Search Results (1,112)

Histone deacetylases (HDACs) are crucial enzymes involved in the regulation of gene expression through chromatin remodeling, impacting numerous cellular processes, including cell proliferation, differentiation, and survival. In recent years, HDACs have emerged as therapeutic targets for neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and Huntington’s disease, given their role in modulating neuronal plasticity, neuroinflammation, and neuronal survival. HDAC inhibitors (HDACi) are small molecules that prevent the deacetylation of histones, thereby promoting a more relaxed chromatin structure and enhancing gene expression associated with neuroprotective pathways. Preclinical and clinical studies have demonstrated that HDACi can mitigate neurodegeneration, reduce neuroinflammatory markers, and improve cognitive and motor functions, positioning them as promising therapeutic agents for NDDs. Given the complexity and multifactorial nature of NDDs, therapeutic success will likely depend on multi-target drugs as well as new cellular and molecular therapeutic targets. Emerging evidence suggests that HDACi can modulate the function of astrocytes, a glial cell type critically involved in neuroinflammation, synaptic regulation, and the progression of neurodegenerative diseases. Consequently, HDACi targeting astrocytic pathways represent a novel approach in NDDs therapy. By modulating HDAC activity specifically in astrocytes, these inhibitors may attenuate pathological inflammation and promote a neuroprotective environment, offering a complementary strategy to neuron-focused treatments. This review aims to provide an overview of HDACs and HDACi in the context of neurodegeneration, emphasizing their molecular mechanisms, therapeutic potential, and limitations. Additionally, it explores the emerging role of astrocytes as targets for HDACi, proposing that this glial cell type could enhance the efficacy of HDACs-targeted therapies in NDD management. Full article

Flammulina velutipes (enoki mushroom) is a functional edible mushroom rich in antioxidants, polysaccharides, mycosterols, fiber, and minerals. Accumulating evidence highlights its therapeutic potential across diverse pathological contexts, including boosting cognitive function. However, its role in neuromodulation has not been systematically explored. This study examined the effects of methanolic and ethanolic extracts of F. velutipes on primary hippocampal neurons. Neurons were treated with different extract concentrations, followed by assessments of cell viability, cytoarchitecture, neuritogenesis, maturation, and neuroprotection under oxidative stress. The extracts were further characterized by GC-MS to identify bioactive metabolites, and molecular docking combined with MM-GBSA binding energy analysis was employed to predict potential modulators. Our results demonstrated that the methanolic extract significantly enhanced neurite outgrowth, improved neuronal cytoarchitecture, and promoted survival under oxidative stress, whereas the ethanolic extract produced moderate effects. Mechanistic studies indicated that these neuroprotective and neurodevelopmental benefits were mediated through activation of the NTRK receptors, as validated by both in vitro assays and molecular docking studies. Collectively, these findings suggest that F. velutipes extracts, particularly methanolic fractions, may serve as promising neuromodulatory agents for promoting neuronal development and protecting neurons from oxidative stress. Full article

Porcine reproductive and respiratory syndrome virus (PRRSV) remains one of the most important pathogens, resulting in huge economic losses to the global pig industry. Ipriflavone is an isoflavone derivative involved in various biological processes, showing anti-inflammatory, anti-apoptotic, antioxidant, and neuroprotective effects. However, the role of ipriflavone in antiviral immune response to PRRSV is unknown. In this study, we discovered that ipriflavone could significantly inhibit PRRSV replication. Moreover, ipriflavone inhibited PRRSV replication regardless of whether ipriflavone was added pre-, co-, or post-PRRSV infection, and ipriflavone mainly inhibited virus replication and assembly stages. Importantly, ipriflavone had the capacity to upregulate the expression levels of IFN-β and ISG56. Additionally, ipriflavone promoted the expression of RIG-I and MAVS, and induced phosphorylation of IRF3 and STAT1, while reducing PRRSV replication. Collectively, ipriflavone could enhance the RIG-I/IRF3 signaling pathway, thereby inhibiting PRRSV replication. These findings will provide an important theoretical basis for the development of therapeutic agents against PRRSV infection. Full article

Erectile dysfunction (ED) and cognitive decline share overlapping vascular, metabolic, and neurodegenerative mechanisms, particularly in aging populations. Phosphodiesterase type 5 inhibitors (PDE5-Is), such as sildenafil and vardenafil, are widely used to treat ED by elevating cyclic guanosine monophosphate (cGMP) levels and enhancing vascular function. Emerging evidence suggests that PDE5-Is may also benefit cognitive function by promoting neurovascular coupling, synaptic plasticity, and neuroprotection. This review synthesizes clinical, preclinical, and mechanistic studies on PDE5-Is in the context of learning, memory, and Alzheimer’s disease, highlighting their potential as therapeutic agents for cognitive impairment. Full article

Ischemic stroke remains a leading cause of mortality and disability worldwide, with current therapies such as intravenous thrombolysis and mechanical thrombectomy benefiting only a limited proportion of patients. Neuroinflammation is a key contributor to secondary brain injury, creating a strong rationale for adjunctive therapies targeting immune modulation. Fingolimod, a sphingosine-1-phosphate receptor (S1PR) modulator originally approved for multiple sclerosis, has shown promising effects in both preclinical and early clinical studies of acute ischemic stroke. Methods: We conducted a structured narrative review of preclinical and clinical studies published between 2015 and 2024, using PubMed, Scopus, and Web of Science databases. Inclusion criteria were original studies evaluating fingolimod in ischemic stroke models or human patients, either as monotherapy or in combination with reperfusion therapies. Exclusion criteria included conference abstracts without peer review, studies lacking mechanistic insight, and non-English publications. Results: Preclinical evidence demonstrates that fingolimod reduces infarct size, preserves blood–brain barrier integrity, and modulates neuroinflammation through multiple mechanisms, including T cell sequestration, microglial polarization, and mitochondrial protection. Clinical trials, though limited in size, suggest improved short- and long-term outcomes when fingolimod is used in combination with intravenous thrombolysis or endovascular therapy, with a manageable safety profile. Novel nanotechnology-based delivery systems further enhance central nervous system (CNS) targeting and reduce systemic side effects. Conclusions: Fingolimod represents a promising multi-targeted adjunctive strategy for ischemic stroke, acting at the intersection of immune modulation, vascular protection, and neuroprotection. While current findings are encouraging, larger randomized controlled trials and biomarker-driven patient selection are needed to validate its clinical utility. This review highlights the translational potential of fingolimod and outlines key directions for future research. Full article

Background: The pathophysiology of Alzheimer’s disease (AD) is strongly linked to damage to the cholinergic systems of the central nervous system (CNS), mainly due to the formation of β-amyloid peptide plaques, which trigger intense inflammatory responses and are currently the main cause of the symptoms of the disease. Among the therapeutic strategies under investigation, classes of natural products with immunomodulatory properties, action on the CNS, and potent antioxidant activity, which contribute to neuroprotection, stand out. Methods: We aimed to evaluate the flavonoid quercetin using in silico, in vitro, and in vivo methods for the treatment of AD. Initially, the compounds were selected, and molecular dynamics simulations were performed. The in vitro assays included tests of antioxidant activity (DPPH), enzymatic inhibition of acetylcholinesterase (AChE), and prediction of oral toxicity. The in vivo studies investigated the effects on scopolamine-induced learning deficits and conducted histopathological analysis of the brain. Results: Quercetin showed structural stability in the complex with (AChE), with no significant alterations in the Root Mean Square Deviation (RMSD), SASA and radius of gyration (Rg) parameters. Through the same method it was possible to predict stability between the quercetin and inducible nitric oxide synthase (iNOS) complex, a possible mechanism for quercetin immunomodulation in the CNS. In the AChE inhibition test, the IC₅₀ obtained for quercetin was 59.15 μg mL⁻¹, while in the antioxidant test with DPPH, the concentration of 33.1 µM exhibited 50% of the scavenging of reactive oxygen species. This corroborates the perspective of quercetin having neuroprotective activity. This activity was also corroborated in vivo, in a zebrafish model, in which quercetin reduced the cognitive deficit induced by scopolamine. Histopathological analysis revealed its ability to prevent atrophy, caused by scopolamine, in the nervous tissue of animals, reinforcing the potential of quercetin as a neuroprotective agent. Conclusions: The results of the tests carried out with quercetin suggest that this molecule has antioxidant, AChE inhibitory, and neuroprotective activities, making it a good candidate for use in future clinical trials to ensure its efficacy and safety. Full article

Dopamine (DA) replacement by L-DOPA administration is the most common and effective treatment for Parkinson’s disease (PD). However, its chronic use leads to important side effects at advanced stages of the disease. Levodopa-induced dyskinesia (LID), characterized by involuntary, abnormal movements, is the main challenge of L-DOPA treatment. Although the causes underlying LID are not fully understood, abnormal plasticity in corticostriatal synapses and dysregulated DA release from serotonin terminals play a crucial role. In recent years, several studies have suggested the involvement of neuroinflammation and oxidative stress in the pathophysiology of LID. Interestingly, different evidence has shown that blocking these pathways reduces LID in experimental animal PD models, pointing to the use of antioxidant/anti-inflammatory agents as a potential therapy for LID. Numerous studies have shown the role of the brain renin–angiotensin system (RAS) and the ROCK pathway in neuroinflammation and oxidative stress. Compounds acting through these routes have strong neuroprotective properties in PD models. Additionally, the use of ROCK inhibitors, such as fasudil, and RAS blockers has shown potent anti-dyskinetic effects. Therefore, compounds acting on the RAS and ROCK pathways could have a dual role, slowing down the degeneration of dopaminergic neurons and reducing the development of LID. Full article

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder and one of the most pressing global health challenges. Increasing evidence highlights oxidative stress as a key factor in its pathogenesis, contributing to amyloid-β accumulation, tau hyperphosphorylation, neuroinflammation, and mitochondrial dysfunction. Oxidative stress markers, detected in the bodily fluids of AD patients, are considered promising diagnostic and prognostic tools. Despite extensive research, currently available therapies remain largely symptomatic, which emphasizes the need to develop novel, disease-modifying strategies. The aim of this review is to summarize current knowledge on the role of oxidative stress in the pathogenesis of AD and to evaluate therapeutic approaches aimed at its reduction. We discuss molecular mechanisms linking reactive oxygen species to neurodegeneration and present pharmacological strategies such as monoamine oxidase inhibitors and multifunctional agents, as well as natural antioxidants, dietary interventions, and novel therapeutic technologies. We pay particular attention to their efficacy, limitations, and translational challenges. A more profound understanding of oxidative stress-related mechanisms may facilitate the development of combined antioxidant, anti-inflammatory, and neuroprotective approaches, offering new perspectives for delaying disease progression and improving patient outcomes. Full article

Background/Objectives: Neurotransmitters such as dopamine and serotonin are critical regulators of mood, cognition, and neuronal homeostasis. This study aimed to evaluate the neuropharmacological potential of Hawaiian plants by investigating their ability to modulate the expression of tyrosine hydroxylase (TH) and tryptophan hydroxylase (TPH), key enzymes in neurotransmitter biosynthesis. Methods: A total of 108 aqueous and methanolic extracts of Hawaiian plants were screened for cytotoxicity against PC-12 and Neuro-2A cells using the MTT assay. Fifty-six non-toxic extracts were selected and further analyzed for TH and TPH expression via quantitative real-time PCR (qPCR). Results: Several extracts significantly upregulated TH and TPH expression without inducing cytotoxicity. Extracts derived from Morinda citrifolia, Pipturus albidus, and Hedychium coronarium showed the most notable activity, suggesting their potential to enhance dopaminergic and serotonergic pathways. Conclusions: The findings highlight the promise of native Hawaiian flora as sources of neuroactive compounds that may support neuroprotection and regeneration. These results provide a foundation for in vivo studies and further exploration of novel neurotherapeutic agents. Full article

Ischemic stroke induces complex neuroinflammatory cascades, where microglial autophagy and mitophagy serve dual roles in both injury amplification and tissue repair. This scoping review synthesized current evidence on their regulatory mechanisms and therapeutic implications. Literature was identified via PubMed and Embase, yielding 79 records, from which 39 original research articles and 13 review papers were included after eligibility screening. Search terms included “microglia,” “autophagy,” and “ischemic stroke.” Protective autophagy was frequently associated with AMPK activation, mTOR inhibition, and mitophagy pathways such as PINK1/Parkin and BNIP3/NIX, facilitating mitochondrial clearance, M2 polarization, and anti-inflammatory signaling. Therapeutic agents such as rapamycin, Tat-Beclin 1, and Urolithin A consistently demonstrated neuroprotection in preclinical stroke models. In contrast, excessive or prolonged autophagic activation was linked to inflammasome amplification, oxidative stress, and phagoptosis. Limited human studies reported associations between elevated serum ATG5 levels or ATG7 polymorphisms and worse clinical outcomes, suggesting preliminary translational relevance. These findings support the potential of phase-specific modulation of microglial autophagy as a therapeutic avenue for stroke, although further validation in human models and development of autophagy biomarkers are needed for clinical application. Full article

Erythropoietin (EPO) is a glycoprotein hormone essential for red blood cell production and a cornerstone therapy for anemia, particularly in chronic kidney disease. Beyond hematopoiesis, EPO exerts pleiotropic effects on metabolism, neuroprotection, and tissue regeneration. This review summarizes current insights into the molecular mechanisms, pharmacokinetics, and clinical applications of recombinant human EPO (rHuEPO) and its analogs, with emphasis on personalized therapeutic strategies. Emerging evidence highlights both therapeutic opportunities and risks, including resistance, cardiovascular complications, and misuse in sports doping. Advances in detection methods, pharmacogenomics, and the development of novel agents such as HIF-prolyl hydroxylase inhibitors are discussed, underscoring the expanding role of EPO in precision medicine. Full article

Neurodegenerative diseases (NDDs) represent a class of incurable and progressive disorders characterized by the gradual degeneration of the structure and function of the nervous system, particularly the brain and spinal cord. A range of innovative therapeutic approaches is currently under investigation, such as stem cell-based therapies, gene-editing platforms such as CRISPR, and immunotherapies directed at pathogenic proteins. Moreover, phytochemicals such as β-caryophyllene and xanthohumol have demonstrated significant neuroprotective potential in preclinical models. These natural agents exert multifaceted effects by modulating neuroinflammatory pathways, oxidative stress responses, and aberrant protein aggregation—pathological mechanisms that are central to the development and progression of neurodegenerative disorders. Recent investigations have increasingly emphasized the optimization of the pharmacokinetic properties of β-caryophyllene and xanthohumol through the development of advanced drug-delivery systems, including polymer- and lipid-based nano- and microscale carriers. Such advancements not only enhance the bioavailability and therapeutic potential of these phytochemicals but also underscore their growing relevance as natural candidates in the development of future interventions for neurodegenerative disorders. Full article

Background/Objectives: Despite surgical interventions, patients experience incomplete nerve function recovery following peripheral nerve (PN) injuries. Levetiracetam (LEV), a third-generation antiepileptic agent and neuromodulator, has shown neuroprotective effects in conditions such as traumatic brain injury and diabetic neuropathy. However, its efficacy in PN injuries remains unexplored. Methods: We conducted an experimental study using 48 rats divided into six groups. After inducing sciatic nerve compression, LEV was administered intraperitoneally at 50 mg/kg/day for 7 days in the acute group and for 28 days in the chronic group. The sciatic functional index (SFI) was assessed on the 7th day in the acute group and on the 7th, 14th, 21st, and 28th days in the chronic group. Histological and tissue assessments were performed post-sacrifice (7th day for acute; 28th day for chronic). Results: Significant differences were observed among the groups in all parameters except capillary structure and inflammatory cell density. LEV-treated groups demonstrated higher GAP-43 and S-100 reactivity, improved SFI scores, and greater neuronal regeneration compared to non-drug groups (p < 0.05). LEV significantly enhances neuronal regeneration, protein expression (GAP-43 and S-100), and SFI outcomes, particularly in the chronic phase. Conclusions: This experimental animal study is the first to demonstrate LEV’s therapeutic potential in PN injury, providing a basis for further exploration. Full article

Background: Echinops is a genus of spiny, herbaceous perennials in the Asteraceae family, known for its distinct morphology and broad pharmacological potential. Both traditional and modern medicinal systems have identified species in this genus as sources of bioactive compounds with anti-inflammatory, antimalarial, antidiabetic, anticancer, and neuroprotective effects. Aims: This study aimed to conduct a systematic literature review and update previous overviews of the recently reported phytochemicals and pharmacological properties of Echinops, systematically summarizing biological activities and their therapeutic applications. Methods: Major electronic medical databases—PubMed, Scopus, Science Direct, Web of Science, and Google Scholar—were systematically searched for publications from 1990 to 2025. Results: A total of 134 studies met our inclusion criteria. Thiophenes and terpenes emerged as characteristic metabolites of the genus, and along with flavonoids and alkaloids, contributed to a wide range of bioactivities. Experimental evidence supports the potential of these compounds as multifunctional agents, although clinical validation remains limited. Conclusions: Echinops is a promising source of structurally diverse metabolites with therapeutic relevance. Further pharmacological and toxicological studies are needed to establish their efficacy and ensure safe medical application. Full article

Astrocyte-derived extracellular vesicles (ADEVs) have emerged as promising neuroprotective agents for ischemic stroke. In this study, we evaluated the therapeutic potential of hypoxia-conditioned ADEVs (HxEVs) administered intracerebroventricularly in a rat model of transient middle cerebral artery occlusion (tMCAO). Serial magnetic resonance imaging (MRI) with diffusion tensor imaging (DTI) was performed at 1, 7, 14, and 21 days post-stroke. HxEV treatment produced a significant reduction in infarct volume from day 1, sustained through day 21, and was accompanied by improvements in motor and sensory recovery. DTI analyses showed progressive normalization of fractional anisotropy (FA) and radial diffusivity (RD), particularly in the corpus callosum and striatum, reflecting microstructural repair. In contrast, mean diffusivity (MD) was less sensitive to these treatment effects. Regional differences in therapeutic response were evident, with earlier and more sustained recovery in the corpus callosum than in other brain regions. Histological findings confirmed greater preservation of dendrites and axons in HxEV-treated animals, supporting the role of these vesicles in accelerating post-stroke neurorepair. Together, these results demonstrate that hypoxia-conditioned ADEVs promote both structural and functional recovery after ischemic stroke. They also highlight the value of DTI-derived biomarkers as non-invasive tools to monitor neurorepair. The identification of region-specific therapeutic effects and the validation of reliable imaging markers provide a strong foundation for future research and development. Full article