Search Results (7,633)

Background/Objectives: Parkinson’s disease (PD) is a progressive neurodegenerative disorder that poses a substantial threat to global human health. Yam (Dioscorea opposita Thunb.) is a traditional medicinal and edible plant that has long been used in Asia, Africa, and the Caribbean. Its major bioactive components, such as dioscin and polysaccharides, have been reported to exhibit neuroprotective effects; however, the impact of dietary yam on PD progression remains to be elucidated. Therefore, we sought to evaluate its neuroprotective potential and the underlying mechanisms in 1-methyl-4-phenyl-1,2,3,6 tetrahydropyridine (MPTP)-induced PD mice. Methods: Mice received six-week dietary yam supplementation. Behavioral, histological, and neurochemical analyses were performed to assess motor function, dopaminergic neuron integrity, and dopamine levels. Gut microbiota and metabolic profiles were analyzed using 16S rRNA gene sequencing and non-targeted metabolomics. Transcriptomic sequencing and Western blot analysis of the substantia nigra pars compacta (SNc) were conducted to investigate molecular mechanisms, and integrative multi-omics analysis was applied to explore microbiota–metabolite–host interactions. Results: Yam supplementation improved motor function, preserved nigrostriatal dopaminergic neurons, and restored striatal dopamine levels in PD mice. Notably, yam was associated with the maintenance of intestinal homeostasis by strengthening barrier integrity and enriching beneficial taxa, including Ileibacterium, Lachnospiraceae NK4A136 group, and Blautia. Consistently, yam also elevated neuroprotective purines and amino acids, including inosine, xanthine, and succinic acid. At the molecular level, yam treatment modulated mitochondrial oxidative phosphorylation by increasing PGC-1α and COX7c expression, and reduced inflammasome-related neuroinflammatory signaling. Integrative modeling showed significant associations between yam-modulated genes and PD-related indices with microbiota and metabolites. Conclusion: These findings suggest that yam may represent a potential dietary strategy for alleviating PD-related neurodegeneration by modulating the microbiota–gut–brain axis. Full article

Remote ischemic conditioning (RIC) is an endogenous strategy that mitigates cerebral injury in preclinical stroke models. However, its bench-to-bedside translation is frequently hindered by complex patient environments that induce RIC resistance and limit its neuroprotective efficacy. To bridge this translational gap, this review systematically examines the extrinsic pathophysiological and pharmacological barriers to RIC. We categorize RIC resistance into three mechanism-driven phenotypes. Impaired signal initiation (Type I) is often linked to diabetic sensorimotor polyneuropathy and the reactive oxygen species-scavenging effects of propofol. Signal transmission blockade (Type II) is associated with specific P2Y12 inhibitors and smoking-induced endothelial dysfunction. Furthermore, effector desensitization (Type III) involves target-organ unresponsiveness exacerbated by aging, chronic hyperglycemia, and postmenopausal estrogen depletion. To address these barriers, potential phenotype-specific optimization strategies are discussed. Ultimately, transitioning from generalized empirical protocols to mechanism-based precision strategies may help bypass RIC resistance in clinical settings and enhance stroke cerebroprotection. Full article

Estrogen deficiency is an established risk factor for menopausal brain dysfunctions in women. Urgent exploration of drugs is needed to improve estrogen deficiency-related brain dysfunctions without the side effects of estrogen supplements. Three-month-old rats had bilateral ovariectomy (OVX) performed and were treated with emodin (EMO, 80 mg/kg/day) and 17 β-estradiol (EST, 0.5 mg/kg/day). Brain functions were evaluated by cognition and emotion-related behavioral tests. Levels of glucagon-like peptide-1 (GLP-1) and estrogen in blood, mRNA levels of estrogen receptor (ER) α, ERβ, GLP-1 receptor (GLP-1R), proprotein convertase subtilisin/kexin type 1 (PCSK1) and proglucagon (proGCG) in intestinal segments, and brain ERα and GLP-1R levels were evaluated. Contractions of isolated intestinal segments were recorded. Additionally, an ERβ antagonist, PHTPP (200 μg/kg/day), was used to clarify the role of ERβ. EST and EMO significantly ameliorated cognition deficit and depressive behaviors in OVX rats, and reduced neuronal loss and synaptic abnormalities in the hippocampus and prefrontal cortex. The blood GLP-1 levels of sham operation rats (sham, 3.09 pg/mL), EMO-treated (2.57 pg/mL) and EST-treated OVX rats (2.64 pg/mL), were higher than that of OVX rats (1.03 pg/mL). EMO had no effect on the blood estrogen level. Furthermore, EMO up-regulated mRNA levels of ERβ in ileum, colon, and cerebral GLP-1R level, while EST increased mRNA levels of ERβ in colon and cerebral ERα level. In vitro intestinal segment spontaneous contraction tests revealed that EMO reduced contraction amplitudes in isolated intestinal segments from OVX rats, with the ileum and proximal colon showing greater sensitivity to EMO. The ileum and colon segments from OVX rats were less sensitive to EST as compared to those of normal rats. Upon PHTPP intervention, the up-regulated intestinal mRNA levels of ERβ, PCSK1, proGCG, blood GLP-1 level by EMO, and the beneficial effects of EMO in abnormal behaviors of OVX rats were significantly inhibited. Overall, it was found that EMO up-regulated blood GLP-1 level via intestinal Erβ-dependent mechanism and increased brain GLP-1R level, which may be involved in the neuroprotection of EMO in OVX animals. Full article

Background/Objectives: Neuritogenesis and synaptogenesis support learning and cognitive function, and hippocampal neurons play central roles in these processes. Cleistocalyx nervosum var. paniala (CNP), a Southeast Asian berry, has reported neuroprotective activities, but its direct effects on hippocampal neurons remain unclear. We investigated whether CNP extract modulates hippocampal neuronal transcriptomes, neuritogenesis, and synaptogenesis. Methods: Primary hippocampal neurons isolated from male and female Wistar rat pups were treated with CNP extract in vitro. Cytotoxicity was assessed to define non-cytotoxic concentrations. Transcriptomic responses were profiled by RNA sequencing and validated by RT-qPCR. Neuritogenesis was quantified by neurite morphology and Sholl analysis. Synaptogenesis was evaluated by synaptic immunocytochemistry. Molecular docking of cyanidin-3-glucoside (C3G) and resveratrol was used to generate mechanistic hypotheses. Results: At 0.1–10 µg/mL, CNP was non-cytotoxic, whereas a 100 µg/mL dose reduced viability; therefore, 10 µg/mL was used in subsequent experiments. Exploratory RNA-seq profiling identified thousands of differentially expressed genes enriched in synapse- and neurite-related pathways, including synaptogenesis signaling, axon guidance, and neuritogenesis. RT-qPCR showed upregulation of Igf1 in males and Glul in females, with sex-dependent modulation of Bdnf and Cask. CNP increased neurite length, branching, and Sholl complexity in both sexes, with a more pronounced effect in males. A male-biased effect was also observed in synapse-related marker colocalization, with increased Syn1–Psd95 colocalization detected in males. Docking suggested plausible interactions of C3G and resveratrol with regulators such as MYC, TP53, and CREB1. Conclusions: CNP extract alters transcriptional networks and enhances neurite outgrowth in primary hippocampal neurons in a sex-dependent manner, with male-biased effects on Syn1–Psd95 colocalization. These findings support further dose–response, mechanistic, and sex-stratified in vivo studies to evaluate its neurobiological potential. Full article

Ostericum palustre (Besser) Besser (synonym Angelica pancicii Vandas ex. Velen.) is a Eurasian species from the Apiaceae family, previously related to the Balkan endemic species A. pancicii. The study aims to provide a thorough profiling of methanol-aqueous extracts from O. palustre leaves, roots, and inflorescences integrated with an evaluation of antioxidant potential and enzyme inhibitory activity towards some therapeutic targets. For the first time, a series of simple coumarins and furanocoumarins alongside phenolic and acylquinic acids, and flavonoids were annotated/dereplicated in the O. palustre of Bulgarian origin by liquid chromatography coupled with quadrupole—Orbitrap high resolution mass spectrometry acquisition platform. According to the discriminant analysis (sPLS-DA) of the biological potential, radical scavenging activity (47.9 mg TE/g in DPPH and 61.8 mg TE/g in ABTS), reducing power (102.2 mg TE/g in CUPRAC and 57.4 mg TE/g in FRAP), and metal-chelating capacity (20.1 mg EDTAE/g) accounted mainly for the stronger antioxidant activity of inflorescences extract than roots and leaves. Root extracts exhibited anti-collagenase, anti-elastase, and anti-hyaluronidase effects with lower IC₅₀ values (IC₅₀ 37.22, 42.47 and 32.09 μg/mL, respectively). Pearson relationship analysis revealed potent antioxidants including furanocoumarins (oxypeucedanin hydrate, xanthotoxol/bergaptol, byakangelicin/isobyakangelicin, ostruthol) and phenolic acids, while a series of angelols alongside feruloylquinic and dicaffeoylquinic acids, and flavonol glycosides hold significance for the neuroprotective activity of the leaves extract. The enzyme inhibitory activity of the root extracts towards collagenase, elastase and hyaluronidase, related to the anti-aging activity, was ascribed to simple hydroxylated/methoxylated coumarins. The study suggests the potential health benefits of O. palustre extracts as antioxidant, anti-aging, and neuroprotective agents. Full article

Cholinergic dysfunction and impaired synaptic plasticity are key mechanisms underlying cognitive decline in neurodegenerative conditions, including Alzheimer’s disease (AD). Schisandra chinensis pomace (SSP), a by-product of fruit processing, contains bioactive lignans and polyphenols with reported neuroprotective properties; however, its effects under cholinergic dysfunction have not been systematically investigated. In this study, the effects of SSP on scopolamine-induced cognitive impairment were evaluated using ex vivo electrophysiological and in vivo behavioral approaches. Multi-electrode array recordings demonstrated that SSP at 0.1 mg/mL significantly restored scopolamine-suppressed hippocampal long-term potentiation (LTP), whereas a higher concentration (1.0 mg/mL) did not restore hippocampal synaptic potentiation. In vivo, C57BL/6N mice received oral SSP (50 or 100 mg/kg/day) for six weeks, with scopolamine administered during the final three weeks. SSP at 50 mg/kg prevented scopolamine-induced body weight loss, attenuated hyperlocomotor activity, and significantly improved memory retention, as evidenced by enhanced performance in the passive avoidance and Morris water maze tests. Furthermore, SSP restored hippocampal brain-derived neurotrophic factor (BDNF) expression and reduced the p-JNK/JNK ratio, indicating modulation of neurotrophic and stress-responsive signaling pathways. Collectively, these findings suggest that SSP attenuates scopolamine-induced cholinergic dysfunction, accompanied by improved hippocampal synaptic plasticity and changes in BDNF and JNK signaling. These results support the potential of SSP as a neuroactive botanical resource under cholinergic challenge. Full article

Background: Menstrual migraine (MM), including pure menstrual migraine (PMM) and menstrually related migraine (MRM), is characterized by attacks occurring in close temporal association with menstruation and is often more severe, longer lasting, and less responsive to treatment than non-menstrual migraine. Prostaglandin-mediated inflammation and calcitonin gene-related peptide (CGRP) release play a key role in MM pathophysiology. Phycocyanin (PC) and palmitoylethanolamide (PEA) are nutraceutical compounds with anti-inflammatory, analgesic, and neuroprotective properties that may be beneficial as short-term perimenstrual prophylaxis. Objectives: To evaluate the effectiveness of an oral supplementation combining phycocyanin and palmitoylethanolamide as a short-term prophylaxis for menstrual migraine in a real-world clinical setting, a retrospective observational study without a control group was conducted in five Italian centers between May 2023 and June 2025. Methods: Clinical records of 800 women were reviewed, and 220 patients receiving perimenstrual supplementation with phycocyanin and palmitoylethanolamide were screened. Sixty-one women diagnosed with migraine without aura, according to the International Classification of Headache Disorders, met all inclusion criteria and were analyzed. Phycocyanin and palmitoylethanolamide were taken at a dosage of two capsules daily from five days before to five days after the onset of menstruation for three consecutive months. Outcomes during the perimenstrual window were compared with a three-month period without supplementation. Primary outcomes included migraine severity, frequency, and duration of the attacks; secondary outcomes included analgesic consumption and menstrual migraine-associated symptoms. Results: Among the 61 included patients, phycocyanin and palmitoylethanolamide supplementation was associated with a significant reduction in migraine severity across all monitored perimenstrual days (p < 0.0001). While the overall monthly frequency of migraine attacks did not change, the number of migraine days during the perimenstrual window significantly decreased from the first month of supplementation (p < 0.05). Moreover, migraine duration during the perimenstrual window was significantly reduced at one, two, and three months of phycocyanin and palmitoylethanolamide supplementation compared with baseline. Analgesic use and the number of days with migraine-associated symptoms (nausea, vomiting, photophobia/phonophobia) were also significantly reduced. Treatment was well tolerated. Conclusions: In this real-world retrospective study, perimenstrual supplementation with phycocyanin and palmitoylethanolamide was associated with reduced severity, duration, and perimenstrual frequency of menstrual migraine attacks, along with decreased analgesic use, suggesting a safe and potentially beneficial short-term prophylactic strategy for women with menstrual migraine. Full article

The effective treatment of neurodegenerative diseases (NDDs), such as Alzheimer’s disease, Parkinson’s disease, and amyotrophic lateral sclerosis, remains a critical challenge in modern medicine. Given the limitations of current therapies, alternative strategies to slow neurodegeneration are urgently needed. This study presents a critical review of the current evidence regarding low-dose ionizing radiation (IR) as a promising modality for modulating neurodegenerative processes. This study examines current experimental data on the effects of low-dose IR (LDIR) on cellular protective and compensatory mechanisms, including evidence from in vivo models of NDDs. Our analysis demonstrates that LDIR enhances antioxidant activity and DNA repair, stimulates autophagy and neuroplasticity, and modulates neuroinflammatory signaling. Collectively, these findings support the hypothesis of the neuroprotective potential of LDIR, underscoring its translational viability provided that strict dosimetric guidelines are followed and individual biological responses are rigorously monitored. Full article

Neurodegenerative diseases involve progressive neuronal loss associated with oxidative stress (OS) and inflammation. Given the limited efficacy of current therapies, natural compounds with multitarget neuroprotective potential are of growing interest. In this study, we investigated the neuroprotective effects of a standardized Magnolia officinalis (L.) bark extract (MOE) in rat brain cortical slices exposed to hydrogen peroxide-induced OS. MOE significantly recovered tissue viability and reduced ROS and malondialdehyde levels caused by OS while attenuating caspase-3, -8, and -9 activation, suggesting modulation of intrinsic and extrinsic apoptotic pathways. Shotgun proteomics using LC-HRMS/MS identified OS-induced protein expression changes reversed by MOE, with fourteen of thirty-three altered proteins rescued by MOE co-treatment. These proteins participate in several processes, including neuronal survival, OS response, and proteostasis. Bioinformatic analysis demonstrated that genes responsible for protein synthesis regulated by MOE are subjected to transcriptional regulation by factors associated with OS, including FOXO4, NRF2, and SP1. The present findings support the hypothesis that MOE exerts multitarget neuroprotective effects by modulating key proteins involved in OS responses and neuronal survival in an acute ex vivo oxidative injury model, suggesting potential relevance for mechanisms associated with NDs. Full article

Aging is accompanied by profound alterations in immune function, termed immunosenescence, and by a chronic, low-grade inflammatory state known as inflammaging. These processes are increasingly recognized as central drivers of age-related neurodegenerative diseases, including Alzheimer’s Disease, Parkinson’s Disease, Amyotrophic Lateral Sclerosis and Multiple Sclerosis. In the central nervous system, senescent microglia and astrocytes lose their homeostatic and neuroprotective functions, while systemic immune aging and blood–brain barrier dysfunction further amplify neuroinflammation and impair protein aggregate clearance. This sustained pro-inflammatory environment promotes synaptic dysfunction, neuronal loss and cognitive decline. Here, we synthesize current knowledge of the mechanistic links among immunosenescence, inflammaging, and neurodegeneration, highlighting innate and adaptive immune dysregulation, mitochondrial impairment, and failed resolution pathways. We further discuss emerging therapeutic strategies, including senolytics, immunoceuticals, microbiome-based interventions and advanced drug delivery systems, aimed at restoring immune homeostasis and enhancing brain resilience. By integrating mechanistic and translational insights, this review provides a framework for developing novel interventions to target immune aging in neurodegenerative diseases. Full article

Recent studies support the concept of a bidirectional lung–brain axis. While neural, immune, and microbial pathways are increasingly recognized in lung-to-brain communication, the role of matrikines—bioactive peptides generated by extracellular matrix (ECM) proteolysis during remodeling—in this inter-organ communication remains underexplored. This review highlights matrikines originating from the lung, particularly the collagen-derived tripeptide Pro-Gly-Pro (PGP) and the elastin-derived hexapeptide Val-Gly-Val-Ala-Pro-Gly (VGVAPG), as potential mediators linking pulmonary pathology with neurological outcomes. The lung is rich in ECM proteins, and inflammatory conditions such as chronic obstructive pulmonary disease (COPD) and emphysema trigger proteolytic activity by matrix metalloproteinases (MMPs) and neutrophil elastase, releasing matrikines into circulation. Under conditions of blood–brain barrier (BBB) dysfunction, they may access the central nervous system (CNS), where they influence neurons, microglia, and astrocytes, modulating neuroinflammation, autophagy, and synaptic integrity. While PGP can exhibit context-dependent neuroprotective effects, its acetylated form and VGVAPG are associated with neurotoxicity, Tau hyperphosphorylation, and microglial activation. Additional matrikines, including Gly-His-Lys (GHK) and endorepellin, may further modulate CNS homeostasis. Collectively, these findings support lung-derived matrikines as circulating mediators of lung-to-brain signaling, providing a novel mechanistic framework linking chronic pulmonary inflammation to neuropathologies, such as stroke and neurodegenerative disorders, and highlighting potential targets for therapeutic intervention. Full article

Background: Traumatic brain injury (TBI) and hypoxic-ischemic encephalopathy (HIE) cause significant pediatric morbidity through primary insults and secondary cascades like excitotoxicity, neuroinflammation, and impaired plasticity. Nerve growth factor (NGF) promotes neuroprotection, anti-inflammation, and repair, but delivery challenges persist. This review evaluates preclinical and clinical evidence on intranasal human recombinant NGF (hr-NGF) to enhance neurorepair in pediatric TBI and HIE patients. It aims to clarify the potential of intranasal hr-NGF as part of future multimodal approaches to enhance brain repair and improve functional recovery across the lifespan. Methods: A PRISMA-guided literature search (2000–2025) was conducted across Scopus, PubMed, and Cochrane CENTRAL using terms like “intranasal NGF”, “TBI”, “HIE”, and “pediatric”. Eligible studies involved pediatric brain injury patients receiving NGF, with outcomes via clinical scales, imaging, or EEG. Results: Preclinical models showed that intranasal NGF reduces lesion volume, inflammation, and deficits while boosting angiogenesis and cholinergic function. Clinically, one child with meningitis and five TBI cases exhibited improved consciousness, spasticity, motor scores, cognition, and brain imaging. Three HIE cases gained voluntary movements, expressivity, and perfusion. No adverse events occurred related to hr-NGF administration. Conclusions: Intranasal hr-NGF safely reactivates plasticity in pediatric brain injury, yielding motor, cognitive, and neurophysiological gains. Preliminary data support multimodal use, but randomized trials are needed to optimize protocols and confirm efficacy. Full article

Nuclear factor erythroid 2-related factor 2 (Nrf2) is a master regulator of the cellular antioxidant response and a promising therapeutic target for Parkinson’s disease (PD). Resibufogenin (RBG), a bioactive bufadienolide from toad venom, has been identified as a potential Nrf2 agonist; however, its application is limited by cytotoxicity and poor drug-like properties. Herein, we report the rational design, synthesis, and biological evaluation of a series of RBG derivatives modified at the C3, C14–C15, and C17 positions. Systematic structure–activity relationship (SAR) studies identified 2-5c, featuring a C3 2-chloroacryloyl group and a C17 pyrimidine substitution, as a potential Nrf2 activator (EC₅₀ = 4.18 μM), exhibiting approximately 7-fold greater activity than RBG. Importantly, 2-5c demonstrated neuroprotective effects in MPP⁺-induced BV2 microglial cells and effectively ameliorated motor deficits in an MPTP-induced PD mouse model. These findings suggest that 2-5c represents a promising candidate for further investigation in the development of novel Nrf2-based therapies for PD. Full article

Background/Objectives: Modern diabetes therapy extends beyond glycemic control and increasingly focuses on comprehensive risk reduction to prevent long-term complications, improve quality of life, and reduce premature mortality. Accordingly, modern therapeutic approaches address not only glucose metabolism but also cardiovascular, renal, and metabolic consequences of diabetes. Within this context, glucagon-like peptide-1 receptor agonists (GLP-1 RAs) have emerged as a significant therapeutic class. In addition to their well-known effects on glycemic control and the metabolic-cardiovascular-renal axis, increasing evidence suggests that these agents may exert a range of pleiotropic effects and opening new therapeutic venues, discussed in this review. Methods: A narrative review of the literature was conducted using the PubMed, Scopus, and Google Scholar databases. Publications from 2014 and 2026 were screened using predefined keywords related to GLP-1 RAs and their potential effects across multiple physiological systems and diseases. Notably, more than 80% of the included studies were published between 2020 and 2026, reflecting the recent growth of research in this field. Results: GLP-1 RAs have been associated with beneficial effects across a wide range of conditions, including substance use disorders, mental health disorders, neurodegenerative diseases, obesity-related complications, liver disease, genitourinary disorders, osteoarthritis, and sleep apnea. While they are currently the most effective pharmacological agents for the treatment of obesity, they also significantly reduce hepatic steatosis and are associated with a decreased risk of developing hepatocellular carcinoma. Furthermore, they have also demonstrated positive effects against prostate cancer, polycystic ovary syndrome (PCOS), improved libido and fertility. Conclusions: GLP-1 RAs should no longer be regarded solely as antihyperglycemic agents. Instead, they represent a versatile therapeutic class with expanding clinical relevance across multiple medical disciplines. While current evidence is promising, further large-scale, well-designed clinical trials are required to define their full therapeutic potential. Full article

Neurological complications, particularly seizures, represent a significant and often under-recognized clinical challenge in pediatric hematologic malignancies. Distinguishing CNS leukemia-associated epilepsy from chemotherapy-induced neurotoxicity is critical for optimizing therapy but remains difficult due to overlapping clinical presentations. This review highlights the distinct molecular mechanisms underlying these two entities. CNS leukemia-associated seizures are primarily driven by blood–brain barrier (BBB) disruption following leukemic infiltration, which triggers a neuroinflammatory cascade involving pro-inflammatory cytokines such as IL-6 and TNF-α, and impairs glutamate homeostasis. In contrast, chemotherapy-induced seizures, particularly those associated with high-dose methotrexate, arise from disrupted folate metabolism, intracellular oxidative stress, and subsequent N-methyl-D-aspartate (NMDA) receptor-mediated excitotoxicity. We provide a comparative analysis of these pathways, integrating current evidence on pharmacogenomic susceptibility—including polymorphisms in methylenetetrahydrofolate reductase (MTHFR) and drug transporter genes—as well as epigenetic factors. By synthesizing these molecular insights, we propose a mechanistic framework for precise clinical differentiation, which may inform biomarker-driven diagnostic approaches and targeted neuroprotective strategies in this vulnerable population. Full article