Metabolic brain disease最新文献

Ketamine (KET) is a drug that has been used as an anesthetic for many years. However, in the last two decades, new properties have been discovered that make it useful in treating various psychiatric and neurological disorders. Ketamine has shown effectiveness in preclinical models and patients with conditions such as depression, Parkinson's disease, and obsessive-compulsive disorder, among others. In the present study, we evaluated the effect of ketamine (KET) (15 mg/kg) administered at 24, 48, and 72 h following permanent middle cerebral artery occlusion (pMCAO) in rats, a model of stroke. Forty male Sprague-Dawley rats (~ 300 g) were randomly assigned to three groups: Sham, pMCAO-Saline, and pMCAO-KET (n = 12 per group). Three rats died during the procedures. Neurological function was assessed using the Bederson score after the final KET administration, 72 h post-occlusion. After the neurological assessment, brains were obtained, and dendritic intersections were measured using Sholl analysis, and GFAP, BDNF, and AMPA protein presence were characterized through immunohistochemistry. Additionally, the expression of the AMPA subunit GRIA1 was evaluated by RT-PCR. Our results indicate that ketamine improves sensorimotor performance after pMCAO, as measured by the Bederson score. We also observed cytoarchitectural changes, including increased dendritic branching following ketamine administration. Moreover, ketamine helped reduce the infarct area and alleviate neuropathological features associated with astrocyte reactivity and microglial infiltration. Also, this was accompanied by plasticity-related changes, evidenced by increased levels of neuroplasticity proteins BDNF and AMPA. These findings suggest that ketamine may be a promising strategy for stroke treatment, with neurobiological changes related to plasticity underlying its effects.

Neurological recovery after ischemic stroke (IS) remains clinically challenging, primarily due to cerebral ischemia-reperfusion injury (CIRI). Oxidative stress contributes to the pathogenesis of CIRI by causing reactive oxygen species excessive accumulation, which disrupts mitochondrial function. Mitophagy maintains mitochondrial function by eliminating damaged or dysfunctional mitochondria. Nevertheless, mitophagy exerts dual effects, either excessive or insufficient activation exacerbates mitochondrial dysfunction. Polygalasaponin F (PGSF), a natural triterpenoid saponin, has been demonstrated to regulate mitochondrial function. Therefore, in this study, we investigated whether PGSF protects against CIRI through inhibiting the mitophagy in vitro and in vivo. Results showed that PGSF attenuated apoptosis both in vivo and in vitro. Moreover, PGSF preserved mitochondrial membrane potential (MMP), reduced mitochondrial reactive oxygen species (mtROS), and ameliorated mitochondrial morphology to improve mitochondrial function in vitro. Furthermore, we revealed that PGSF ameliorates CIRI via modulation of mitophagy, evidenced by a reduced LC3II/LC3I ratio, decreased colocalization of LC3 with mitochondria, while enhancing the levels of TOM20 and p62. In conclusion, our findings imply that PGSF alleviates CIRI through inhibiting mitophagy and reducing apoptosis, demonstrating its therapeutic potential.

Type 2 diabetes mellitus (T2DM), which occurs due to frequent consumption of a high-fat diet (HFD), is recognized as a significant risk factor for progressive cognitive decline. The present study investigates the potential neuroprotective effects of fisetin, alone and in combination with Lactobacillus, in an HFD-STZ-induced T2DM rat model. Diabetes was induced by feeding HFD and a single dose of STZ injection of 45 mg/kg intraperitoneally in albino Wistar rats. After confirmation of the diabetic state, rats were administered fisetin (25, 50 mg/kg) orally, in combination with Lactobacillus at 1.5 × 10⁹ CFU/mL. Cognition and memory were analyzed by NORT, MWM, EPM, biochemical markers, neurotransmitters, and molecular (NF-κB via immunohistochemistry) assessments, along with histopathological analysis of tissues, were performed. Fisetin, alone and in combination with Lactobacillus, treatment restored cognitive deficits and glucose level, as well as attenuated lipid profile, biochemical, and neurochemical abnormalities in rats (p < 0.05 vs. STZ-HFD group). Further, the combination of fisetin (50 mg/kg/p.o.) with Lactobacillus (1.5 × 10⁹ CFU/mL) significantly achieved a protective effect as compared to treatment with fisetin alone in diabetic rats (p < 0.05 vs. STZ-HFD Fisetin 25 and 50 mg/kg/ p.o. group). Results of the study revealed that the combination of fisetin with Lactobacillus exhibits impressive anti-oxidant, modulates neurotransmitter levels, and suppresses the NF-κB pathway, promising a strategy for treating diabetes-associated cognitive problems.

Consumption of a high-carbohydrate (HC) diet, which is commonly associated with obesity, has been linked to anxiety-like and compulsive behaviors. This association is predominantly attributed to chronic low-grade inflammation, which affects both the peripheral tissues and the central nervous system. Microglial cells, which are essential for neuroinflammation, exacerbate psychiatric disorders, such as depression and anxiety. Minocycline, a second-generation tetracycline antibiotic, exhibits anti-inflammatory and neuroprotective properties by modulating the activation of microglia. This study aimed to investigate whether minocycline alleviates compulsive and anxiety-like behaviors, as well as inflammatory responses, in mice fed an HC diet. Male BALB/c mice were fed standard chow (control diet) or high-carbohydrate (HC) diet for 12 weeks. Minocycline (50 mg/kg) was administered for 7 days (intraperitoneally) or 15 days (orally, by gavage) before the end of the dietary protocol. Behavioral assessments using the Marble Burying (MB) and novelty suppressed feeding (NSF) tests were conducted 24 h after the end of the diet. Brain, adipose tissue, and serum samples were analyzed for morphological and biochemical changes. Minocycline treatment for 15 days, but not for 7 days, reversed compulsive and anxiety-like behaviors. It also reduced microglial activation in the prefrontal cortex and the hippocampus. Despite these central effects, minocycline showed a limited influence on the peripheral metabolic parameters altered by the HC diet. This study highlights the role of microglial cells in HC diet-related behavioral changes in male mice and indicates that minocycline exerts central anti-inflammatory effects. These findings warrant further studies to confirm their relevance in other animal models and their potential applicability to anxiety and obsessive-compulsive disorders in humans.

Multiple sclerosis (MS) is characterized by demyelination. In demyelinated MS lesions, the recruitment, differentiation, and maturation of oligodendrocyte progenitor cells (OPCs) into oligodendrocytes (OLGs) are inhibited, leading to remyelination failure. Promoting OLG differentiation and maturation has emerged as a promising strategy for enhancing remyelination in MS. Here, we investigated whether Oxymatrine (OMT), a pharmacologically active compound derived from the traditional Chinese herb Sophora flavescens, regulates OLG differentiation and maturation, and remyelination. In this study, OMT was applied to OLG cultures in vitro and injected into the corpus callosum of a toxin-induced demyelination rat model in vivo. Our results showed that OMT potentially inhibited OLG maturation in vitro. Furthermore, in the demyelination model, remyelination was possibly impaired, and OLG maturation was likely suppressed by OMT, which possibly is due to OMT-induced apoptosis in OLGs. Although OMT possibly impairs remyelination in this model, the exploration of Chinese herbal compounds for MS therapy remains a novel and promising field for future interventions. These findings underscore the complexity of herbal pharmacology and suggest that compounds like OMT may exert dualistic effects on neurodegeneration depending on disease stage, cellular targets, or microenvironmental cues, warranting cautious translational exploration.

Background: Acanthopanax senticosus (Rupr. et. Maxim.) Harms (ASH), a widely used traditional Chinese herbal medicine, possesses various therapeutic effects, such as the ability to tonify the spleen and kidney, strengthen muscles and bones, and promote consciousness and nerve relaxation. Previous research has indicated its good efficacy in treating Parkinson's disease (PD). We aimed to investigate the effects of ASH on changes in neurotransmitter and metabolite levels within the brain tissue of α-synuclein (α-syn) transgenic mice with PD. Additionally, we sought to explore the potential mechanisms by which ASH treats PD and the targets of action of ASH. α-Syn transgenic mice were chosen as a suitable model of PD. Hematoxylin‒eosin (HE) staining was used to detect changes in neurons in the substantia nigra. Immunohistochemistry (IHC) was performed to measure tyrosine hydroxylase (TH) activity in the substantia nigra and the areal density of α-syn in the striatum. Moreover, we measured the pole climbing time and autonomous activity to assess motor ability. Nontargeted matrix-assisted laser desorption ionization mass spectrometry imaging (MALDI-MSI) was used to investigate changes in neurotransmitter levels in each brain region of the mice and further identify the regions in which ASH exerts its effects. ASH reduced the climbing time and increased the number of autonomous movements in PD model mice. HE staining, along with IHC, indicated that ASH interfered with the accumulation of α-syn, increased TH activity, and mitigated neuronal damage. The MALDI-MSI results revealed that ASH could significantly increase dopamine (DA) levels in brain tissue by increasing the levels of 3-methoxytyramine (3-MT) in the striatum and cerebral cortex, acetylcholine (Ach) in the substantia nigra pars compacta (SNc), γ-amino butyric acid (GABA) in the hippocampus (Hip), and 3,4-dihydroxyphenylglycol (DOPEG) in the globus pallidus interna/substantia nigra reticulata (Gpi/SNr) complex, while decreasing 5-HIAA levels in the Hip, cerebral cortex, and striatum. Additionally, the behavioral correlation analysis suggested that the SNc may be a crucial region for the ability of ASH to ameliorate behavioral dysfunction in PD model mice. ASH can regulate DA release by modulating the metabolism of neurotransmitters in brain tissue, particularly in the SNc, thereby influencing the basal ganglia circuit and alleviating the symptoms of PD, and monoamine oxidase (MAO) plays a vital role throughout this metabolic process.

Obsessive-compulsive disorder (OCD) is a mental illness of unwanted recurrent thoughts and compulsive behaviors. The significance of the microbiota-gut-brain axis has been increasingly documented in the manifestation of neuropsychiatric disorders. Herein, we investigated the impact of synbiotic containing Faecalibacterium prausnitzii ATCC 27,766 (F. prausnitzii) and prebiotics [fructooligosaccharides (FOS) and galactooligosaccharides (GOS)] on quinpirole-induced OCD-like symptoms in rats. Repeated quinpirole injections led to compulsive- and anxiety-like behaviors, as rats showed reduced head-dipping behavior in the hole board test, increased marble burying and self-grooming behaviors, and decreased exploration of open areas during elevated plus maze testing. Treatment with Faecalibacterium prausnitzii combined with prebiotics (FOS and GOS) over a six-week period improved these behavioral alterations, reducing signs of repetitive, compulsive, and anxiety-related behaviors. Notably, neither open-field locomotion nor body weight showed significant differences between the experimental groups. In molecular studies, synbiotic treatment showed a reversal of elevated levels/mRNA expression of TNF-α and IL-6 in the frontal cortex and increased mRNA expression of tryptophan hydroxylase (TPH-1) in the colon of quinpirole-injected rats. The cohorts of rats received synbiotic treatment showed normalization of intestinal parameters, including fecal short-chain fatty acid concentrations (acetate, propionate, and butyrate), as well as improvements in intestinal morphology markers such as villi-crypt ratios, goblet cell populations, occludin and TPH1 expression in the colon. These findings highlight the potential benefits of synbiotic laden with F. prausnitzii and prebiotics (FOS + GOS) in alleviating quinpirole-induced OCD-like symptoms by reshaping animal gut-brain-axis mediators.

Astrocytes are pivotal modulators of neuronal health and brain function through their roles in metabolic support, synaptic regulation, neurotransmitter recycling, and the maintenance of the blood-brain barrier. However, aging and environmental challenges compromise astrocytic function, setting the stage for neurodegeneration. Recent findings reveal that age-related astrocyte senescence-characterized by mitochondrial decline, structural atrophy, and a pro-inflammatory shift-undermines their capacity to support neurons, leading to cognitive decline and neurodegenerative conditions such as Alzheimer's disease. Environmental factors, notably dietary influences, further modulate astrocytic behavior. High-fat diets may initially enhance aspects of astrocytic function, such as glutamate clearance; yet prolonged exposure often triggers maladaptive metabolic shifts and neuroinflammation. In contrast, caloric restriction promotes metabolic flexibility and exerts anti-inflammatory effects, thereby preserving astrocytic integrity. Sleep also plays a crucial role by facilitating glymphatic clearance and synaptic maintenance, whereas sleep deprivation disrupts calcium signaling and exacerbates inflammatory processes. This review synthesizes recent advances in the metabolic, immune, and intercellular mechanisms underlying astrocytic dysfunction in aging. By integrating these insights, we highlight the therapeutic potential of targeting astrocyte-mediated processes to preserve cognitive resilience and counteract neurodegeneration.

Background: Traumatic brain injury (TBI) is an important cause of death and disability worldwide. Vascular endothelial cells (ECs) injury has been confirmed to be a risk factor for the development of severe sequelae of TBI, and suppressor of cytokine signaling 2 (SOCS2) regulates the fate of endothelial cells. Therefore, this study aimed to investigate the role of SOCS2 in EC injury after TBI and elucidate its potential molecular mechanisms.

Methods: A TBI rat model was induced via controlled cortical impact (CCI), and a TBI cell model was constructed by treating RBE4 cells with oxygen-glucose deprivation (OGD). RT‒qPCR and western blotting were used to detect key gene and protein expression levels; JC-1 staining was applied to measure the mitochondrial membrane potential; a lactate dehydrogenase (LDH) release assay was conducted to assess the cell death rate; flow cytometry was utilized to detect reactive oxygen species (ROS) levels; and a neutral comet assay was performed to evaluate DNA damage. Additionally, hematoxylin‒eosin (H&E) staining, syndecan-1 content measurement, and the Evans blue extravasation test were combined to comprehensively assess brain tissue pathology and blood‒brain barrier integrity.

Results: Our study revealed that in TBI rat brain tissues and OGD-treated RBE4 cells, the expression of the endothelial barrier-related proteins ZO-1 and Occludin decreased, whereas the levels of parthanatos-associated proteins (PARP1, PAR, and nuclear AIF), JAK2/STAT3 signaling pathway activation markers (p-JAK2/JAK2 and p-STAT3/STAT3), and the DNA damage marker γ-H2AX significantly increased. Additionally, both TBI rat brain tissues and OGD-treated RBE4 cells exhibited reduced mitochondrial membrane potential and elevated ROS levels, with OGD-induced RBE4 cells showing substantial DNA damage and cell death. Notably, the expression of SOCS2 was downregulated in both the TBI and OGD models, and SOCS2 overexpression markedly alleviated the aforementioned injuries induced by TBI or OGD, suggesting that SOCS2 might mitigate TBI-related endothelial cell damage by reducing mitochondrial impairment and parthanatos. Mechanistically, SOCS2 attenuated PARP1-mediated mitochondrial damage and parthanatos by promoting PARP1 ubiquitination, triggering its degradation, and inhibiting the activation of the JAK2/STAT3 signaling pathway, ultimately ameliorating TBI-induced endothelial cell injury.

Conclusion: Our study revealed a novel regulatory role of SOCS2 in EC injury following TBI and elucidated its underlying mechanism. This discovery of the previously unknown role of the SOCS2-PARP1-JAK2/STAT3 regulatory axis in the TBI-related damage to ECs will provide new ideas for the development of neuroprotective strategies targeting SOCS2.

Parkinson's disease (PD) ranks as the second most prevalent neurodegenerative condition affecting individuals in their middle age and beyond. Its hallmark features include the abnormal accumulation of α-synuclein protein and the progressive loss of dopaminergic neurons. A substantial body of evidence supports the notion that an imbalance in the gut microbiome, known as dysbiosis, contributes to the misfolding and accumulation of α-synuclein, a key pathological feature of PD. This finding raises the possibility that restoring the gut microbiome, particularly the bacteria associated with α-synuclein, could serve as a promising therapeutic approach for PD. There is evidence that β-glucan can play an important role in the reconstitution of gut microbiome. In this regard, this study reviews the evidence showing the role of β-glucan in reducing α-synuclein accumulation and mitigating the progression of PD. This scooping review study presents promising prospects for advancing novel therapeutic approaches to benefit individuals with PD.