.P.; Kerridge, C.; Doores, K.J.; Swanson, C.M.; Neil, S.J.D. The Polybasic Cleavage Site in SARS-CoV-2 Spike Modulates Viral Sensitivity to Type I Interferon and IFITM2. J. Virol. 2021, 95, e02422-20. [Google Scholar] [CrossRef]
  181. Johnson, B.A.; Xie, X.; Bailey, A.L.; Kalveram, B.; Lokugamage, K.G.; Muruato, A.; Zou, J.; Zhang, X.; Juelich, T.; Smith, J.K.; et al. Loss of furin cleavage site attenuates SARS-CoV-2 pathogenesis. Nature 2021, 591, 293–299. [Google Scholar] [CrossRef] [PubMed]
  182. Balestrieri, E.; Minutolo, A.; Petrone, V.; Fanelli, M.; Iannetta, M.; Malagnino, V.; Zordan, M.; Vitale, P.; Charvet, B.; Horvat, B.; et al. Evidence of the pathogenic HERV-W envelope expression in T lymphocytes in association with the respiratory outcome of COVID-19 patients. EBioMedicine 2021, 66, 103341. [Google Scholar] [CrossRef] [PubMed]
  183. Chang, C.; Chen, P.-T.; Chang, G.-D.; Huang, C.-J.; Chen, H. Functional Characterization of the Placental Fusogenic Membrane Protein Syncytin1. Biol. Reprod. 2004, 71, 1956–1962. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  184. Huppertz, B. The Critical Role of Abnormal Trophoblast Development in the Etiology of Preeclampsia. Curr. Pharm. Biotechnol. 2018, 19, 771–780. [Google Scholar] [CrossRef]
  185. Zhang, L.; Richards, A.; Barrasa, M.I.; Hughes, S.H.; Young, R.A.; Jaenisch, R. Reverse-transcribed SARS-CoV-2 RNA can integrate into the genome of cultured human cells and can be expressed in patient-derived tissues. Proc. Natl. Acad. Sci. USA 2021, 118, e2105968118. [Google Scholar] [CrossRef]
  186. Mi, S.; Lee, X.; Li, X.-P.; Veldman, G.M.; Finnerty, H.; Racie, L.; LaVallie, E.; Tang, X.-Y.; Edouard, P.; Howes, S.; et al. Syncytin is a captive retroviral envelope protein involved in human placental morphogenesis. Nature 2000, 403, 785–789. [Google Scholar] [CrossRef]
  187. Wang, X.; Huang, J.; Zhu, F. Human Endogenous Retroviral Envelope Protein Syncytin-1 and Inflammatory Abnormalities in Neuropsychological Diseases. Front. Psychiatry 2018, 9, 422. [Google Scholar] [CrossRef]
  188. Chen, C.-P.; Chen, L.-F.; Yang, S.-R.; Chen, C.-Y.; Ko, C.-C.; Chang, G.-D.; Chen, H. Functional Characterization of the Human Placental Fusogenic Membrane Protein Syncytin 21. Biol. Reprod. 2008, 79, 815–823. [Google Scholar] [CrossRef] [Green Version]
  189. Conde-Agudelo, A.; Romero, R. SARS-CoV-2 infection during pregnancy and risk of preeclampsia: A systematic review and meta-analysis. Am. J. Obstet. Gynecol. 2021, 226, 68–89.e3. [Google Scholar] [CrossRef]
  190. Terán, Y.; Ponce, O.; Betancourt, L.; Hernández, L.; Rada, P. Amino acid profile of plasma and cerebrospinal fluid in preeclampsia. Pregnancy Hypertens. Int. J. Women’s Cardiovasc. Health 2012, 2, 416–422. [Google Scholar] [CrossRef]
  191. Lu, J.; Zhang, Q.; Tan, D.; Luo, W.; Zhao, H.; Ma, J.; Liang, H.; Tan, Y. GABA A receptor π subunit promotes apoptosis of HTR-8/SVneo trophoblastic cells: Implications in preeclampsia. Int. J. Mol. Med. 2016, 38, 105–112. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  192. Licht, P.; Harbarth, P.; E Merz, W. Evidence for a modulation of human chorionic gonadotropin (hCG) subunit messenger ribonucleic acid levels and hCG secretion by gamma-aminobutyric acid in human first trimester placenta in vitro. Endocrinology 1992, 130, 490–496. [Google Scholar] [CrossRef] [PubMed]
  193. Vacher, C.-M.; Lacaille, H.; O’Reilly, J.J.; Salzbank, J.; Bakalar, D.; Sebaoui, S.; Liere, P.; Clarkson-Paredes, C.; Sasaki, T.; Sathyanesan, A.; et al. Placental endocrine function shapes cerebellar development and social behavior. Nat. Neurosci. 2021, 24, 1392–1401. [Google Scholar] [CrossRef] [PubMed]
  194. Cheng, Y.-W.; Chao, T.-L.; Li, C.-L.; Chiu, M.-F.; Kao, H.-C.; Wang, S.-H.; Pang, Y.-H.; Lin, C.-H.; Tsai, Y.-M.; Lee, W.-H.; et al. Furin Inhibitors Block SARS-CoV-2 Spike Protein Cleavage to Suppress Virus Production and Cytopathic Effects. Cell Rep. 2020, 33, 108254. [Google Scholar] [CrossRef]
  195. Becker, G.L.; Sielaff, F.; Than, M.E.; Lindberg, I.; Routhier, S.; Day, R.; Lu, Y.; Garten, W.; Steinmetzer, T. Potent Inhibitors of Furin and Furin-like Proprotein Convertases Containing Decarboxylated P1 Arginine Mimetics. J. Med. Chem. 2009, 53, 1067–1075. [Google Scholar] [CrossRef] [Green Version]
  196. Devi, K.P.; Pourkarim, M.R.; Thijssen, M.; Sureda, A.; Khayatkashani, M.; Cismaru, C.A.; Neagoe, I.B.; Habtemariam, S.; Razmjouei, S.; Kashani, H.R.K. A perspective on the applications of furin inhibitors for the treatment of SARS-CoV-2. Pharmacol. Rep. 2022, 74, 425–430. [Google Scholar] [CrossRef]
  197. Yakala, G.K.; Cabrera-Fuentes, H.A.; Crespo-Avilan, G.E.; Rattanasopa, C.; Burlacu, A.; George, B.L.; Anand, K.; Mayan, D.C.; Corlianò, M.; Hernández-Reséndiz, S.; et al. FURIN Inhibition Reduces Vascular Remodeling and Atherosclerotic Lesion Progression in Mice. Arter. Thromb. Vasc. Biol. 2019, 39, 387–401. [Google Scholar] [CrossRef] [Green Version]
  198. AbdelMassih, A.F.; Ye, J.; Kamel, A.; Mishriky, F.; Ismail, H.-A.; Ragab, H.A.; El Qadi, L.; Malak, L.; Abdu, M.; El-Husseiny, M.; et al. A multicenter consensus: A role of furin in the endothelial tropism in obese patients with COVID-19 infection. Obes. Med. 2020, 19, 100281. [Google Scholar] [CrossRef]
  199. Pomorski, T.G.; Menon, A.K. Lipid somersaults: Uncovering the mechanisms of protein-mediated lipid flipping. Prog. Lipid Res. 2016, 64, 69–84. [Google Scholar] [CrossRef] [Green Version]
  200. Whitlock, J.M.; Chernomordik, L.V. Flagging fusion: Phosphatidylserine signaling in cell—Cell fusion. J. Biol. Chem. 2021, 296, 100411. [Google Scholar] [CrossRef]
  201. Braga, L.; Ali, H.; Secco, I.; Chiavacci, E.; Neves, G.; Goldhill, D.; Penn, R.; Jimenez-Guardeño, J.M.; Ortega-Prieto, A.M.; Bussani, R.; et al. Drugs that inhibit TMEM16 proteins block SARS-CoV-2 spike-induced syncytia. Nature 2021, 594, 88–93. [Google Scholar] [CrossRef] [PubMed]
  202. Cheng, Y.; Feng, S.; Puchades, C.; Ko, J.; Figueroa, E.; Chen, Y.; Wu, H.; Gu, S.; Han, T.; Li, J.; et al. Identification of a conserved drug binding pocket in TMEM16 proteins. Preprint Res. Sq. 2022, 1, rs.3.rs-1296933. [Google Scholar] [CrossRef]
  203. Cairns, D.M.; Dulko, D.; Griffiths, J.K.; Golan, Y.; Cohen, T.; Trinquart, L.; Price, L.L.; Beaulac, K.R.; Selker, H.P. Efficacy of Niclosamide vs Placebo in SARS-CoV-2 Respiratory Viral Clearance, Viral Shedding, and Duration of Symptoms Among Patients with Mild to Moderate COVID-19. JAMA Netw. Open 2022, 5, e2144942. [Google Scholar] [CrossRef] [PubMed]
  204. Pedemonte, N.; Galietta, L.J. Structure and Function of TMEM16 Proteins (Anoctamins). Physiol. Rev. 2014, 94, 419–459. [Google Scholar] [CrossRef] [Green Version]
  205. Slawecki, M.L.; Carlson, G.C.; Keller, A. Differential distribution of inositol 1,4,5-triphosphate receptors in the rat olfactory bulb. J. Comp. Neurol. 1997, 389, 224–234. [Google Scholar] [CrossRef]
  206. Egorova, P.A.; Bezprozvanny, I.B. Inositol 1,4,5-trisphosphate receptors and neurodegenerative disorders. FEBS J. 2018, 285, 3547–3565. [Google Scholar] [CrossRef] [Green Version]
  207. Heuser, K.; Nome, C.G.; Pettersen, K.H.; Åbjørsbråten, K.S.; Jensen, V.; Tang, W.; Sprengel, R.; Taubøll, E.; A Nagelhus, E.; Enger, R. Ca2+ Signals in Astrocytes Facilitate Spread of Epileptiform Activity. Cereb. Cortex 2018, 28, 4036–4048. [Google Scholar] [CrossRef] [Green Version]
  208. Park, S.J.; Jeong, J.; Park, Y.-U.; Park, K.-S.; Lee, H.; Lee, N.; Kim, S.-M.; Kuroda, K.; Nguyen, M.D.; Kaibuchi, K.; et al. Disrupted-in-schizophrenia-1 (DISC1) Regulates Endoplasmic Reticulum Calcium Dynamics. Sci. Rep. 2015, 5, 8694. [Google Scholar] [CrossRef] [Green Version]
  209. de Bartolomeis, A.; Tomasetti, C.; Cicale, M.; Yuan, P.-X.; Manji, H.K. Chronic treatment with lithium or valproate modulates the expression of Homer1b/c and its related genes Shank and Inositol 1,4,5-trisphosphate receptor. Eur. Neuropsychopharmacol. 2012, 22, 527–535. [Google Scholar] [CrossRef] [Green Version]
  210. Khanim, F.; Ferretti, L.; Raffles, S.; Giles, H.; Jankute, M.; Merrick, B.; Bunce, C.; Drayson, M. Epilepsy doses of valproate combined with the anti-helminthic, niclosamide, synergistically kill myeloma cells: A potent new anti-myeloma drug combination. Exp. Hematol. 2014, 42, S26. [Google Scholar] [CrossRef]
  211. Akgun, O.; Erkisa, M.; Ari, F. Effective and new potent drug combination: Histone deacetylase and Wnt/β-catenin pathway inhibitors in lung carcinoma cells. J. Cell. Biochem. 2019, 120, 15467–15482. [Google Scholar] [CrossRef] [PubMed]
  212. Batti, L.; Sundukova, M.; Murana, E.; Pimpinella, S.; Reis, F.D.C.; Pagani, F.; Wang, H.; Pellegrino, E.; Perlas, E.; Di Angelantonio, S.; et al. TMEM16F Regulates Spinal Microglial Function in Neuropathic Pain States. Cell Rep. 2016, 15, 2608–2615. [Google Scholar] [CrossRef] [PubMed] [Green Version]
  213. Bandman, E.; Walker, C.R.; Strohman, R.C. Diazepam Inhibits Myoblast Fusion and Expression of Muscle Specific Protein Synthesis. Science 1978, 200, 559–561. [Google Scholar] [CrossRef] [PubMed]
  214. Volke, V.; Soosaar, A.; Koks, S.; Vasar, E.; Männistö, P. l-Arginine abolishes the anxiolytic-like effect of diazepam in the elevated plus-maze test in rats. Eur. J. Pharmacol. 1998, 351, 287–290. [Google Scholar] [CrossRef]
  215. Gong, L.; Zhang, X.; Qiu, K.; He, L.; Wang, Y.; Yin, J. Arginine promotes myogenic differentiation and myotube formation through the elevation of cytoplasmic calcium concentration. Anim. Nutr. 2021, 7, 1115–1123. [Google Scholar] [CrossRef]
  216. Williams, M.; Risley, E.A. Ivermectin Interactions with Benzodiazepine Receptors in Rat Cortex and Cerebellum In Vitro. J. Neurochem. 1984, 42, 745–753. [Google Scholar] [CrossRef]
  217. Bhandage, A.K.; Olivera, G.C.; Kanatani, S.; Thompson, E.; Loré, K.; Varas-Godoy, M.; Barragan, A. A motogenic GABAergic system of mononuclear phagocytes facilitates dissemination of coccidian parasites. eLife 2020, 9, e60528. [Google Scholar] [CrossRef]
  218. Tian, J.; Middleton, B.; Kaufman, D. GABAA-Receptor Agonists Limit Pneumonitis and Death in Murine Coronavirus-Infected Mice. Viruses 2021, 13, 966. [Google Scholar] [CrossRef]
  219. Kittler, J.T.; Delmas, P.; Jovanovic, J.N.; Brown, D.A.; Smart, T.G.; Moss, S.J. Constitutive Endocytosis of GABAA Receptors by an Association with the Adaptin AP2 Complex Modulates Inhibitory Synaptic Currents in Hippocampal Neurons. J. Neurosci. 2000, 20, 7972–7977. [Google Scholar] [CrossRef] [Green Version]
  220. Ngo, D.-H.; Vo, T.S. An Updated Review on Pharmaceutical Properties of Gamma-Aminobutyric Acid. Molecules 2019, 24, 2678. [Google Scholar] [CrossRef] [Green Version]
  221. Shimada, M.; Hasegawa, T.; Nishimura, C.; Kan, H.; Kanno, T.; Nakamura, T.; Matsubayashi, T. Anti-Hypertensive Effect of γ-Aminobutyric Acid (GABA)-Rich Chlorella on High-Normal Blood Pressure and Borderline Hypertension in Placebo-Controlled Double Blind Study. Clin. Exp. Hypertens. 2009, 31, 342–354. [Google Scholar] [CrossRef]
  222. Shyamaladevi, N.; Jayakumar, A.; Sujatha, R.; Paul, V.; Subramanian, E. Evidence that nitric oxide production increases γ-amino butyric acid permeability of blood-brain barrier. Brain Res. Bull. 2002, 57, 231–236. [Google Scholar] [CrossRef]
  223. Yoto, A.; Murao, S.; Motoki, M.; Yokoyama, Y.; Horie, N.; Takeshima, K.; Masuda, K.; Kim, M.; Yokogoshi, H. Oral intake of γ-aminobutyric acid affects mood and activities of central nervous system during stressed condition induced by mental tasks. Amino Acids 2011, 43, 1331–1337. [Google Scholar] [CrossRef] [PubMed]
  224. Czuczwar, S.J.; Patsalos, P.N. The New Generation of GABA Enhancers. CNS Drugs 2001, 15, 339–350. [Google Scholar] [CrossRef] [PubMed]
  225. Iaria, P.; Blacher, J.; Asplanato, M.; Edric, K.; Safar, M.; Girerd, X. Une nouvelle cause d’hypertension artérielle résistante: La co-prescription avec des traitements anticomitiaux [A new cause of resistant arterial hypertension: Coprescription with anti-convulsant treatments]. Arch. Mal. Coeur. Vaiss. 1999, 92, 1005–1008. [Google Scholar]
  226. Chen, H.-H.; Li, Y.-D.; Cheng, P.-W.; Fang, Y.-C.; Lai, C.-C.; Tseng, C.-J.; Pan, J.-Y.; Yeh, T.-C. Gabapentin Reduces Blood Pressure and Heart Rate through the Nucleus Tractus Solitarii. Acta Cardiol. Sin. 2019, 35, 627–633. [Google Scholar] [CrossRef]
  227. Kitajima, T.; Kanbayashi, T.; Saito, Y.; Takahashi, Y.; Ogawa, Y.; Sugiyama, T.; Kaneko, Y.; Aizawa, R.; Shimizu, T. Diazepam reduces both arterial blood pressure and muscle sympathetic nerve activity in human. Neurosci. Lett. 2004, 355, 77–80. [Google Scholar] [CrossRef]
  228. Lokensgard, J.R.; Gekker, G.; Hu, S.; Arthur, A.F.; Chao, C.C.; Peterson, P.K. Diazepam-mediated inhibition of human immunodeficiency virus type 1 expression in human brain cells. Antimicrob. Agents Chemother. 1997, 41, 2566–2569. [Google Scholar] [CrossRef] [Green Version]
  229. Lin, A.; Elbezanti, W.O.; Schirling, A.; Ahmed, A.; Van Duyne, R.; Cocklin, S.; Klase, Z. Alprazolam Prompts HIV-1 Transcriptional Reactivation and Enhances CTL Response Through RUNX1 Inhibition and STAT5 Activation. Front. Neurol. 2021, 12, 663793. [Google Scholar] [CrossRef]
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Figure 1. SARS-CoV-2 downregulates GABA by inducing endothelial senescence directly (by protein–protein interactions) and indirectly (via mitochondrial dysfunction and ANG II upregulation). A dysfunctional endothelial barrier facilitates microbial translocation from the GI tract, where the flora is immunologically tolerated, into the systemic circulation, where it evokes inflammation and immunogenicity. Legend: NSP6, nonstructural protein 6, ORF8, open reading frame 8, IL-17, interleukin 17, TMEM16F, transmembrane protein 16F, TLR4, toll-like receptor 4, NSP4, nonstructural protein 4, NSP8, nonstructural protein 8, ORF9C, open reading frame 9C, ORF3a, open reading frame 3a, LPS, lipopolysaccharide.
Figure 1. SARS-CoV-2 downregulates GABA by inducing endothelial senescence directly (by protein–protein interactions) and indirectly (via mitochondrial dysfunction and ANG II upregulation). A dysfunctional endothelial barrier facilitates microbial translocation from the GI tract, where the flora is immunologically tolerated, into the systemic circulation, where it evokes inflammation and immunogenicity. Legend: NSP6, nonstructural protein 6, ORF8, open reading frame 8, IL-17, interleukin 17, TMEM16F, transmembrane protein 16F, TLR4, toll-like receptor 4, NSP4, nonstructural protein 4, NSP8, nonstructural protein 8, ORF9C, open reading frame 9C, ORF3a, open reading frame 3a, LPS, lipopolysaccharide.
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Figure 2. Human RAS consists of two opposing branches, the proinflammatory/prooxidative (driven by ANG II) branch and the anti-inflammatory/antioxidant (driven by ANG 1-7) one. ANG II, acting via AT-1Rs, induces EC senescence. ARBs and GABA negatively regulate AT-1Rs, opposing ANG II. The protective RAS branch, comprised of ANG 1-7, alamandine, and their respective receptors Mas and MrgD, inhibit inflammation and oxidative stress. SARS-CoV-2 engagement with ACE-2 disrupts the entire anti-inflammatory/antioxidant branch, leading to unchecked ANG II accumulation and premature EC senescence. Legend: ANG I, angiotensin I, ACEi, angiotensin-converting enzyme inhibitors, ANG II, angiotensin II, ARBs, angiotensin receptor blockers, AT-1r, angiotensin receptor type 1, ROS, reactive oxygen species, ANG1-7, angiotensin 1-7, MasR, Mas receptor, MrgD, MrgD receptor, NO, nitric oxide.
Figure 2. Human RAS consists of two opposing branches, the proinflammatory/prooxidative (driven by ANG II) branch and the anti-inflammatory/antioxidant (driven by ANG 1-7) one. ANG II, acting via AT-1Rs, induces EC senescence. ARBs and GABA negatively regulate AT-1Rs, opposing ANG II. The protective RAS branch, comprised of ANG 1-7, alamandine, and their respective receptors Mas and MrgD, inhibit inflammation and oxidative stress. SARS-CoV-2 engagement with ACE-2 disrupts the entire anti-inflammatory/antioxidant branch, leading to unchecked ANG II accumulation and premature EC senescence. Legend: ANG I, angiotensin I, ACEi, angiotensin-converting enzyme inhibitors, ANG II, angiotensin II, ARBs, angiotensin receptor blockers, AT-1r, angiotensin receptor type 1, ROS, reactive oxygen species, ANG1-7, angiotensin 1-7, MasR, Mas receptor, MrgD, MrgD receptor, NO, nitric oxide.
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Figure 3. Neuronal cell–cell fusion occurs physiologically, in normal aging, or pathologically, in various conditions, including viral infections, Alzheimer’s disease (AD), multiple sclerosis (MS), radiation exposure, or chemotherapy [76] Neuronal syncytia formation likely accounts for previously unexplained phenomena, such as aneuploidy, somatic mosaicism, and neuronal cell cycle reactivation, documented in various neuropsychiatric conditions.
Figure 3. Neuronal cell–cell fusion occurs physiologically, in normal aging, or pathologically, in various conditions, including viral infections, Alzheimer’s disease (AD), multiple sclerosis (MS), radiation exposure, or chemotherapy [76] Neuronal syncytia formation likely accounts for previously unexplained phenomena, such as aneuploidy, somatic mosaicism, and neuronal cell cycle reactivation, documented in various neuropsychiatric conditions.
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Figure 4. In the GI tract, ACE-2 dimerizes with the neutral amino acid transporter B0AT1 involved in Trp absorption. Trp, an Ahr ligand, coordinates host–microbiota interaction and local metabolism. Dysfunctional Trp absorption and defective Ahr may contribute to barrier disruption and microbial translocation into the systemic circulation. Legend: Trp, tryptophan, B0AT1, neutral amino acid transporter, AHR, aryl hydrocarbon receptor.
Figure 4. In the GI tract, ACE-2 dimerizes with the neutral amino acid transporter B0AT1 involved in Trp absorption. Trp, an Ahr ligand, coordinates host–microbiota interaction and local metabolism. Dysfunctional Trp absorption and defective Ahr may contribute to barrier disruption and microbial translocation into the systemic circulation. Legend: Trp, tryptophan, B0AT1, neutral amino acid transporter, AHR, aryl hydrocarbon receptor.
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Sfera, A.; Thomas, K.G.; Sasannia, S.; Anton, J.J.; Andronescu, C.V.; Garcia, M.; Sfera, D.O.; Cummings, M.A.; Kozlakidis, Z. Neuronal and Non-Neuronal GABA in COVID-19: Relevance for Psychiatry. Reports 2022, 5, 22. https://doi.org/10.3390/reports5020022

AMA Style

Sfera A, Thomas KG, Sasannia S, Anton JJ, Andronescu CV, Garcia M, Sfera DO, Cummings MA, Kozlakidis Z. Neuronal and Non-Neuronal GABA in COVID-19: Relevance for Psychiatry. Reports. 2022; 5(2):22. https://doi.org/10.3390/reports5020022

Chicago/Turabian Style

Sfera, Adonis, Karina G. Thomas, Sarvin Sasannia, Jonathan J. Anton, Christina V. Andronescu, Michael Garcia, Dan O. Sfera, Michael A. Cummings, and Zisis Kozlakidis. 2022. "Neuronal and Non-Neuronal GABA in COVID-19: Relevance for Psychiatry" Reports 5, no. 2: 22. https://doi.org/10.3390/reports5020022

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