Neuroprotection最新文献

Postoperative delirium (POD), a prevalent neurological complication in older surgical patients, adversely affects recovery. Isoflurane, a common inhalational anesthetic, exhibits neurotoxic potential, but its role in POD pathogenesis remains unclear. Network toxicology and molecular docking strategies identified 38 shared targets between isoflurane (PubChem/ChEMBL) and POD (GeneCards). Protein-protein interaction networks (STRING/Cytoscape) screened eight core genes: catechol-O-methyltransferase (COMT), angiotensin l-converting enzyme (ACE), solute carrier family 6, member 3 (SLC6A3), cathepsin B (CTSB), apoptosis-related cysteine peptidase (CASP3), B-lymphoblastoma-2 gene (BCL-2), coagulation factor VII (F7), and nuclear receptor subfamily 3 (NR3C1). Functional enrichment (Gene Ontology [GO]/Kyoto Encyclopedia of Genes and Genomes [KEGG]) analyzed biological pathways. Key pathways implicated include calcium signaling, dopamine/catecholamine synaptic uptake, cholinergic synapses, endocrine resistance, and estrogen signaling. Molecular docking confirmed strong binding affinity between isoflurane and core targets (e.g., CASP3: affinity-5.54 kcal/mol), highlighting dopaminergic disruption and apoptotic activation. This study elucidates isoflurane's multi-target neurotoxicity in POD, providing a mechanistic foundation for mitigating postoperative neurological complications.

Stroke can cause motor sensory impairment and cognitive impairment. Current interventions focus on thrombolysis or thrombectomy in the acute stage, and promoting the recovery of neurological function during the chronic stage. However, so far, the effect on ischemic brain injury has been limited. Many patients do not receive timely and effective treatment, resulting in high rates of disability and mortality worldwide. In recent years, basic studies have shown that stem cells and their exosomes have a good effect on the protection of nerve function in ischemic brain injury, which has attracted the attention of researchers. This review describes the progress of the work on the stem cells and exosomes in ischemic stroke, in particular, the promising therapy of exosomes.

The risk factors and neuropathologies of cognitive decline and the onset and progression of dementia-related disorders were, until recently, obtuse. A critical predisposing factor to Alzheimer's disease (AD) that has emerged is glucose dysmetabolism. It is now understood that energy imbalances or excess nutrient intake sit in the crosshairs of neurodegeneration. Within the brain, the regulation of glucose operates semiautonomously from the periphery to ensure a defended, uninterrupted supply of glucose for neuronal processes. In this localized brain energetic milieu, hyperglycemia, hyperinsulinemia, and insulin resistance constitute independent risk factors for AD. Disturbances in the blood‒brain barrier (BBB) and brain insulin resistance are two newly understood insults connecting glucose metabolism with AD. This dysglycemia waylays insulin signaling, an otherwise potentially protective mechanism against AD plaques. In parallel, studies in the clinical setting demonstrate that glucose-lowering in patients with type 2 diabetes (T2D) reduces the risk of AD. The American Diabetes Association (ADA) elevated its guidelines to include cognitive issues (or risk) as a comorbidity in T2D patient treatment plans. Choice of antidiabetes therapy is imperative: evidence supports the use of metformin, dipeptidyl peptidase 4 inhibitors, glucagon-like peptide-1 receptor analogs, and sodium glucose cotransporter 2 inhibitors to help prevent and mitigate cognitive outcomes and AD. Sulfonylureas, on the other hand, may actually worsen cognitive deficits and integrity. We are at a fascinating juncture: preclinical research is at a stage to inform the development of rational previously unexplored targets. Simultaneously, current clinical evidence is translatable now into real-world strategies to reduce the incidence and severity of comorbid AD in our aging population.

Adaptive plasticity, the brain's ability to reorganize and form new neural connections after injury, is crucial for recovery following acquired brain injury (ABI). This process involves axonal sprouting, dendritic remodeling, and neurogenesis, which restore neural connections and compensate for lost functions. While neuroinflammation and reactive astrocytes aid tissue repair, optimizing these responses to minimize secondary damage remains a challenge. Brain-derived neurotrophic factor (BDNF) plays a vital role in neurogenesis and dendritic growth, positioning it as a potential therapeutic target for brain repair. Rehabilitation strategies that stimulate these adaptive changes can enhance neuroplasticity and functional recovery. The complexity of ABI recovery is influenced by factors such as injury severity, age, and genetic and epigenetic factors, which regulate neuronal repair and synaptic plasticity. Maladaptive plasticity refers to compensatory mechanisms that initially aid recovery but ultimately become harmful. Severe injuries like traumatic brain injury (TBI) and stroke can trigger adaptive responses, such as axonal sprouting, but excessive reliance on these processes may become maladaptive. In contrast, mild TBIs offer greater recovery potential. Age-related differences in plasticity complicate recovery, with younger individuals exhibiting greater plasticity and older adults experiencing reduced plasticity and increased likelihood of maladaptive changes. Genetic factors, such as BDNF gene polymorphisms and DNA methylation, influence recovery outcomes. Neuroinflammation plays a dual role: acute inflammation supports recovery, while chronic inflammation can exacerbate damage. Precision medicine, tailored to an individual's genetic and epigenetic profile, offers promising strategies to optimize recovery. Growth factors like BDNF and insulin-like growth factor 1 (IGF-1) are essential for neurogenesis, synaptic plasticity, and neural network reorganization, supporting both structural and functional recovery. However, maladaptive plasticity must be managed carefully for effective recovery. Targeted rehabilitation therapies, along with pharmacological agents and neuromodulation techniques, offer insights into personalized treatment strategies to enhance adaptive plasticity and optimize ABI recovery outcomes. This review explores the mechanisms of adaptive plasticity following ABI and discusses therapeutic interventions to support and optimize recovery, offering promising avenues for improving patient outcomes.

Major depressive disorder (MDD) is a complex psychiatric condition increasingly linked to chronic neuroinflammation, particularly in the context of aging, stress, and systemic comorbidities. While microglia have traditionally been the focus of neuroimmune studies, growing evidence highlights astrocytes as central regulators in the pathogenesis of MDD. This review synthesizes current findings on the multifaceted roles of astrocytes in neuroplasticity, neurotransmission, metabolic support, and blood-brain barrier regulation. It explores how astrocyte reactivity and the release of pro-inflammatory cytokines are often triggered by psychosocial stress, aging, and peripheral immune activation and contribute to synaptic dysfunction and cognitive impairment. The review also examines the bidirectional crosstalk between astrocytes and microglia, astrocytic calcium signaling, epigenetic modulation via histone lactylation, and metabolic pathways involving lactate. Special attention is given to the region-specific and phenotype-dependent responses of astrocytes, as well as their influence on the onset and maintenance of depressive symptoms. Additionally, therapeutic strategies targeting astrocyte-mediated pathways, including anti-inflammatory agents, metabolic modulators, repetitive transcranial magnetic stimulation, and inflammasome inhibitors, are discussed. Finally, methodological challenges and future research directions are outlined, emphasizing the need for precision medicine approaches in developing astrocyte-targeted interventions for MDD.

Background: Preeclampsia (PE) is a serious hypertensive disorder of pregnancy that has lifelong deleterious effects, including increased risk of stroke postpartum (PP). Here we determined if previous PE exacerbates ischemic injury in the PP period and investigated underlying mechanisms including oxidative stress and collateral perfusion.

Methods: Female Sprague-Dawley rats were studied at 4-9 months PP, after either a normal pregnancy (NormP-PP n = 7) or experimental PE (ePE) induced via high cholesterol diet during gestation (ePE-PP n = 9). Animals underwent transient middle cerebral artery occlusion (tMCAO) for 2 hours with 1 hour reperfusion. Dual-site laser Doppler flowmetry measured changes in cerebral blood flow (CBF) in the MCA and collateral territories. Ischemic injury was measured by 2,3,5-triphenyl tetrazolium chloride staining. Circulating 8-isoprostane, 3-nitrotyrosine (3-NT), and oxidized low-density lipoprotein (oxLDL) were measured by enzyme-linked immunosorbent assays. In separate groups of animals, NormP-PP (n = 10) and ePE-PP (n = 9) that were 3-4 months PP, isolated pial collateral vessels, leptomeningeal anastomoses (LMAs), and mesenteric arteries were studied using pressure myography.

Results: Previous ePE pregnancy worsened stroke outcome in the PP state, significantly increasing infarction in ePE-PP vs. NormP-PP animals (40.6 ± 7.6% vs. 13.7 ± 6.5%; p <0.01) and edema (5.1 ± 2.0% vs. 2.6 ± 0.4%; p < 0.01), despite comparable changes in CBF in both MCA and pial collateral territories during ischemia and reperfusion. When infarction was analyzed as a function of perfusion deficit, ePE-PP animals had greater sensitivity to ischemia. Pial collaterals had increased pressure-induced myogenic tone vs. NormP-PP rats. Percent tone at 80 mmHg for ePE-PP vs. NormP-PP was 15.5 ± 1.6% vs. 8.6 ± 1.9% (p <0.01). In addition, ePE-PP animals had significantly elevated circulating 8-isoprostane and 3-NT, but not oxLDL, after tMCAO (*p<0.05 and **p<0.01, respectively).

Conclusions: We found worsened stroke outcome after ePE pregnancy that was related to increased sensitivity to ischemia, increased pial collateral tone, and elevated levels of oxidative stress markers. Thus, the pathologic effects of ePE persisted PP and negatively impacted stroke outcome.

Recent evidence suggests a more important role of the gut microbiota in neurodegenerative diseases (NDDs) given its relationship through the microbiota-gut-brain as an active communication system aiding in maintaining homeostasis between the brain and the gut. This review focuses on how modulation of gut microbiota can serves as a therapeutic strategy for NDDs, emphasizing the neuroprotective effects of probiotics. Probiotics are live microorganisms that confer health benefits, and their interaction with gut-microbiota influences neurogenesis, neurotransmitter regulation, and neuroinflammation. Recent advancements, including germ-free animal models, fecal microbiota transplantation (FMT), and diverse probiotic strains, have revealed the underlying mechanisms linking gut health to brain function. Notably, several Lactobacillus and Bifidobacterium species have been shown to exert neuroprotective effects via the upregulation of neurotrophic factors such as brain-derived neurotrophic factor and enhancing mitochondrial function through reducing the impacts of oxidative stress. Interestingly, FMT has exhibited a degree of success in overcoming cognitive impairment and motor deficits in preclinical studies and clinical trials. However, further research is warranted to explore its therapeutic potential in humans. Overall, this review highlights the significant role of gut microbiota in NDDs and advocates for gut-targeted interventions as innovative approaches to mitigate these diseases.

Fatiguing syndromes affect millions of patients in the United States and globally, but are grossly underserved in the clinic and in the contemplative design of basic research.Myalgic encephalomyelitis/chronic fatigue syndrome (ME/CFS) is a complex multisystem metabolic-immune-inflammatory disorder. Although research on this condition is in its infancy, it appears to involve the immune system and central nervous system malfunction, with cellular oxidative stress as a predominant feature.Approximately half of the cases of long-haul coronavirus disease 2019 meet the diagnostic criteria for ME/CFS, burgeoning the number of affected individuals.Recent strides in neurobiology have yet to transfer the understanding of the neurodegenerative aspects, and potential for neuroprotection, of ME/CFS.ME/CFS may represent a useful paradigm and research model for the study of the impact of sustained oxidative stress on the central nervous system and the body at large.

Ischemic stroke, the second leading cause of human mortality, presents a formidable challenge to healthcare. Following ischemic insult, the brain undergoes intricate pathological transformations, prominently marked by mitochondrial damage, including swelling, fission, and mitophagy, collectively termed mitochondrial quality control disorder. Mitochondria, pivotal in energy regulation and oxidative stress modulation, play a critical role in neuronal apoptosis post-stroke. To solve the problems caused by mitochondrial quality control disorders, mitochondrial transfer has become a new therapeutic strategy for central nervous system diseases. Mitochondrial transfer refers to the process by which certain cell types export their mitochondria and pass them on to other cell types, a process also known as intercellular mitochondrial transfer. Mechanistically, mitochondrial transfer occurs via tunneling nanotubes, extracellular vesicles, and free mitochondrial transfer, exerting multifaceted effects such as anti-inflammatory, anti-lipid peroxidation, ferroptosis modulation, and enhancement of mitochondrial metabolism. This review explores the therapeutic efficacy, current obstacles, and future prospects of mitochondrial transfer in ischemic stroke, offering insights to researchers and instilling hope in patients for conquering this debilitating condition.