Search Results (6,746)

Multiple sclerosis (MS) is a chronic, immune-mediated disorder of the central nervous system (CNS) characterized by inflammation, demyelination, axonal degeneration, and gliosis. Its pathophysiology involves a complex interplay of genetic susceptibility, environmental triggers, and immune dysregulation, ultimately leading to progressive neurodegeneration and functional decline. Although significant advances have been made in disease-modifying therapies (DMTs), many patients continue to experience disease progression and unmet therapeutic needs. Drug repurposing—the identification of new indications for existing drugs—has emerged as a promising strategy in MS research, offering a cost-effective and time-efficient alternative to traditional drug development. Several compounds originally developed for other diseases, including immunomodulatory, anti-inflammatory, and neuroprotective agents, are currently under investigation for their efficacy in MS. Repurposed agents, such as selective sphingosine-1-phosphate (S1P) receptor modulators, kinase inhibitors, and metabolic regulators, have demonstrated potential in promoting neuroprotection, modulating immune responses, and supporting remyelination in both preclinical and clinical settings. Simultaneously, artificial intelligence (AI) is transforming drug discovery and precision medicine in MS. Machine learning and deep learning models are being employed to analyze high-dimensional biomedical data, predict drug–target interactions, streamline drug repurposing workflows, and enhance therapeutic candidate selection. By integrating multiomics and neuroimaging data, AI tools facilitate the identification of novel targets and support patient stratification for individualized treatment. This review highlights recent advances in drug repurposing and discovery for MS, with a particular emphasis on the emerging role of AI in accelerating therapeutic innovation and optimizing treatment strategies. Full article

Oxidative stress significantly contributes to the exacerbation of brain damage during cerebral ischemia-reperfusion injury (CIR/I). In our previous study, purified cornel iridoid glycoside (PCIG), consisting of morroniside (MOR) and loganin (LOG), showed neuroprotective effects against CIR/I. To further explore the antioxidative effects and underlying molecular mechanisms, we applied PCIG, MOR, and LOG to rats injured by middle cerebral artery occlusion/reperfusion (MCAO/R) as well as H₂O₂-stimulated PC12 cells. Additionally, the molecular docking analysis was performed to assess the interaction between the PCIG constituents and Kelch-like ECH-associated protein 1 (Keap1). The results showed that the treated rats experienced fewer neurological deficits, reduced lesion volumes, and lower cell death accompanied by decreased levels of malondialdehyde (MDA) and protein carbonyl, as well as increased activities of superoxide dismutase (SOD) and glutathione peroxidase (GSH-Px). In H₂O₂-stimulated PC12 cells, the treatments decreased reactive oxygen species (ROS) production, mitigated mitochondrial dysfunction, and inhibited mitochondrial-dependent apoptosis. Moreover, the treatments facilitated Nuclear factor (erythroid-derived 2)-like 2 (Nrf2) translocation into the nucleus and selectively increased the expression of NAD(P)H quinone oxidoreductase 1 (NQO-1) and heme oxygenase 1 (HO-1) through MOR and LOG, respectively. Both MOR and LOG demonstrated strong binding affinity to Keap1. These findings suggested that PCIG, rather than any individual components, might serve as a valuable treatment for ischemic stroke by activating the Nrf2/NQO-1 and Nrf2/HO-1 signaling pathway. Full article

The rhythm of epileptiform activity occurs in various brain injuries (ischemia, stroke, concussion, mechanical damage, AD, PD). The epileptiform rhythm is accompanied by periodic Ca²⁺ pulses, which are necessary for the neurotransmitter release, the repair of damaged connections between neurons, and the growth of new projections. The duration and amplitude of these pulses depend on intracellular calcium-binding proteins. The effect of the synthetic fast calcium buffer BAPTA on the epileptiform activity of neurons induced by the GABA(A)-receptor inhibitor, bicuculline, was investigated in a 14-DIV rat hippocampal culture. In the epileptiform activity mode, neurons periodically synchronously generate action potential (AP) bursts in the form of paroxysmal depolarization shift (PDS) clusters and their corresponding high-amplitude Ca²⁺ pulses. Changes in the paroxysmal activity and Ca²⁺ pulses were recorded continuously for 10–11 min as BAPTA accumulated. It was shown that during BAPTA accumulation, transformation of neuronal patch activity occurs. Moreover, GABAergic and glutamatergic neurons respond differently to the presence of calcium buffer. Experiments were performed on two populations of neurons: a population of GABAergic neurons that responded selectively to ATPA, a calcium-permeable GluK1 kainate receptor agonist, and a population of glutamatergic neurons with a large amplitude of cluster depolarization (greater than −20 mV). These neurons made up the majority of neurons. In the population of GABAergic neurons, during BAPTA accumulation, the amplitude of PDS clusters decreases, which leads to a switch from the PDS mode to the classical burst mode with an increase in the electrical activity of the neuron. In glutamatergic neurons, the duration of PDS clusters decreased during BAPTA accumulation. However, the amplitude changed little. The data obtained showed that endogenous calcium-binding proteins play a significant role in switching the epileptiform rhythm to the recovery rhythm and perform a neuroprotective function by reducing the duration of impulses in excitatory neurons and the amplitude of impulses in inhibitory neurons. Full article

The present study aimed to standardize germinated oat extracts (GOEs) by profiling avenanthramides (AVNs) and phenolic acids and evaluate their neuroprotective effects against Aβ_1-42-induced cytotoxicity in human neuroblastoma (SH-SY5Y) cells. GOEs were standardized to contain 1652.56 ± 3.37 µg/g dry weight (dw) of total AVNs, including 468.52 ± 17.69 µg/g AVN A, 390.33 ± 10.26 µg/g AVN B, and 641.22 ± 13.89 µg/g AVN C, along with 490.03 ± 7.83 µg/g dw of ferulic acid, using a validated analytical method. Treatment with AVN C and GOEs significantly inhibited Aβ_1-42-induced cytotoxicity (p < 0.05). Furthermore, both AVNs and GOEs markedly reduced Aβ_1-42-induced reactive oxygen species (ROS) generation in SH-SY5Y cells, showing significant scavenging activity at concentrations of 25 μg/mL (AVNs) and 50 μg/mL (GOEs) (p < 0.05). RT-PCR analysis revealed that AVNs and GOEs effectively downregulated the expression of inflammation- and apoptosis-related genes triggered by Aβ_1-42 exposure. These findings suggest that GOEs rich in AVNs may serve as a potential functional ingredient for enhancing memory function through the inhibition of neuroinflammation and oxidative stress. Full article

Cardiopulmonary bypass (CPB) is associated with significant neurological complications, yet the mechanisms underlying brain injury remain unclear. This study investigated the role of interleukin-17A (IL-17A) in exacerbating CPB-induced neuronal apoptosis and identified vulnerable brain regions. Utilizing a rat CPB model and an oxygen–glucose deprivation/reoxygenation (OGD/R) cellular model, we demonstrated that IL-17A levels were markedly elevated in the hippocampus post-CPB, correlating with endoplasmic reticulum stress (ERS)-mediated apoptosis. Transcriptomic analysis revealed the enrichment of IL-17 signaling and apoptosis-related pathways. IL-17A-Neutralizing monoclonal antibody (mAb) and the ERS inhibitor 4-phenylbutyric acid (4-PBA) significantly attenuated neurological deficits and hippocampal neuronal damage. Mechanistically, IL-17A activated the Act1-IRE1-JNK1 axis, wherein heat shock protein 90 (Hsp90) competitively regulated Act1-IRE1 interactions. Co-immunoprecipitation confirmed the enhanced Hsp90-Act1 binding post-CPB, promoting IRE1 phosphorylation and downstream caspase-12 activation. In vitro, IL-17A exacerbated OGD/R-induced apoptosis via IRE1-JNK1 signaling, reversible by IRE1 inhibition. These findings identify the hippocampus as a key vulnerable region and delineate a novel IL-17A/Act1-IRE1-JNK1 pathway driving ERS-dependent apoptosis. Targeting IL-17A or Hsp90-mediated chaperone switching represents a promising therapeutic strategy for CPB-associated neuroprotection. This study provides critical insights into the molecular crosstalk between systemic inflammation and neuronal stress responses during cardiac surgery. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder characterized by cognitive decline, memory loss, and neuronal dysfunction. It is driven by the accumulation of amyloid-beta (Aβ) plaques, Tau protein hyperphosphorylation, oxidative stress, and neuroinflammation. Resveratrol (RSV) is a natural polyphenolic compound found in grapes, berries, and red wine that has garnered attention for its potential neuroprotective properties in combating AD. The neuroprotective effects of RSV are mediated through the activation of sirtuins (SIRT1), inhibition of Aβ aggregation, modulation of Tau protein phosphorylation, and the attenuation of oxidative stress and inflammatory responses. RSV also enhances mitochondrial function and promotes autophagy, which are important processes for maintaining neuronal health. Preclinical studies have demonstrated its efficacy in reducing Aβ burden, improving cognitive performance, and mitigating synaptic damage; however, challenges such as poor bioavailability, rapid metabolism, and limited blood–brain barrier penetration restrict its clinical applicability. Recent technological advances and selected modifications are being explored to overcome these limitations and enhance its therapeutic efficacy. This review summarizes the multifaceted neuroprotective mechanisms of RSV, the synergistic potential of natural compounds in enhancing neuroprotection, and the advancements in formulation strategies aimed at mitigating AD pathology. Leveraging the therapeutic potential of natural compounds represents a compelling paradigm shift for AD management, paving the way for future clinical applications. Full article

Flavonoids constitute a broad class of naturally occurring chemical compounds classified as polyphenols, widely present in various plants, fruits, and vegetables. They share a common flavone backbone, composed of two aromatic rings (A and B) connected by a three-carbon bridge forming a heterocyclic ring (C). One representative flavonoid is chrysin, a compound found in honey, propolis, and passionflower (Passiflora spp.). Chrysin exhibits a range of biological activities, including antioxidant, anti-inflammatory, anticancer, neuroprotective, and anxiolytic effects. Its biological activity is primarily attributed to the presence of hydroxyl groups, which facilitate the neutralization of free radicals and the modulation of intracellular signaling pathways. Cellular uptake of chrysin and other flavonoids occurs mainly through passive diffusion; however, certain forms may be transported via specific membrane-associated carrier proteins. Despite its therapeutic potential, chrysin’s bioavailability is significantly limited due to poor aqueous solubility and rapid metabolism in the gastrointestinal tract and liver, which reduces its systemic efficacy. Ongoing research aims to enhance chrysin’s bioavailability through the development of delivery systems such as lipid-based carriers and nanoparticles. Full article

Neuroinflammation is the major contributor to the pathology of neonatal hypoxic–ischemic (HI) brain injury. Our previous studies have demonstrated that microRNA210 (miR210) inhibition with antisense locked nucleic acid (LNA) inhibitor mitigates neuroinflammation and provides neuroprotection after neonatal HI insult. However, the underlying mechanisms remain elusive. In the present study, using miR210 knockout (KO) mice and microglial cultures, we tested the hypothesis that miR210 promotes microglial activation and neuroinflammation through suppressing mitochondrial function in microglia after HI. Neonatal HI brain injury was conducted on postnatal day 9 (P9) wild-type (WT) and miR210 knockout (KO) mouse pups. We found that miR210 KO significantly reduced brain infarct size at 48 h and improved long-term locomotor functions assessed by an open field test three weeks after HI. Moreover, miR210 KO mice exhibited reduced IL1β levels, microglia activation and immune cell infiltration after HI. In addition, in vitro studies of microglia exposed to oxygen–glucose deprivation (OGD) revealed that miR210 inhibition with LNA reduced OGD-induced expression of Il1β and rescued OGD-mediated downregulation of mitochondrial iron–sulfur cluster assembly enzyme (ISCU) and mitochondrial oxidative phosphorylation activity. To validate the link between miR210 and microglia activation, isolated primary murine microglia were transfected with miR210 mimic or negative control. The results showed that miR210 mimic downregulated the expression of mitochondrial ISCU protein abundance and induced the expression of proinflammatory cytokines similar to the effect observed with ISCU silencing RNA. In summary, our results suggest that miR210 is a key regulator of microglial proinflammatory activation through reprogramming mitochondrial function in neonatal HI brain injury. Full article

Microglia, the brain’s resident innate immune cells, play a fundamental role in maintaining neural homeostasis and mediating responses to injury or infection. Upon activation, microglia undergo morphological and functional changes, including phenotypic switching between pro- and anti-inflammatory types and the release of different inflammatory mediators. These processes contribute to neuroprotection and the pathogenesis of various central nervous system (CNS) disorders. Mast cells, although sparsely located in the brain, exert a significant influence on neuroinflammation through their interactions with microglia. Through degranulation and secretion of different mediators, mast cells disrupt the blood–brain barrier and modulate microglial responses, including alteration of microglial phenotypes. Notably, mast cell-derived factors, such as histamine, interleukins, and tryptase, activate microglia through various pathways including protease-activated receptor 2 and purinergic receptors. These interactions amplify inflammatory cascades via various signaling pathways. Previous studies have revealed an exceedingly complex crosstalk between mast cells and microglia suggesting a bidirectional regulation of CNS immunity, implicating their cooperation in both neurodegenerative progression and repair mechanisms. Here, we review some of the diverse communication pathways involved in this complex interplay. Understanding this crosstalk may offer novel insights into the cellular dynamics of neuroinflammation and highlight potential therapeutic targets for a variety of CNS disorders. Full article

Background/Objectives: Chemotherapy-induced neuropathic pain (CINP) represents a critical challenge in oncology, emerging as a common and debilitating side effect of widely used chemotherapeutic agents, such as paclitaxel (PTX). Current therapeutic interventions and preventive strategies for CINP are largely insufficient, as they fail to address the underlying peripheral nerve damage, highlighting an urgent need for the development of new drugs. This study aimed to investigate the dual-function effects on normal cell protection and tumor suppression of BMX-001, a redox-active manganese metalloporphyrin that has demonstrated antioxidant and anti-inflammatory properties, which offers potential in protecting central nervous system tissues and treating CINP. Methods: This study assessed BMX-001’s different roles in protecting normal cells while acting as a pro-oxidant and pro-inflammatory molecule in cancer cells in vitro. We also evaluated its neuroprotective effect in preclinical PTX-induced CINP models in vivo. Results: Our results showed significant reductions in mechanical and cold allodynia, decreased pro-inflammatory cytokine levels, and restored antioxidant capacity in peripheral nerves and dorsal root ganglia (DRGs) following BMX-001 treatment. Conclusions: Overall, our study highlights the therapeutic potential of BMX-001 to mitigate CINP and enhance anticancer efficiency. Its dual-selective mechanism supports the future clinical investigation of BMX-001 as a novel adjunct to chemotherapeutic regimens. Full article

S100 proteins, a family of Ca²⁺-binding proteins, play numerous roles in cellular processes such as proliferation, differentiation, and apoptosis. Recent evidence has highlighted their critical involvement in neuroinflammation, a pathological hallmark of various neurodegenerative disorders including Alzheimer’s disease, multiple sclerosis, and Parkinson’s disease. Among these proteins, S100B and S100A8/A9 are particularly implicated in modulating inflammatory responses in the CNS. Acting as DAMPs, they interact with pattern recognition receptors like RAGE and TLRs, triggering pro-inflammatory signaling cascades and glial activation. While low concentrations of S100 proteins may support neuroprotective functions, increased levels are often associated with exacerbated inflammation and neuronal damage. This review explores the dualistic nature of S100 proteins in neuroinflammatory processes, their molecular interactions, and their potential as biomarkers and therapeutic targets in neurodegenerative disease management. Full article

Honey is a natural product of honeybees that has been consumed for centuries due to its nutritional value and potential health benefits. Recent scientific research has focused on its antioxidant capacity, which is linked to a variety of bioactive compounds such as phenolic acids, enzymes (e.g., glucose oxidase, catalase), flavonoids, ascorbic acid, carotenoids, amino acids, and proteins. Together, these components work synergistically to neutralize free radicals, regulate antioxidant enzyme activity, and reduce oxidative stress. This review decisively outlines the antioxidant effects of honey and presents compelling clinical and experimental evidence supporting its critical role in preventing diseases associated with oxidative stress. Honey stands out for its extensive health benefits, which include robust protection against cardiovascular issues, notable anticancer and anti-inflammatory effects, enhanced glycemic control in diabetes, immune modulation, neuroprotection, and effective wound healing. As a recognized functional food and dietary supplement, honey is essential for the prevention and adjunct treatment of chronic diseases. However, it faces challenges due to variations in composition linked to climatic conditions, geographical and floral sources, as well as hive management practices. The limited number of large-scale clinical trials further underscores the need for more research. Future studies must focus on elucidating honey’s antioxidant mechanisms, standardizing its bioactive compounds, and examining its synergistic effects with other natural antioxidants to fully harness its potential. Full article

Allicin (ALC), a naturally occurring organosulfur compound derived from garlic (Allium sativum), exhibits potential neuroprotective properties. Parkinson’s disease (PD) is a progressive neurodegenerative disease characterized by degeneration of dopaminergic neurons and motor dysfunction. This study utilized bioinformatics and network pharmacology methods to predict the anti-PD mechanism of ALC and established in vivo and in vitro PD models using 6-hydroxydopamine (6-OHDA) for experimental verification. Network pharmacological analysis indicates that apoptosis regulation and the PKA/p-CREB/BDNF signaling pathway are closely related to the anti-PD effect of ALC, and protein kinase A (PKA) and dopamine transporter (DAT) are key molecular targets. The experimental results show that ALC administration can alleviate the cytotoxicity of SH-SY5Y induced by 6-OHDA and simultaneously improve the motor dysfunction and dopaminergic neuron loss in PD mice. In addition, ALC can also activate the PKA/p-CREB/BDNF signaling pathway and increase the DAT level in brain tissue, regulate the expression of BAX and Bcl-2, and reduce neuronal apoptosis. These results indicate that ALC can exert anti-PD effects by up-regulating the PKA/p-CREB/BDNF/DAT signaling pathway and inhibiting neuronal apoptosis, providing theoretical support for the application of ALC in PD. Full article

Diabetic retinopathy (DR) is a progressive, multifactorial complication of diabetes and one of the major global causes of visual impairment. Its pathogenesis involves chronic hyperglycaemia-induced oxidative stress, inflammation, mitochondrial dysfunction, neurodegeneration, and pathological angiogenesis, as well as emerging systemic contributors such as gut microbiota dysregulation. While current treatments, including anti-vascular endothelial growth factor (anti-VEGF) agents, corticosteroids, and laser photocoagulation, have shown clinical efficacy, they are largely limited to advanced stages of DR, require repeated invasive procedures, and do not adequately address early neurovascular and metabolic abnormalities. Resveratrol (RSV), a naturally occurring polyphenol, has emerged as a promising candidate due to its potent antioxidant, anti-inflammatory, neuroprotective, and anti-angiogenic properties. This review provides a comprehensive analysis of the molecular mechanisms by which RSV exerts protective effects in DR, including modulation of oxidative stress pathways, suppression of inflammatory cytokines, enhancement of mitochondrial function, promotion of autophagy, and inhibition of pathological neovascularisation. Despite its promising pharmacological profile, the clinical application of RSV is limited by poor aqueous solubility, rapid systemic metabolism, and low ocular bioavailability. Various routes of administration, including intravitreal injection, topical instillation, and oral and sublingual delivery, have been investigated to enhance its therapeutic potential. Recent advances in drug delivery systems, including nanoformulations, liposomal carriers, and sustained-release intravitreal implants, offer potential strategies to address these challenges. This review also explores RSV’s role in combination therapies, its potential as a disease-modifying agent in early-stage DR, and the relevance of personalised medicine approaches guided by metabolic and genetic factors. Overall, the review highlights the therapeutic potential and the key translational challenges in positioning RSV as a multi-targeted treatment strategy for DR. Full article

Purpose: Our understanding of the influence of preterm birth and related perinatal exposures on early brain development is limited, hampering personalized optimization of neuroprotective strategies. This study assesses the effect of gestational age (GA) at birth on brain volumes at term-equivalent age (TEA) in infants without overt brain injury born across the GA spectrum. Methods: A cohort of infants born across the GA spectrum (25–40 weeks’ gestation) underwent 3T brain MRI around TEA (40–46 weeks postmenstrual age). Eight brain regions, intracranial and total tissue volumes were segmented using MANTiS (morphologically adaptive neonatal tissue segmentation toolbox). Segmentations were visually quality-checked and excluded if segmentation failed. Absolute TEA volume in relation to GA was assessed using univariate and multivariate (correction for postmenstrual age) linear regression analysis. Statistical significance was set at p < 0.05. Post hoc scatter plots of brain volumes relative to intracranial volumes were created. Results: Fifty infants were included (mean GA = 35.0 [SD = 3.3, range = 25.7–40.1] weeks). A higher GA at birth was significantly related to lower cerebrospinal fluid (p = 0.004) and amygdala (p = 0.02) volumes; no significant relation was found between GA and other volumes. Post hoc analyses showed positive trends between GA and several brain structures, including total brain tissue, cortical gray matter, deep gray matter, hippocampus, cerebellum and brainstem volumes. Conclusions: Our results suggest that GA has an effect on TEA brain volumes that is independent of brain lesions, with lower GA being associated with smaller brain tissue volumes and significantly larger cerebrospinal fluid volume. Preterm birth and related exposures may thus affect early brain growth and contribute to neurodevelopmental challenges encountered by preterm-born children. Full article