Journal of Molecular Neuroscience最新文献

Microglia are resident macrophages within the central nervous system, serving as the first responders to neuroinflammation. Glucocorticoids (GCs) may cause damage to brain tissue, but the specific mechanism remains unclear. This study was divided into two parts: a glucocorticoid receptor (GR) mitochondrial translocation intervention experiment and a mitochondrial oxidative stress inhibition experiment. BV-2 microglia were stimulated with dexamethasone (DEX) and treated with either tubastatin-A or mitoquinone (MitoQ) for 24 h. Our results showed that DEX increased the translocation of GRs to mitochondria, and this effect was accompanied by decreases in the expression of mitochondrially encoded cytochrome c oxidase 1 (MT-CO1) and mitochondrially encoded cytochrome c oxidase 3 (MT-CO3) and increases in the expression of NOD-like receptor thermal protein domain–associated protein 3 (NLRP3), caspase-1, and Gasdermin D (GSDMD). The level of mitochondrial respiratory chain complex IV (MRCC IV) and adenosine triphosphate (ATP) was decreased. An elevation in the level of mitochondrial oxidative stress and the opening of the mitochondrial permeability transition pore (mPTP) was also observed. Mechanistically, tubastatin-A significantly suppressed the mitochondrial translocation of GRs, improved the expression of mitochondrial genes, promoted the restoration of mitochondrial function, and inhibited pyroptosis. MitoQ significantly prevented mitochondrial oxidative stress, improved mitochondrial function, and reduced apoptosis and pyroptosis. Both tubastatin-A and MitoQ suppressed DEX-induced pyroptosis. This study substantiates that the increase in the mitochondrial translocation of GRs mediated by GCs exacerbates oxidative stress and pyroptosis in microglia, which indicates that the regulation of mitochondrial pathways by GCs is pathogenic to microglia.

Graphical Abstract

The increase in mitochondrial translocation of GRs mediated by GCs aggravates mitochondrial dysfunction and oxidative stress, leading to pyroptosis in BV-2 microglia. Tubastatin-A and MitoQ can inhibit GR translocation and oxidative stress in mitochondria, respectively, and these effects can inhibit pyroptosis and other damage induced by GCs to microglia.

Ischemic stroke is typified by hypoxia and a cascade of pathophysiological events, including metabolic dysfunction, ionic dysregulation, excitotoxicity, inflammatory infiltration, and oxidative stress. These ultimately result in neuronal apoptosis or necrosis with constrained neuroregenerative capabilities. In this study, neural stem cells (NSCs) under conditions of oxygen–glucose deprivation (OGD) in vitro and following middle cerebral artery occlusion (MCAO) in vivo were explored. Transcriptome sequencing revealed a decline in NSC differentiation and neurogenesis after OGD exposure, which was related to cellular senescence. This observation was corroborated by increased senescence markers in the MCAO mouse model, reduction in NSC numbers, and decline in neurogenesis. Importantly, iMSC-sEVs (induced mesenchymal stem cells-small extracellular vesicles) have the therapeutic potential to alleviate NSC senescence and rejuvenate their regenerative capacities both in vitro and in vivo. Moreover, iMSC-sEVs contribute to the recovery of cognitive function and synapse loss caused by MCAO.

Mounting evidence suggests a significant correlation between depressive disorders and neurodegenerative conditions, encompassing Alzheimer’s disease and Parkinson’s disease (PD). Depression represents a substantial non-motor manifestation frequently identified in individuals with PD, posing a significant threat to patients’ overall well-being and necessitating the implementation of effective management strategies. Despite its high prevalence, impacting over 40% of PD patients, the precise cellular and molecular mechanisms underlying depression and its relationship to dopaminergic system degeneration remain largely ambiguous. In this study, we presented our findings demonstrating distinct characteristics of cortical astrocytes in PD patients compared to reactivated glial cells in the substantia nigra. We identified a subset of differentially expressed genes associated with depressive disorders from PD-associated cortical astrocytes. Furthermore, we uncovered the potential involvement of the hypoxia signaling in driving cortical astrocytic dysfunctions. Through a comprehensive investigation utilizing transcriptome and chromatin accessibility analyses on cultured human astrocytes, we revealed that hypoxic treatment could induce similar expression changes observed in cortex from PD patients. Additionally, we provided evidence that activation of the HIF-1 signaling pathway suppressed the expression of key components of mitochondrial ribosomes and electron transport chain proteins COX2 and CYTB, resulting in abnormal mitochondrial membrane potential. Our results underscore the potential impact of glial metabolic abnormalities on the development of depressive disorders associated with Parkinson’s disease.

Previous research has found that an adaptive response to ferroptosis involving glutathione peroxidase 4 (GPX4) is triggered after intracerebral hemorrhage. However, little is known about the mechanisms underlying adaptive responses to ferroptosis. To explore the mechanisms underlying adaptive responses to ferroptosis after intracerebral hemorrhage, we used hemin-treated HT22 cells to mimic brain injury after hemorrhagic stroke in vitro to evaluate the antioxidant enzymes and performed bioinformatics analysis based on the mRNA sequencing data. Further, we determined the expression of GSTO2 in hemin-treated hippocampal neurons and in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH) by using Western blot. After hemin treatment, the antioxidant enzymes GPX4, Nrf2, and glutathione (GSH) were upregulated, suggesting that an adaptive response to ferroptosis was triggered. Furthermore, we performed mRNA sequencing to explore the underlying mechanism, and the results showed that 2234 genes were differentially expressed. Among these, ten genes related to ferroptosis (Acsl1, Ftl1, Gclc, Gclm, Hmox1, Map1lc3b, Slc7a11, Slc40a1, Tfrc, and Slc39a14) were altered after hemin treatment. In addition, analysis of the data retrieved from the GO database for the ten targeted genes showed that 20 items on biological processes, 17 items on cellular components, and 19 items on molecular functions were significantly enriched. Based on the GO data, we performed GSEA and found that the glutathione metabolic process was significantly enriched in the hemin phenotype. Notably, the expression of glutathione S-transferase omega (GSTO2), which is involved in glutathione metabolism, was decreased after hemin treatment, and overexpression of Gsto2 decreased lipid reactive oxygen species level in hemin-exposed HT22 cells. In addition, the expression of GSTO2 was also decreased in a mouse model of hippocampus-intracerebral hemorrhage (h-ICH). The decreased expression of GSTO2 in the glutathione metabolic process may be involved in ferroptotic neuronal injury following hemorrhagic stroke.

Galanin-like peptide (GALP) is a neuropeptide that was first isolated and identified from the porcine hypothalamus. Studies have described an anti-obesity effect of GALP. We previously found that intracerebroventricular administration of GALP in mice resulted in an increase in respiratory exchange rate 12 to 16 h later. GALP may also affect glucose metabolism, but the detailed mechanism has not been elucidated. In this study, we investigated the effects of GALP on glucose and lipid metabolism in the liver. Nine-week-old male C57BL / 6 J mice were administered a single intracerebroventricular dose of saline or GALP and dissected 16 h later. There were no significant between-group differences in body weight and blood glucose levels. With regard to gene and protein expression, G6Pase associated with hepatic gluconeogenesis was significantly reduced in the GALP group. In addition, the hepatokines selenoprotein P and fetuin-A, which induce insulin resistance in the liver, were significantly decreased in the GALP group. These results suggest that intracerebroventricular administration of GALP decreases the expression of key hepatokines, thereby enhancing glucose metabolism.

Neurotrauma is a significant cause of morbidity and mortality worldwide. For instance, traumatic brain injury (TBI) causes more than 30% of all injury-related deaths in the USA annually. The underlying cause and clinical sequela vary among cases. Patients are liable to both acute and chronic changes in the nervous system after such a type of injury. Cerebrovascular disruption has the most common and serious effect in such cases because cerebrovascular autoregulation, which is one of the main determinants of cerebral perfusion pressure, can be effaced in brain injuries even in the absence of evident vascular injury. Disruption of the blood–brain barrier regulatory function may also ensue whether due to direct injury to its structure or metabolic changes. Furthermore, the autonomic nervous system (ANS) can be affected leading to sympathetic hyperactivity in many patients. On a cellular scale, the neuroinflammatory cascade medicated by the glial cells gets triggered in response to TBI. Nevertheless, cellular and molecular reactions involved in cerebrovascular repair are not fully understood yet. Most studies were done on animals with many drawbacks in interpreting results. Therefore, future studies including human subjects are necessarily needed. This review will be of relevance to clinicians and researchers interested in understanding the underlying mechanisms in neurotrauma cases and the development of proper therapies as well as those with a general interest in the neurotrauma field.

The conventional method of one drug being used for one target has not yielded therapeutic solutions for Lewy body dementia (LBD), which is a leading progressive neurological disorder characterized by significant loss of neurons. The age-related disease is marked by memory loss, hallucinations, sleep disorder, mental health deterioration, palsy, and cognitive impairment, all of which have no known effective cure. The present study deploys a network medicine pipeline to repurpose drugs having considerable effect on the genes and proteins related to the diseases of interest. We utilized the novel SAveRUNNER algorithm to quantify the proximity of all drugs obtained from DrugBank with the disease associated gene dataset obtained from Phenopedia and targets in the human interactome. We found that most of the 154 FDA-approved drugs predicted by SAveRUNNER were used to treat nervous system disorders, but some off-label drugs like quinapril and selegiline were interestingly used to treat hypertension and Parkinson’s disease (PD), respectively. Additionally, we performed gene set enrichment analysis using Connectivity Map (CMap) and pathway enrichment analysis using EnrichR to validate the efficacy of the drug candidates obtained from the pipeline approach. The investigation enabled us to identify the significant role of the synaptic vesicle pathway in our disease and accordingly finalize 8 suitable antidepressant drugs from the 154 drugs initially predicted by SAveRUNNER. These potential anti-LBD drugs are either selective or non-selective inhibitors of serotonin, dopamine, and norepinephrine transporters. The validated selective serotonin and norepinephrine inhibitors like milnacipran, protriptyline, and venlafaxine are predicted to manage LBD along with the affecting symptomatic issues.