Search Results (86)

Hericium erinaceus (H. erinaceus), a medicinal mushroom, is a source of bioactive compounds with demonstrated neuroprotective potential. This activity is primarily attributed to two distinct classes of compounds: erinacines from the mycelium, which potently induce the synthesis of neurotrophins, protein growth factors essential for neuronal survival and health, and hericenones from the fruiting body, which subsequently appear to enhance or potentiate neurotrophin-activated signaling pathways. Preclinical evidence substantiates their ability to enhance neurotrophin levels, particularly Nerve Growth Factor (NGF) and Brain-Derived Neurotrophic Factor (BDNF), and activate their cognate Trk receptors. Activation of these pathways, including PI3K/AKT/mTOR and MAPK/ERK, converges on transcription factors such as CREB, promoting neuronal survival, neurite outgrowth, and synaptic plasticity. However, the precise molecular mechanisms linking these small molecules to the complex orchestration of neurotrophic gene expression remain incompletely defined. This review synthesizes current knowledge of the neurotrophic pharmacology of H. erinaceus bioactives and proposes a novel framework suggesting that non-coding RNAs (ncRNAs) play a key regulatory role. We hypothesize that hericenones and erinacines modulate key transcriptional hubs, such as CREB, Nrf2, and NF-κB, which in turn regulate the expression of specific ncRNAs (e.g., miR-132, miR-146a) known to control neurogenesis, synaptogenesis, oxidative stress, and neuroinflammation. This ncRNA-mediated mechanism may represent an un-explored axis that explains the pleiotropic neuroprotective effects of these compounds. We critically appraise the existing preclinical evidence, identify significant methodological limitations and translational gaps, and propose a structured research roadmap to test these ncRNA-centric hypotheses, aiming to accelerate the rational development of H. erinaceus-derived compounds for neurodegenerative diseases. Full article

Background/Objectives: Ischemic stroke is a leading cause of death and disability, and neuroprotection therapies, or those that increase recovery, are not available. While the garlic-derived bioactive compound S-allyl cysteine (SAC) has shown neuroprotective properties, its subacute long-term effects remain underexplored, particularly in females. Methods: We evaluated whether SAC supports functional recovery after ischemia/reperfusion (IR), focusing on neurotrophin signaling, tropomyosin receptor kinase B (TrkB), protein kinase B (AKT), and extracellular signal-regulated kinase (ERK). Adult female Wistar rats underwent 1 h of ischemia and 15 days of reperfusion. SAC (100 mg/kg, i.p.) was administered at the onset of reperfusion and daily for 15 days. Motor and cognitive deficit tests were performed. Infarct area, Ki67, brain-derived neurotrophic factor (BDNF), vascular endothelial growth factor (VEGF), nerve growth factor (NGF), pTrkB, pAKT, and pERK levels were quantified in the cortex, striatum, and hippocampus. Results: MicroPET analysis revealed comparable glucose uptake between the IR and IR + SAC groups, indicating similar ischemic severity. SAC reduced infarct area (54.7%) and significantly improved motor deficits (53.9%), circling behavior (38.9%), and long-term memory compared with ischemia/reperfusion (IR) animals. SAC increased the proportion of Ki67-positive cells (4.3-fold in the cortex and 1.8-fold in the striatum) and enhanced neurotrophin levels, NGF (cortex), BDNF (cortex and striatum), VEGF (striatum), pTrkB, pAKT, and pERK (cortex and striatum). Conclusions: SAC supports post-ischemic recovery, improving motor performance and preserving long-term recognition memory, effects that could be associated with increased cell proliferation, neurotrophin levels, and activation of the TrkB, AKT, and ERK pathways. Full article

Olive pomace (OP), a by-product of olive oil production, is a sustainable resource rich in bioactive compounds with potential applications in cosmetics and pharmaceuticals. This study investigates the protective effects of olive pomace juice (OPJ) against H₂O₂-induced neuronal damage and LPS-induced inflammatory responses in HT22 and BV2 cells, respectively. OPJ suppressed H₂O₂-induced cell death and exerted anti-apoptotic effects by reducing the BAX/BCL2 ratio and caspase-3 cleavage. OPJ also mitigated neurodegenerative hallmarks by decreasing amyloid fibrils formation and inhibiting β-secretase and acetylcholinesterase (AChE) activity. Mechanistically, OPJ enhanced antioxidant response by upregulating Nrf2 and its downstream molecule HO-1, along with increasing mRNA levels of antioxidant enzymes, including catalase, SOD1, and GPx. OPJ further activated AMPKα–SIRT1–PGC1α signaling and CREB–BDNF–TrkB signaling, suggesting modulation of key antioxidant, anti-apoptotic, and neurotrophic pathways. In BV2 cells, OPJ downregulated pro-inflammatory cytokines (IL-6 and IL-1β) and decreased iNOS and COX-2 expression through suppression of NF-κB and MAPK signaling pathways. HPLC analysis identified hydroxytyrosol (10.92%) as the major active compound in OPJ, which compared with tyrosol (2.18%), and hydroxytyrosol exhibited greater neuroprotective and anti-inflammatory effects than tyrosol. This study highlights the potential of OPJ and its major compound, hydroxytyrosol, as functional agents for mitigating neurodegeneration-related cellular response, supporting its application in the food and pharmaceutical industries. Full article

Brain-derived growth factor, BDNF, has critical roles in a wide variety of neuronal aspects, including cell survival, differentiation, and synaptic function after their maturation. TrkB, a high-affinity receptor for BDNF, is a major contributor in these neuronal aspects, and its functions are exerted via stimulating intracellular signaling pathways including the mitogen-activated protein kinase (MAPK) pathways. As a family of MAPKs, the functions of ERK1/2, p38MAPK, and JNKs have been extensively studied using in vivo and in vitro neuronal systems. ERK 1/2, a major serine-threonine kinase and belonging to the MAPK family, also works as a downstream molecule after activation of the BDNF/TrkB system. Interestingly, growing evidence has demonstrated that ERK1/2 signaling exerts a positive or negative influence on neurons in both healthy and pathological conditions in the central nervous system (CNS). Indeed, activation of ERK 1/2 stimulated by the BDNF/TrkB system is involved in the regulation of synaptic plasticity. On the other hand, overactivation of ERK1/2 signaling under pathological conditions is closely related to neurodegeneration. Furthermore, cell stress activates p38MAPKs and JNK signaling, contributing to the progression of neurodegeneration. In this review, we show how MAPK pathway signaling affects neuronal fate, including cell survival or cell death, in the CNS. Moreover, we discuss the involvement of overactivation of MAPK signaling in the neurodegeneration observed in Alzheimer’s disease (AD), Parkinson’s disease (PD), and Huntington’s disease (HD). Full article

Fine particulate matter (PM_2.5), which contains heavy metals such as Al, Fe, Mg, and Mn, among others, induces cognitive dysfunction through oxidative stress, neuroinflammation, and impaired mitochondria. This study evaluated the neuroprotective effects of a 40% ethanol extract of Polygonum multiflorum (EPM) on PM_2.5-induced cognitive dysfunction in a mouse model. Behavioral assessments demonstrated attenuated learning and memory impairment following EPM treatment. Redox homeostasis was restored through increased expression of superoxide dismutase (SOD) and glutathione (GSH) and decreased levels of malondialdehyde (MDA) and mitochondrial reactive oxygen species (mtROS) in the EPM group. Mitochondrial function was attenuated, as indicated by recovery of mitochondrial membrane potential and ATP levels. EPM inhibited neuroinflammation by downregulating the TLR4-MyD88-NF-κB pathway and maintaining blood–brain barrier integrity through the upregulation of tight junction proteins. It modulated neuronal apoptosis through the JNK pathway, reducing the accumulation of amyloid-beta and phosphorylated tau. Synaptic plasticity was preserved through upregulation of BDNF/TrkB signaling and cholinergic neurotransmission via regulation of acetylcholine (ACh), acetylcholinesterase (AChE), and choline acetyltransferase (ChAT). To standardize EPM, high-performance liquid chromatography (HPLC) confirmed the presence of the bioactive compound, tetrahydroxystilbene glucoside (TSG). These findings suggest that EPM may be a promising functional food candidate for mitigating PM_2.5-related cognitive impairments. Full article

Non-invasive brain stimulation (NIBS) techniques—including repetitive transcranial magnetic stimulation (rTMS), theta-burst stimulation (TBS), paired associative stimulation (PAS), transcranial direct current stimulation (tDCS), and transcranial alternating current stimulation (tACS)—have emerged as valuable tools for modulating neural activity and promoting plasticity. Traditionally, their effects have been interpreted within a binary framework of long-term potentiation (LTP)-like and long-term depression (LTD)-like plasticity, largely inferred from changes in motor evoked potentials (MEPs). However, existing models do not fully capture the complexity of the biological processes engaged by these techniques and despite extensive clinical application, the cellular and molecular mechanisms underlying NIBS remain only partially understood. This systematic review, conducted in accordance with the PRISMA 2020 guidelines, synthesizes evidence from in vivo, in vitro, and ex vivo studies to delineate how NIBS influences neurotransmission through intracellular signaling, gene expression, and protein synthesis at the cellular level. Emphasis is placed on the roles of classical synaptic models, grounded in Ca²⁺-dependent glutamatergic signaling and receptor phosphorylation dynamics, as well as broader forms of plasticity involving BDNF–TrkB signaling, epigenetic modifications, neuroimmune and glial interactions, anti-inflammatory pathways, and apoptosis- and survival-related cascades. By integrating findings in humans with those in animal and cellular models, we identify both shared and technique-specific molecular mechanisms underlying NIBS-induced effects, highlighting emerging evidence for multi-pathway, non-binary plasticity mechanisms. Understanding these convergent pathways provides a mechanistic foundation for refining stimulation paradigms and improving their translational relevance for treatment of neurological and psychiatric disorders. Full article

The substantial interest in plant-based drugs or plant-derived phytocompounds drives researchers to conduct comprehensive investigations on their therapeutic properties. Mollugin, one of the major active constituents of Rubia cardifolia, has been well-studied for its pharmacological properties, demonstrating potent anti-inflammatory properties by suppressing the TAK-1-mediated activation of NF-κB/MAPK and enhancing the Nrf2/HO-1-mediated antioxidant response. It exhibits strong anticancer effects through ferroptosis via IGF2BP3/GPX4 pathways, induces mitochondrial apoptosis, and targets NF-κB, ERK, and PI3K/Akt/mTOR to suppress tumor progression. Mollugin also inhibits JAK2/STAT and PARP1 pathways, suppressing IL-1β expression via the modulation of ZFP91. Moreover, it regulates the MAPK/p38 pathway, promotes neuroprotection, and improves cognitive performance through GLP-1 receptor activation. Mollugin promotes osteogenesis by activating the BMP-2/Smad1/5/8 signaling pathway and downregulates MAPK, Akt, and GSK3β expression, leading to the inhibition of osteoclastogenesis. It overcomes multidrug resistance by downregulating MDR1/P-gp, CREB, NF-κB, and COX-2 through AMPK activation. Its antibacterial effect is mediated by strong binding to FUR, UDP, and IpxB proteins in Enterobacter xiangfangensis. Mollugin mitigates Klebsiella pneumoniae infection, suppresses adipogenesis without causing cytotoxicity, and protects endothelial cells via the BDNF/TrkB-Akt signaling pathway. Synthetic derivatives of mollugin, such as oxomollugin and azamollugin, have shown enhanced anticancer and anti-inflammatory effects by regulating EGFR, PKM2, TLR4/MyD88/IRAK/TRAF6, and NF-κB/IRF3 pathways with improved solubility and stability. Collectively, these findings emphasize the broad-spectrum activity of mollugin. This review provides a critical interpretation of the mechanistic pathways regulated by mollugin and its derivatives, emphasizing their pharmacological significance and exploring their potential for future translation as multitarget drug candidates. Full article

Objective: Neuronal growth regulator 1 (Negr1) is a GPI-anchored neuronal cell adhesion molecule of the IgLON superfamily associated with multiple psychiatric disorders. This study aimed to investigate behavioral and molecular adaptations to social isolation (SI) stress in Negr1-deficient (Negr1^−/−) mice. Methods: Male and female Negr1^−/− and wild-type (Wt) mice (n = 10 per group) were exposed to two weeks of SI or group housing (Ctl). Behavioral assays assessed exploratory and anxiety-like behavior. Gene expression analyses in the prefrontal cortex and hippocampus were performed using RT-qPCR, focusing on GABAergic, neurotrophic, and IgLON family genes. Results: SI-induced weight loss in Negr1^−/− mice compared to Wt was evident in both sexes but more pronounced in males. Behaviorally, SI Wt males showed stress-induced hyperactivity compared to Ctl Wt, whereas SI Negr1^−/− males exhibited blunted exploratory behavior relative to SI Wt in the open field test (OFT). Negr1^−/− females showed reduced exploration in the elevated plus maze (EPM), suggesting increased anxiety. Hippocampal Pvalb was downregulated in SI Negr1^−/− mice of both sexes compared to Wts, with a stronger decrease in males, indicating heightened male vulnerability in GABAergic interneuron function. In males, SI reduced hippocampal Bdnf in both genotypes, whereas Ntrk2 (TrkB) upregulation occurred only in Negr1^−/− mice, suggesting a genotype-specific compensatory response. Hippocampal expression of Fgfr2 and IgLON members (Ntm1a/1b, Lsamp1a/1b) was increased in SI Negr1^−/− males compared to SI Wt, with minimal changes in females. Conclusions: Negr1 deficiency leads to sex-specific behavioral and molecular adaptations to social isolation stress, highlighting the role of Negr1 in modulating neurotrophic and GABAergic signaling pathways under adverse environmental conditions. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disease, characterized by the accumulation of amyloid beta (aβ) plaques and neurofibrillary tangles, along with progressive deterioration of cognitive function. AD is the most common form of dementia and affects over 55 million people worldwide. Current treatments for AD are symptomatic-based rather than curative, which calls for the development of new therapeutic strategies. Stem cell therapy has shown promising results for neurodegenerative diseases, including AD. Brain-derived neurotrophic factor (BDNF) and its receptor, tropomyosin receptor kinase B (TrkB), and their downstream signalling cascades play crucial role in modulating neuronal survival, development and synaptic plasticity, which are vital for cognitive functioning, and this pathway is dysregulated in AD. While the BDNF/TrkB signalling pathway dysregulation and stem cell therapy are each widely studied in AD, the interplay between those two remains underexplored. This review focuses on the mechanistic insights of the BDNF/TrkB signalling pathway in normal physiological condition and AD, along with the effects of stem cell therapy on the pathway and its downstream cascades. The findings highlight the therapeutic outcomes in increasing BDNF/TrkB levels and functions, restoring synaptic plasticity, modulating downstream substrates activities and improving cognitive functions. In addition, challenges, limitations and future directions of stem cell therapy are discussed, underscoring the therapeutic benefits of this therapy for AD by modulating the BDNF/TrkB signalling pathway. Full article

Background/Objectives: Baihe Dihuang Tang (BDT), a classical herbal formula from Zhang Zhongjing’s Han Dynasty work Jin Gui Yao Lue, is widely used to treat depressive disorder by nourishing Yin, clearing heat, and tonifying the heart and lungs. However, its pharmacological mechanisms remain unclear. This study aims to explore BDT’s antidepressant effects via MAOA-regulated serotonin (5-HT) metabolism and synaptic plasticity, supported by experimental validation, while using network pharmacology to predict MAOA-targeting active components. Methods: Active components and targets of BDT were screened using TCMSP, TCMID, and other databases, and then a component-target-pathway network was constructed. A chronic restraint stress (CRS)-induced depressive mouse model was established. Behavioral tests, including open field test (OFT), elevated plus maze (EPM), forced swimming test (FST) and tail suspension test (TST), were conducted to evaluate antidepressant effects. ELISA, qRT-PCR, and Western blot were employed to assess hippocampal 5-HT metabolism (MAOA, 5-HT/5-HIAA ratio) neurotrophic signaling (BDNF, TrkB) and synaptic plasticity-related proteins (PSD-95, SYN1). Results: BDT significantly reduced FST/TST immobility time and improved anxiety-like behaviors in OFT/EPM. BDT treatment downregulated MAOA expression, elevated hippocampal 5-HT/5-HIAA ratio, activated BDNF/TrkB pathway, and upregulated PSD-95/SYN1. Network pharmacology confirmed MAOA’s central role, identifying MAOA/serotonergic synapse modulation as BDT’s main mechanism and pinpointing Ferulic acid, Caffeate, Stigmasterol, (−)-nopinene, Eugenol, and cis-Anethol as MAOA-targeting bioactive components. Conclusions: BDT ameliorates depressive-like behaviors. This effect is mechanistically linked to suppression of MAOA-mediated 5-HT catabolism—a key validated target. This suppression elevates hippocampal 5-HT bioavailability, thereby activating BDNF/TrkB signaling and promoting synaptic plasticity. Network pharmacology confirmed MAOA as a primary target and identified specific modulatory bioactive components. Full article

Over the past two decades, immune–inflammatory dysregulation has emerged as a central paradigm in the biology of mood disorders. Patients with major depression (MDD) and bipolar disorder (BD) frequently display low-grade systemic inflammation. Elevated C-reactive protein (CRP), interleukin-6 (IL-6), and tumor necrosis factor-α (TNF-α) identify clinically relevant subgroups of patients characterized by greater severity, cognitive impairment, and poor treatment response. Changes in the gut microbiota and disruptions of the blood–brain barrier (BBB) act as important gateways through which systemic immune activity can influence the brain. At the intracellular level, pattern-recognition receptors activate convergent hubs including NF-κB, JAK/STAT, and MAPK cascades, while the NLRP3 inflammasome integrates mitochondrial dysfunction and oxidative stress with IL-1β release and pyroptosis. These pathways converge on glial dysregulation, impaired BDNF/TrkB signaling, and kynurenine pathway (KP) alterations, fostering excitotoxicity and synaptic deficits. Translational studies demonstrate that elevated CRP and IL-6 predict poor antidepressant outcomes. Anti-inflammatory agents such as infliximab and celecoxib show efficacy in specific subgroups of patients. Emerging multi-omics approaches identify immuno-metabolic biotypes, supporting the rationale for biomarker-guided stratification. These findings define an ‘inflammatory biotype’ of mood disorders and highlight the need for biomarkers and precision-based trials to guide treatment. Full article

Indoleamine 2,3-dioxygenase (IDO) activation by seizures elevates toxic tryptophan metabolites linked to seizure exacerbation. Brain-derived neurotrophic factor (BDNF)/tyrosine kinase B (TrkB) signaling, oxidative stress, and mitochondrial respiratory chain complex dysfunction contribute to temporal lobe epilepsy (TLE), but their regulatory links remain unclear. Male Kunming mice were grouped into Control, Control + 1-Methyl-DL-tryptophan (1-MT), TLE, and TLE + 1-MT. TLE was induced with 300 mg/kg pilocarpine. Two weeks after modeling, 1-MT (50 mg/kg) was administered twice daily for two weeks in 1-MT groups. Assessments included video monitoring to record seizure frequency and duration; Nissl and Fluoro-Jade B (FJB) staining to evaluate neuronal damage; real-time quantitative PCR (qRT-PCR) and Western blot to detect IDO, BDNF, and TrkB expression; assays for the following oxidative stress markers: malondialdehyde (MDA), glutathione (GSH), superoxide dismutase (SOD), catalase (CAT); and detection of mitochondrial complex I/IV activities. Results showed TLE mice had significantly increased IDO expression, BDNF/TrkB over-activation, elevated oxidative stress, impaired mitochondrial complex I/IV activities, severe neuronal damage, and increased seizure frequency/duration. 1-MT intervention reversed all these pathological changes, restoring levels to near-control status. This indicates IDO activation promotes TLE progression, which is associated with modulation of the BDNF/TrkB signaling pathway, exacerbation of oxidative stress, and impairment of mitochondrial complex I/IV activities—supporting IDO as a potential therapeutic target for TLE. Full article

Major depressive disorder (MDD) is a prevalent and disabling psychiatric condition with limited treatment options for patients who are resistant to conventional pharmacological and psychotherapeutic interventions. Stem cell (SC)-based therapies have emerged as a promising experimental approach, offering multifaceted mechanisms of action including neurogenesis, immunomodulation, antioxidative protection, and neuromodulation. This narrative review synthesizes current evidence from preclinical studies and early-phase clinical trials on the efficacy of mesenchymal stem cells (MSCs), neural stem cells (NSCs), and induced pluripotent stem cells (iPSCs) in alleviating depressive-like behaviors. Mechanistic insights include enhanced hippocampal neurogenesis, modulation of the brain-derived neurotrophic factor (BDNF)–TrkB pathway, attenuation of neuroinflammation through microglial polarization, and restoration of serotonergic signaling via peripheral-to-central pathways such as via the vagus nerve. In addition, the therapeutic potential of extracellular vesicles (EVs) and intranasal administration as non-invasive delivery strategies is discussed. While animal and first preclinical studies suggest potential benefit, significant translational barriers remain, including issues of scalability, long-term safety, and ethical considerations. Further rigorous studies are needed to validate stem-cell-based therapies as viable treatments for MDD. Full article

Apelin-13, a neuropeptide, has been recognized for its neuroprotective properties. Our previous study found apelin-13 improves cognitive function in Alzheimer’s disease (AD) rats by inhibiting neuroinflammation through upregulation of BDNF/TrkB signaling pathway. However, the precise mechanism by which apelin-13 modulates BDNF remains unclear. Thus, this study aimed to unravel the specific regulatory mechanism by which apelin-13 regulates BDNF. Bilaterally intracerebroventricular injection with Aβ25–35 was used to establish an in vivo model of AD. For the generation of METTL3 KO rats, the Crispr/Cas9 method was applied. PC12 cells were treated with Aβ25–35 to establish an in vitro model of AD. The cognitive function of the rats was evaluated with the Morris water maze and the novel object recognition test. Hippocampal damage and neuron loss were detected through H&E and immunofluorescent staining. METTL3, BDNF, TrkB, and p-TrkB were examined by Western blotting. Inflammation-related cytokines, IBA1, GFAP, IL-1β, and TNF-α were detected by Western blotting, immunofluorescent staining, ELISA, and qRT-PCR. m6A modification level was evaluated through MeRIP. A flow cytometer was applied to evaluate cell apoptosis. Cell proliferation was examined using MTT. m6A methylation inhibitor DAA reverses the improvement effect of apelin-13 on cognitive function, hippocampal nerve damage, neuron loss, and neuroinflammation in Aβ25–35-treated rats. Further results showed that apelin-13 upregulated METTL3, BDNF-AS m6A methylation, inhibited BDNF-AS expression, and subsequently upregulated BDNF/TrkB signaling pathway and reduced neuroinflammation in in vivo and in vitro AD models in a dose-dependent manner. Knockdown of METTL3 abolished apelin-13’s improvement effect in AD rats. Apelin-13-mediated upregulation of METTL3 enhances neuroinflammation inhibition and BDNF/TrkB signaling pathway via m6A-dependent downregulation of lncRNA BDNF-AS, thus ameliorating AD. Our study offers novel insights into the pathogenesis of AD and identifies potential drug targets for its treatment. Full article

Ionizing radiation (IR) as a stress inducer has a significant impact on various normal stem cells differentiation through activation of various signaling pathways. Low levels of oxidative stress of IR may preserve or even enhance cell differentiation. In response to IR, reactive oxygen species (ROS) can activate various signaling pathways that promote cell differentiation, notably through the involvement of nuclear factor erythroid 2–related factor 2 (NRF2). NRF2 interacts with multiple pathways, including Wnt/β-catenin (osteogenesis), PPARγ (adipogenesis), and BDNF/TrkB (neurogenesis). This response is dose-dependent: low doses of IR activate NRF2 and support differentiation, while high doses can overwhelm the antioxidant system, resulting in cell death. However, the quality of various types of IR, such as proton and carbon ion radiation, may have a varied impact on stem cells (SCs) differentiation compared to X-rays. Hence, activation of the NRF2 signaling pathway in SCs and cell differentiation depends on the level of stress and the quality and quantity of IR. This review is an update to explore how IR modulates SCs fate toward osteogenic, adipogenic, and neurogenic lineages through the NRF2 signaling pathway. We highlight mechanistic insights, dose-dependent effects, and therapeutic implications, bridging gaps between experimental models and clinical translation. Full article