Search Results (209)

Serotonin receptors, in particular 5-HT_1A and 5-HT_2A receptors, are important molecular targets for the central nervous system (CNS) disorders, such as schizophrenia, depression, anxiety disorders, memory deficits, and many others. Here, we present structural and pharmacological evaluation of a serotonin receptor ligand, SERAAK2, identified in a structure-based virtual screening campaign. Molecular docking studies revealed that SERAAK2 binds with its molecular targets via Asp3.32 as the main anchoring point, which is typical for orthosteric ligands of aminergic GPCRs. Molecular dynamics simulations confirmed the stability of the ligand binding poses in the studied receptors. MMGBSA calculations were in accordance with the receptor in vitro binding affinity studies, which indicated that SERAAK2 is a potent ligand of 5-HT_1A and 5-HT_2A receptors. It was also found that SERAAK2 displays favorable ADMET parameters. The demonstrated anxiolytic- and antidepressant-like effects of SERAAK2 in animal models, which may involve its interaction with 5-HT_1A receptors, warrant further studies to confirm these activities and elucidate the underlying mechanisms. Full article

3-chloromethcathinone (3-CMC) is a synthetic cathinone that gained relevance, having been involved in a large number of seizures and poisoning reports. Despite this, literature currently lacks information on its pharmaco-toxicological effects. This study aims to investigate the acute sensorimotor and physiological effects of 3-CMC (0.1–30 mg/kg; i.p.) in male and female CD-1 mice and its effects (1 and 10 mg/kg) on Prepulse Inhibition (PPI). Furthermore, we describe a series of 3-CMC (or CMC)-related human intoxications (Italy, 2014–2025) registered by the PCC–National Toxicology Information Centre. Finally, we predicted the ADMET properties of 3-CMC compared to 2-CMC, 4-CMC, 2-MMC, and two 3-CMC metabolites. 3-CMC induced in mice locomotor stimulation in mice, relevant tachypnoea and hypothermia, sensorimotor, and PPI alterations were observed only at high doses, with minor sex differences. All intoxications were non-fatal and involved male patients showing psychomotor agitation, psychosis, aggressiveness, CNS depression, but also cardiac arrhythmias, thoracic pain, and tachypnea. N-dealkylation, N-hydroxylation, and phenyl hydroxylation were the main predicted reactions. Drug–drug interaction potential and cardiotoxicity were suggested for all compounds. This interdisciplinary study elucidates 3-CMC effects and its associated risks, opening new objectives for future studies on CMC compounds to provide critical information to clinicians and the toxicological field. Full article

Epilepsy is one of the most prevalent neurological disorders, severely impacting quality of life. The burden of epilepsy is exacerbated by high rates of neuropsychiatric comorbidities such as depression, anxiety, and post-traumatic stress disorder. The molecular mechanisms linking epilepsy to these comorbidities remain unclear. Epileptogenesis and recurrent seizures implicate multiple processes including changes in the extracellular matrix, structural and functional neuroplasticity, neuroinflammation, and neurodegeneration. The plasminogen activation (PA) system—a complex system of proteins that function as both proteases and signaling molecules—modulates these processes in the central nervous system (CNS) under normal conditions and following potentially epileptogenic insults. Notably, the PA system is also dysregulated in stress-related psychiatric disorders. In this review, we first provide an overview of the role of PA system in the CNS with an emphasis on the mechanisms related to epilepsy. We then explore the hypothesis that the components of the PA system components constitute a shared pathological link implicated in both epileptogenesis and psychiatric disorders. We summarize clinical and preclinical evidence demonstrating that seizures and other brain insults disrupt the PA system, and that similar dysregulation is observed in stress-related psychiatric conditions. We propose that PA system dysregulation is a potential molecular substrate linking epileptogenesis and neuropsychiatric comorbidities, presenting a promising target for future research aimed at understanding the mechanisms underlying the development of behavioral comorbidities in epilepsy. Full article

Major depressive disorder (MDD) is a multifaceted psychiatric disorder that has been a longstanding focus of research. However, its underlying mechanisms remain underexplored. Recently, the inflammatory hypothesis has gained attention, highlighting inflammation’s role in MDD progression. Potential contributors to increased systemic inflammation in MDD include hyperactivation of the hypothalamic–pituitary–adrenal axis, dysregulation of the sympathetic nervous system, gut microbiota imbalances, the “pathogen host defense” hypothesis, and damage-associated molecular patterns. Traditional pathways explaining how systemic inflammation affects the central nervous system (CNS) do not fully account for the observed desynchrony between systemic and neuroinflammation in most depressed individuals. Alternative models suggest mechanisms such as reduced blood–brain barrier permeability and the involvement of immune cells from the skull. This review examines the link between inflammation and MDD, focusing on systemic and neuroinflammation interactions, with special emphasis on the heterogeneity of MDD symptoms and the potential impact of dysfunction in the brain’s lymphatic system. Gaining insight into the origins of inflammation in both the central nervous system and the peripheral body, along with their interactions, offers an important understanding of the inflammatory mechanisms associated with MDD for future treatment. Full article

Background: Childhood cancer survivors (CCSs) are at heightened risk of long-term neurocognitive and emotional difficulties that can affect educational attainment, social participation, and overall quality of life. These outcomes vary across developmental stages and are influenced by treatment modality, age at diagnosis, and central nervous system (CNS) involvement. Methods: A comprehensive literature search was conducted in PubMed, Scopus, PsycINFO, and Web of Science for articles published between January 2000 and June 2024. Search terms included combinations of “childhood cancer survivors,” “neurocognitive outcomes,” “executive function,” “emotional regulation,” and related MeSH terms. Inclusion criteria required peer-reviewed studies assessing CCS using standardized neuropsychological or emotional measures. Results: Evidence indicates persistent deficits in processing speed, working memory, and higher-order executive functions, with additional challenges in attention and memory. Emotional difficulties, including anxiety, depression, and social withdrawal, were prevalent and often co-occurred with cognitive impairments. Developmental timing of cancer and treatment was a key determinant of outcome. Family functioning, school reintegration support, and broader social environments emerged as important moderators of resilience. Conclusions: CCSs face complex, interrelated cognitive and emotional challenges that warrant early identification and ongoing, developmentally tailored intervention. Integrated approaches combining cognitive remediation and psychosocial support appear most effective. Future research should prioritize longitudinal designs, multi-informant assessments, and culturally sensitive frameworks to inform targeted prevention and rehabilitation strategies. Our synthesis highlights that deficits in processing speed and working memory are most pronounced following CNS-directed therapies during early developmental stages, whereas emotional vulnerabilities such as anxiety and social withdrawal often emerge later in adolescence. Interventions combining cognitive remediation, targeted psychosocial support, and structured school reintegration show the strongest evidence for improving adaptive outcomes. Coordinated survivorship care across healthcare, educational, and family systems is essential to sustain developmental recovery. Full article

Treatment options for major depression are limited: only about one-third of patients achieve remission with first line treatments with no established predictive markers. Parameters associated with treatment refractory depression, including metabolic markers (increased BMI, increased triglyceride levels), inflammation markers (C-reactive protein, CRP), autonomic disturbances (reduced blood pressure, reduced heart rate variability), and brain morphology changes (increased volume of the choroid plexus and brain ventricle volumes), may serve such purpose. These features can be linked mechanistically to an increase in aldosterone plasma concentration due to a reduced mineralocorticoid receptor (MR) sensitivity. The primary CNS target of aldosterone is the nucleus of the solitary tract (NTS), which is also the entry point of the vagus nerve. This nucleus integrates signals from endocrine, inflammatory, chemoreceptive, and physiological parameters, including blood pressure. In search of a mechanism to overcome this pathology, we identified a molecule which is derived from the licorice plant glycyrrhiza glabra, namely glycyrrhizin and its biologically active metabolite enoxolone. These molecules potentially reverse the above-described pathology. They inhibit the enzyme 11beta hydroxysteroid-dehydrogenase type 2 (11betaHSD2) and the toll-like receptor 4 (TLR4). 11betaHSD2 regulates the activity of the mineralocorticoid receptor (MR) by degrading cortisol/corticosterone, which allows aldosterone to bind to the MR. TLR4 is the ligand for lipopolysaccharide (LPS, endotoxin) and trigger of innate immunity. Consequently, patients with increased inflammation markers, increased aldosterone, or low blood pressure may preferentially benefit from the treatment with glycyrrhizin/enoxolone. Importantly, these patients can be identified BEFORE treatment is initiated. Clinically, patients sharing these biological indicators are primarily young females or patients with a history of childhood trauma. A combination of enoxolone with standard antidepressants may therefore avoid a trial-and-error approach and allow to achieve recovery faster. Full article

γ-aminobutyric acid (GABA), the primary inhibitory neurotransmitter in the central nervous system (CNS), regulates neuronal excitability, synaptic plasticity, and oscillatory activity essential for cognition, emotion, and behavior. Disruptions in GABAergic signaling are increasingly recognized as key contributors to a range of neurodevelopmental disorders (NDDs), including schizophrenia (SZ), autism spectrum disorder (ASD), major depressive disorder (MDD), bipolar disorder (BD), and intellectual disability (ID). In this review, we analyze the data available from the literature concerning the components of the GABA pathway. We describe the main steps of GABA metabolism, including GABA synthesis and release, GABA receptors neurotransmission, GABA reuptake and catabolism, and evaluate their involvement in the pathogenesis of neurodevelopmental disorders. We suggest the possibility of existence of so far undescribed mechanisms which maintain the concentrations of GABA at a relatively physiological level when the function of glutamic acid decarboxylases is compromised by mutations. Searching for these mechanisms could be important for better understanding neurodevelopment and could give a clue for future searches for new therapeutic approaches for treating or alleviating the symptoms of BD and SZ. We also argue that the metabolic stage of the GABA pathway has only a minor direct effect on GABA signaling and rather causes clinical effects due to accumulation of neurotoxic byproducts. Full article

Maternal Immune Activation (MIA) is a phenomenon of pathophysiological stimulation of the maternal immune system during gestation which potentially leads to functional and structural disturbances of fetal neurogenesis. It occurs due to the alteration of paracrine signals between the maternal organism and the developing nervous system of the fetus. Any disturbances in the brain at embryonic and early postnatal stages might compromise its natural developmental trajectory, which could potentially increase the risk of developing neuropsychiatric disorders, such as schizophrenia, autistic spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), major depressive and bipolar disorders, etc. Presumably, all these conditions could initiate the development of age-related cognitive impairment in late ontogenesis, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and others. As the main immune cell population in the CNS, microglia both mediate its proper development and receive pathological stimuli from the maternal organism. This could lead to microglia premature activation and could become a part of the mechanisms of the fetal CNS development alterations. In this review, we discuss the role of prenatal activation of microglia in neuropsychiatric disorders and neurodegenerative disease development. We highlight approaches to modeling MIA, as well as sex differences in the morphological and functional state of microglia in the context of physiological conditions. There is a hypothesis discussed regarding the contribution of these distinctions to neuropsychiatric disorders and neurodegenerative disease incidence, prevalence, and progression in males and females. Full article

Background/Objectives: Neuropsychiatric disorders such as Parkinson’s disease, depression, and Alzheimer’s disease are characterized by deficits in catecholaminergic neurotransmission. Conventional pharmacotherapies have several limitations, including poor blood–brain barrier permeability, rapid peripheral metabolism, systemic toxicity, and suboptimal brain bioavailability. This review evaluates nanoparticle-based strategies that can overcome these limitations by enhancing the delivery of catecholaminergic drugs to the central nervous system (CNS). Methods: A narrative synthesis was conducted based on a comprehensive review of research articles published by July 2025. Articles were retrieved from PubMed, Scopus, and Web of Science. The studies examined nanoformulations of catecholaminergic agents with a focus on CNS delivery, BBB penetration, toxicity, and therapeutic outcomes in neuropsychiatric disease models. Results: Evidence shows that nanoparticle platforms can stabilize drugs and extend their release time. They can also enable BBB penetration. These platforms reduce peripheral side effects and improve behavioral and neurochemical outcomes in preclinical models. Conclusions: Nanoparticles are a promising strategy for optimizing pharmacotherapy for CNS disorders associated with catecholamine deficiencies. However, more research is needed on their long-term safety, bioaccumulation, and clinical feasibility before they can be widely adopted. Full article

Alzheimer’s disease (AD) and major depressive disorder (MDD) are prevalent central nervous system (CNS) disorders that share overlapping symptoms but differ in underlying molecular mechanisms. Distinguishing these mechanisms is essential for developing targeted diagnostic and therapeutic strategies. In this study, we integrated multi-tissue transcriptomic datasets from brain and peripheral samples to identify differentially expressed microRNAs (miRNAs) in AD and MDD. Functional enrichment analyses (KEGG, GO) revealed that dysregulated miRNAs in AD were associated with MAPK, PI3K–Akt, Ras, and PD-1/PD-L1 signaling, pathways linked to synaptic plasticity, neuroinflammation, and immune regulation. In contrast, MDD-associated miRNAs showed enrichment in Hippo signaling and ubiquitin-mediated proteolysis, implicating altered neurogenesis and protein homeostasis. Network analysis highlighted key disease- and tissue-specific miRNAs, notably hsa-miR-1202 and hsa-miR-24-3p, with potential roles in neuronal survival and molecular network regulation. These findings suggest that miRNAs may serve as non-invasive biomarkers for diagnosis, prognosis, and treatment monitoring in both disorders. While therapeutic targeting of miRNAs offers promise, challenges such as blood–brain barrier penetration and tissue-specific delivery remain. This integrative approach provides a translational framework for advancing miRNA-based strategies in CNS disease research. Full article

The renin-angiotensin system (RAS) has evolved from being considered solely a peripheral endocrine system for cardiovascular control to being recognized as a complex molecular network with important functions in the central nervous system (CNS) and peripheral nervous system (PNS). Here we examine the organization, mechanisms of action, and clinical implications of cerebral RAS in physiological conditions and in various neurological pathologies. The cerebral RAS operates autonomously, synthesizing its main components locally due to restrictions imposed by the blood–brain barrier. The key elements of the system are (pro)renin; (pro)renin receptor (PRR); angiotensinogen; angiotensin-converting enzyme types 1 and 2 (ACE1 and ACE2); angiotensin I (AngI), angiotensin II (AngII), angiotensin III (AngIII), angiotensin IV (AngIV), angiotensin A (AngA), and angiotensin 1-7 (Ang(1-7)) peptides; RAS-regulating aminopeptidases; and AT1 (AT1R), AT2 (AT2R), AT4 (AT4R/IRAP), and Mas (MasR) receptors. More recently, alamandine and its MrgD receptor have been included. They are distributed in specific brain regions such as the hypothalamus, hippocampus, cerebral cortex, and brainstem. The system is organized into two opposing axes: the classical axis (renin/ACE1/AngII/AT1R) with vasoconstrictive, proinflammatory, and prooxidative effects, and the alternative axes AngII/AT2R, AngIV/AT4R/IRAP, ACE2/Ang(1-7)/MasR and alamandine/MrgD receptor, with vasodilatory, anti-inflammatory, and neuroprotective properties. This functional duality allows us to understand its role in neurological physiopathology. RAS dysregulation is implicated in multiple neurodegenerative diseases, including Alzheimer’s disease (AD), Parkinson’s disease (PD), and neuropsychiatric disorders such as depression and anxiety. In brain aging, an imbalance toward hyperactivation of the renin/ACE1/AngII/AT1R axis is observed, contributing to cognitive impairment and neuroinflammation. Epidemiological studies and clinical trials have shown that pharmacological modulation of the RAS using ACE inhibitors (ACEIs) and AT1R antagonists (ARA-II) not only controls blood pressure but also offers neuroprotective benefits, reducing the incidence of cognitive decline and dementia. These effects are attributed to direct mechanisms on the CNS, including reduction of oxidative stress, decreased neuroinflammation, and improved cerebral blood flow. Full article

B-raf (rapidly accelerated fibrosarcoma) is a crucial player within the ERK/MAPK signaling pathway. In the CNS, B-raf has been implicated in neuronal differentiation, long-term memory, and major depression. Mice with forebrain neuron-specific B-raf knockout show behavioral deficits in spatial learning tasks and impaired hippocampal long-term potentiation (LTP). To elucidate the mechanism(s) underlying diminished synaptic plasticity in B-raf-deficient mice, we performed whole-cell recordings from CA1 pyramidal cells in hippocampal slices of control and B-raf mutant mice. We found that the NMDA/AMPA ratio of excitatory postsynaptic currents (EPSCs) at the Schaffer collateral—CA1 pyramidal cell synapses was significantly reduced in B-raf mutants, which would at least partially account for their impaired LTP. Interestingly, the reduced NMDA component of field postsynaptic potentials in mutant preparations was partially reinstated by blocking the apamin-sensitive small-conductance Ca²⁺-activated K⁺ (SK) channels, which have also been reported to modulate hippocampal LTP and learning tasks. To determine the impact of B-raf-dependent signaling on SK current, we isolated the apamin-sensitive tail current after a strong depolarizing event and found indeed a significantly bigger SK current in B-raf-deficient cells compared to controls, which is consistent with the reduced action potential firing and the stronger facilitating effect of apamin on CA1 somatic excitability in B-raf-mutant hippocampus. Our data suggest that B-raf signaling readjusts the delicate balance between NMDA receptors and SK channels to promote synaptic plasticity and facilitate hippocampal learning and memory. Full article

Calcium channel blockers (CCBs), originally developed for cardiovascular indications, have gained attention for their therapeutic potential in neuropsychiatric, endocrine, and pain-related disorders. In neuropsychiatry, nimodipine and isradipine, both L-type CCBs, show mood-stabilizing and neuroprotective effects, with possible benefits in depression, bipolar disorder, and schizophrenia. In endocrinology, verapamil, a non-dihydropyridine L-type blocker, has been associated with the preservation of pancreatic β-cell function and reduced insulin dependence in diabetes. CCBs may also aid in managing primary aldosteronism and pheochromocytoma, particularly in patients with calcium signaling mutations. In pain medicine, α2δ ligands and selective blockers of N-type and T-type channels demonstrate efficacy in neuropathic and inflammatory pain. However, their broader use is limited by challenges in central nervous system (CNS) penetration, off-target effects, and heterogeneous trial outcomes. Future research should focus on pharmacogenetic stratification, novel delivery platforms, and combination strategies to optimize repurposing of CCBs across disciplines. Full article

The Aptian–Albian interval represents a significant cooling phase within the Cretaceous “hothouse” climate, marked by dynamic climatic fluctuations. High-resolution continental records are essential for reconstructing terrestrial climate and ecosystem evolution during this period. This study examines a lacustrine-dominated succession of the Shahezi Formation (Lishu Rift Depression, Songliao Basin, NE Asia) to access paleo-weathering intensity and paleoclimate variability between the Middle Aptian and Early Albian (c. 118.2–112.3 Ma). Multiple geochemical proxies, including the Chemical Index of Alteration (CIA), were applied within a sequence stratigraphic framework covering four stages of lake evolution. Our results indicate that a hot and humid subtropical climate predominated in the Lishu paleo-lake, punctuated by transient cooling and drying events. Periods of lake expansion corresponded to episodes of intense chemical weathering, while two distinct intervals of aridity and cooling coincided with phases of a reduced lake level and fan delta progradation. To address the impact of potassium enrichment on CIA values, we introduced a rectangular coordinate system on A(Al₂O₃)-CN(CaO* + Na₂O)-K(K₂O) ternary diagrams, enabling more accurate weathering trends and CIA corrections (CIA_corr). Uncertainties in CIA correction were evaluated by integrating geochemical and petrographic evidence from deposits affected by hydrothermal fluids and external potassium addition. Importantly, our results show that metasomatic potassium addition cannot be reliably inferred solely from deviations in A-CN-K diagrams or the presence of authigenic illite and altered plagioclase. Calculations of “excess K₂O” and CIA_corr values should only be made when supported by robust geochemical and petrographic evidence for external potassium enrichment. This work advances lacustrine paleoclimate reconstruction methodology and highlights the need for careful interpretation of weathering proxies in complex sedimentary systems. Full article

Background/Objectives: Dimethyl trisulfide (DMTS) is a naturally occurring polysulfide with known antioxidant and neuroprotective properties. DMTS is a lipophilic transient receptor potential ankyrin 1 (TRPA1) ligand that reaches the central nervous system (CNS). Its role in the CNS, particularly regarding depression-like behaviour, has yet to be explored. This study investigates the influence of DMTS on stress responses and whether this effect is mediated through the TRPA1 ion channel, known for its role in stress adaptation. Using a mouse model involving three-week exposure, we examined the impact of DMTS on depression-like behaviour and anxiety and identified the involved brain regions. Methods: Our methods involved testing both Trpa1-wild-type and gene-knockout mice under CUMS conditions and DMTS treatment. DMTS was administered intraperitoneally at a dose of 30 mg/kg on days 16 and 20 of the 21-day CUMS protocol—in hourly injections seven times to ensure sustained exposure. Various behavioural assessments—including the open field, marble burying, tail suspension, forced swim, and sucrose preference tests—were performed to evaluate anxiety and depression-like behaviour. Additionally, we measured body weight changes and the relative weights of the thymus and adrenal glands, while serum levels of corticosterone and adrenocorticotropic hormone were quantified via ELISA. FOSB (FBJ murine osteosarcoma viral oncogene homolog B) immunohistochemistry was utilised to assess chronic neuronal activation in stress-relevant brain areas. Results: Results showed that CUMS induces depression-like behaviour, with the response being modulated by the TRPA1 status and that DMTS treatment significantly reduced these effects when TRPA1 channels were functional. DMTS also mitigated thymus involution due to hypothalamic–pituitary–adrenal (HPA) axis dysregulation. Conclusions: Overall, DMTS appears to relieve depressive and anxiety symptoms through TRPA1-mediated pathways, suggesting its potential as a dietary supplement or adjunct therapy for depression and anxiety. Full article