Molecular Neurobiology最新文献

Lithium is the most commonly used medicine to treat bipolar disorder (BD). It is considered a mood regulator, and the mechanisms underlying this effect still need to be elucidated. Some modulations are involved in neuroprotection, including neuronal communication, neuron differentiation and survival, synaptic modulation and plasticity, modulation of cognition, contribution to antioxidant defense, and reduction of inflammation, glial dysfunction, and apoptosis. In general, about 50% of the concentrations in serum are in the brain. However, it is essential to note that many gene expression differences influence the concentrations and actions of individuals. This review discusses the various mechanisms of lithium in BD I and II, its effects on neurotransmitters and receptors, the hypothalamic-pituitary-adrenal (HPA) axis, inflammation and neuroinflammation, immune functions, oxidative and nitrosative stress, mitochondrial respiratory chain function, intracellular signaling, and brain plasticity, as well as toxicity and side effects.

This study is the first to comprehensively explore both intracellular and computational mechanisms through which Neuropeptide S (NPS) protects against paraquat-induced dopaminergic toxicity in a Parkinson's disease (PD)-like SH-SY5Y cell model. Paraquat induces oxidative stress, mitochondrial dysfunction, and dopaminergic neuron loss, mimicking key PD features. Bioinformatic analyses, including Reactome pathway mapping and molecular docking, confirmed a high-affinity interaction between NPS and its receptor NPSR1, activating GPCR-associated signaling. NPS treatment restored intracellular dopamine and ATP levels and increased tyrosine hydroxylase (TH) and vesicular monoamine transporter 2 (VMAT) expression. Cell viability was assessed using the MTT assay, while dopamine levels were measured via LC-MS/MS. p-ERK1/2, total ERK1/2, and Nrf2 were quantified by ELISA and western blot. Oxidative stress markers, including TBARS, MAO-A, MAO-B, and COMT, were analyzed by ELISA. Gene expression of Bax, Bcl-2, Caspase-3, Caspase-8, DAT, and VMAT was evaluated by qRT-PCR. TH, c-Fos, and NPSR1 were visualized using immunofluorescence. NPS significantly improved cell viability and restored ATP levels compromised by paraquat exposure. It also reduced TBARS, MAO-B, and COMT levels, reversed paraquat-induced ERK1/2 phosphorylation, and restored Nrf2 and MAO-A expression. Additionally, NPS upregulated the anti-apoptotic marker Bcl-2. Most of these protective effects were abolished in the presence of the NPSR antagonist ML154, indicating a receptor-mediated mechanism of action. In conclusion, NPS was found to attenuate oxidative stress, support mitochondrial and dopaminergic function, and influence apoptosis-related signaling in our cellular model. These findings suggest that targeting the NPS/NPSR1 system may hold therapeutic potential in neurodegenerative diseases such as PD, warranting further in vivo validation.

Astrocytes are central regulators of neural homeostasis, synaptic function, and neuroinflammatory responses in the central nervous system (CNS). Upon pathological stimuli, astrocytes undergo reactive transformations, producing pro-inflammatory cytokines, reactive oxygen species (ROS), and chemokines, which exacerbate neuronal injury. Flavonoids, a diverse class of polyphenolic compounds found in fruits, vegetables, and medicinal plants, have emerged as potent modulators of astrocyte activity, promoting neuroprotection and cognitive enhancement. These compounds, including quercetin, hesperetin, rutin, casticin, and anthocyanins, attenuate astrocyte-mediated neuroinflammation by suppressing NF-κB, MAPK, TLR, and NLRP3 inflammasome signaling while activating antioxidant pathways such as Nrf2 and PI3K/Akt. Flavonoid-mediated modulation also enhances the synthesis and release of neurotrophic factors, including BDNF, GDNF, NGF, and TGF-β1, which support synaptic plasticity, dendritic spine formation, and network connectivity. By preserving astrocytic homeostasis, reducing gliosis, and regulating astrocyte-microglia crosstalk, flavonoids mitigate cytokine-mediated neuronal damage, restore synaptic integrity, and improve learning and memory in models of neurodegeneration, ischemia, and neuroinflammation. Preclinical evidence suggests that flavonoids can cross the blood-brain barrier, exhibit low toxicity, and synergize with other neuroprotective interventions. Understanding the molecular mechanisms of flavonoid-astrocyte interactions provides insight into precision therapeutic strategies aimed at alleviating neuroinflammation and enhancing CNS resilience, offering promising avenues for the prevention and treatment of cognitive and neurodegenerative disorders.

Microplastic (MPs) pollution is widespread in the environment and poses growing risks to food safety and human health. In a 60-day oral exposure study, male Swiss mice received MPs (10 mg/kg b.wt), and the neuroprotective potential of taurine (Tau, 200 mg/kg b.wt) was evaluated. MPs exposure induced pronounced anxiety-like behavior, evidenced by increased peripheral zone activity in the open field test (+ 81.1%) and elevated anxiety index in the elevated plus maze (+ 75.9%), along with significant memory and spatial learning impairments in the Y-maze (increased trials + 31.6% and latency + 75.2%). Neurochemically, MPs increased acetylcholinesterase (AChE) activity (+ 89.4%) while reducing dopamine (-29.4%) and γ-aminobutyric acid (GABA) (-17.9%) levels. MPs also triggered marked oxidative stress, as shown by elevated reactive oxygen species (+ 107.6%) and malondialdehyde (+ 249.0%), accompanied by reduced total antioxidant capacity (-26.2%). At the molecular level, MPs downregulated CREB1 (-82.2%) and BDNF (-80.2%) while markedly upregulating AKT1 (~ fivefold) and pro-inflammatory cytokines (TNF-α, IL-6, CXCL-10, and IL-1β; 5.2-7.2-fold). Histopathological analysis revealed severe neurodegenerative alterations across the cerebrum, hippocampus, and cerebellum. Tau co-treatment significantly ameliorated MPs' induced neurotoxicity by reducing anxiety and memory deficits, lowering AChE activity (- 17.3%), restoring dopamine (+ 28.8%) and GABA (+ 14.2%) levels, attenuating oxidative stress (ROS -45.4% and MDA -44.7%), suppressing inflammatory gene expression (-51.0 to -68.1%), and partially normalizing CREB1 and BDNF expression (+239% and +240%, respectively). Collectively, these findings identify Tau as a promising natural neuroprotective agent against MPs' induced neurotoxicity.

Gulf War Illness (GWI) is a chronic, multi-system condition affecting a substantial proportion of veterans deployed during the 1990-1991 Gulf War. Neurological complications, including cognitive impairment, musculoskeletal pain, fatigue, depression, and migraine, represent a major clinical burden. Evidence implicates neuroinflammation, oxidative stress, mitochondrial dysfunction, and epigenetic dysregulation as central mechanisms, with emerging data suggesting early tauopathy and sex-specific immune responses. Neuroimaging studies reveal hippocampal atrophy, white matter disruptions, and increased translocator protein (TSPO) binding, while biomarker analyses identify elevated C-reactive protein (CRP), leptin, and matrix metalloproteinases. Genetic factors, such as HLA alleles, may modulate susceptibility. Animal models corroborate these findings, demonstrating hippocampal dysfunction, neurotransmitter imbalance, and neuroimmune activation following exposure to Gulf War-related chemicals. Therapeutic evidence supports cognitive behavioral therapy (CBT), exercise, and mindfulness-based interventions, with ongoing trials exploring vagus nerve stimulation, anti-inflammatory agents, and mitochondrial-targeted therapies. This review synthesizes current knowledge on GWI-related neurological dysfunction, highlights diagnostic and therapeutic advances, and underscores the need for biomarker-driven, sex-specific, and personalized approaches to improve outcomes for affected veterans.

mRNA translational repression by eukaryotic initiation factor 4E-binding proteins (4E-BPs), plays a critical role in synaptic plasticity and the formation of long-term memory (LTM). Among the three 4E-BP paralogs, 4E-BP2 is the predominant form expressed in neurons, and its full-body deletion in mice causes memory deficits. Mice lacking 4E-BP2 in GABAergic inhibitory interneurons, but not excitatory neurons, display autistic-like behaviors and deficits in object location and recognition. The specific mRNAs translationally regulated by 4E-BP2 in GABAergic interneurons, and how they contribute to spatial and associative memory, are unknown. Here, we show that conditional knockout (cKO) mice lacking 4E-BP2 selectively in GABAergic interneurons exhibit impairments in long-term spatial and contextual fear memory formation. We further demonstrate that 4E-BP2 deletion controls the translation of selective mRNAs in interneurons without increasing general protein synthesis. One of the mRNAs is Gal, which encodes a neuropeptide that modulates memory. Our findings provide evidence that 4E-BP2 selectively controls the translation of a subset of mRNAs in inhibitory neurons that are required for LTM formation.

Damage following ischemic stroke is worsened by microglial activation and subsequent neuroinflammation. Polypyrimidine tract binding protein 2 (Ptbp2) can influence the chemotaxis and repolarization of cancer-related macrophages; however, its specific role in microglial polarization and the underlying mechanisms are not yet fully understood. This study aimed to elucidate the neuroprotective mechanisms of Ptbp2 and examine its effects on microglial activation, neuroinflammation, and glucose metabolism following cerebral ischemia. Mice model of ischemic stroke was developed using temporary middle cerebral artery occlusion (tMCAO). Adeno-associated viruses were used for overexpression and knockdown in C57 mice, and microglial polarization, blood-brain barrier (BBB) integrity, and glycolytic parameters in the peri-infarct cortex were evaluated. RNA sequencing (RNA-seq) was performed on mouse brain tissues. To investigate the underlying mechanisms, the mouse brain microvascular endothelial cell line bEnd.3 and BV2 microglial cell line were used. The protective effect of Ptbp2 on BBB integrity following stroke was evaluated by targeted overexpression and knockdown. We found that Ptbp2 overexpression reduced microglia-mediated neuroinflammation and BBB damage while inhibiting pathological glycolysis, according to findings from both in vitro and in vivo studies. Additionally, Ptbp2 level was significantly downregulated in patients with stroke compared to controls, and was inversely correlated with the severity of neural impairment. Our study unveils novel immunomodulatory mechanisms in stroke and highlights Ptbp2 and its regulatory network as potential therapeutic targets for stroke.

Spinal cord injuries (SCI) are associated with significant physical and economic burdens on individuals and healthcare systems. Research has shown that several molecular and cellular interactions significantly contribute to SCI progression. The initiation and development of SCI are strongly linked to cellular stress mechanisms, notably those associated with the endoplasmic reticulum (ER), which gives rise to the unfolded protein response (UPR). This systematic review discusses the molecular pathways involved in ER stress, particularly the role of the activating transcription factor 6 (ATF6)-mediated apoptosis pathway and the role of CCAAT/enhancer-binding homologous protein (CHOP) in SCI pathogenesis. Prolonged ER stress exacerbates neuronal degeneration and apoptosis, making it a key factor in SCI. Efforts to inhibit this pathway via genetic or pharmacological interventions have shown potential in addressing cellular dysfunction and preventing SCI-related degeneration. Moreover, pharmacological approaches that mitigate ER stress, for example, by promoting protein folding, are promising for enhancing neuronal survival and reducing damage after SCI. Complementary strategies, such as maintaining metabolic health and engaging in physical activity, could also help fortify the spinal cord against ER stress-related damage. These preventive and therapeutic approaches underscore the importance of targeting ER stress to minimize SCI onset and progression, offering valuable insights for improved care and recovery.