Methylmercury (MeHg) poisoning can lead to Minamata disease, often manifesting as motor dysfunction. We aimed to establish a quantitative evaluation method for MeHg exposure-associated motor dysfunction in the common marmoset (Callithrix jacchus). Three male marmosets were orally administered MeHg (1.5 mg Hg/kg/day) for 2 weeks, followed by a 2-week non-treatment period; three control marmosets received vehicle. Walking and spontaneous behavior were recorded weekly. After marking body segments, bounding gait videos were analyzed to assess locomotion speed, hip joint position, knee angle, dorsal neck-to-torso angle, and spontaneous behavior. In Hg-1 (MeHg-exposed marmoset with earliest symptom onset), locomotion speed and stride length decreased, while stride time increased. In Hg-2 (second marmoset to exhibit symptom onset), hip joint position and knee angle initially showed relatively normal fluctuations during bounding gait. However, their lower limits decreased following MeHg administration, and the dorsal neck-to-torso angle shifted from negative to positive. Spontaneous activity of Hg-1 and Hg-2 significantly decreased after MeHg administration. These results indicate that MeHg exposure-associated motor dysfunction in marmosets can be detected using our method, with particularly prominent lower-limb abnormalities. Furthermore, cerebrospinal fluid proteomic profiling revealed coordinated disruptions converging on three pathological axes-neuronal injury and neuroprotective responses, neuronal metabolic failure and cytosolic enzyme leakage, and impaired transport and homeostatic regulation-identifying nine proteins as candidate biomarkers. Proteomic alterations were consistent with the observed neuronal injury, neuroinflammation, metabolic dysfunction, and impaired homeostatic regulation in affected motor pathways. These findings establish the marmoset as a translational primate model for neurotoxicological assessments and biomarker discovery.

Paclitaxel (PTX) is an effective antineoplastic agent used against various types of cancer. However, its use is limited in many patients due to intolerable side effects, including neurotoxicity. This study examined the effects of aerobic interval training and/or hesperidin (HES) on neuroinflammation and memory impairment caused by PTX in rats. Thirty male Wistar rats were randomly divided into five groups: Sham (SH), PTX, PTX + exercise (EX), PTX + HES, and PTX + EX + HES. To induce PTX toxicity, 2 mg/kg of PTX was injected intraperitoneally into the rats on days 1, 3, 5, 7, and 9. The aerobic exercise program involved five treadmill interval training sessions per week for seven weeks, with each session consisting of 2-minute running intervals. In the first week, the rats completed six repetitions, increasing by one each week until reaching 12 in the final week. Exercise intensity gradually increased from 60% of maximum speed in the first week to 75% in the last week. Between intervals, active rest lasted one minute at 40-45% of maximum speed. HES (100 mg/kg) was administered orally one hour before exercise starting on the tenth day after PTX injection. The Shuttle box and Morris water maze tests assessed changes in avoidance and spatial memory. Animals were finally sacrificed, and hippocampal tissue samples were collected to evaluate inflammatory and oxidative stress markers, including tumor necrosis factor-α (TNF-α), interleukin (IL)-6, IL-10, malondialdehyde (MDA), glutathione (GSH), and brain-derived neurotrophic factor (BDNF). Avoidance and spatial memory significantly improved in the exercise and supplement groups compared to the PTX group (P < 0.05), with the most notable improvement in spatial memory observed in the PTX + EX + HES group. The PTX group showed a significant increase in TNF-α, IL-6, and MDA levels compared to the other groups (p˂0.05 - 0.001). Conversely, IL-10 and BDNF levels were significantly lower in the PTX group compared to other groups (p ˂ 0.05 - 0.001). Our results demonstrate that PTX impairs memory and learning ability; however, aerobic interval training and HES supplementation increase BDNF levels and enhance avoidance and spatial memory. Thus, these treatments may help mitigate chemotherapy side effects. Further research is necessary to determine safe and effective dosages.

N-(1,3-dimethylbutyl)-N'-phenyl-p-phenylenediamine (6PPD) and its oxidation product 6PPD-Q are emerging tire-derived environmental contaminants that have been detected in human biological samples; however, their neurotoxic mechanisms remain unclear. This study employed network toxicology, transcriptomic analysis, and machine learning to explore the potential neurotoxic associations between 6PPD/6PPD-Q and Parkinson's disease (PD). By integrating four target prediction platforms and three disease databases, a total of 260 potential toxic targets associated with 6PPD/6PPD-Q-related PD were identified. Eighty-two differentially expressed genes were identified from GEO datasets, and five candidate genes were obtained through intersection analysis. Among the five candidate genes, KCND3, PSEN2, and SLC18A2 were consistently selected by three machine-learning algorithms (LASSO, SVM-RFE, and Boruta). Validation analysis showed that all core genes were significantly downregulated in the substantia nigra tissues of PD patients, with area under the curve (AUC) values of 0.917 for KCND3, 0.757 for PSEN2, and 0.819 for SLC18A2. Mendelian randomization analysis provided preliminary genetic evidence consistent with a causal association between elevated SLC18A2 expression levels and reduced PD risk (OR = 0.488, 95% CI: 0.273-0.870, P = 0.015). Molecular docking analysis showed favorable predicted binding scores between 6PPD/6PPD-Q and the three target proteins. Exploratory immune analysis suggested alterations in activated dendritic cells and γδ T cells in PD. Collectively, these findings suggest potential neurotoxic relevance of 6PPD/6PPD-Q to PD and provide a basis for further experimental investigation.

Parkinson's disease is a complex neurodegenerative disorder that results from the interplay of genetic, environmental, and age-associated factors. The characteristic pathological feature of the disease is the presence of aggregated forms of the intrinsically disordered protein α-synuclein. Protein aggregates eventually form Lewy bodies, which are associated with the death of dopaminergic neurons. Elevated expression, mutations in the coding sequence, increased misfolding, and decreased degradation contribute to the aggregation of α-synuclein, associated with the disease. Mutations in the SNCA gene, which encodes α-synuclein, are predominantly associated with the familial form of the disease. The majority of the identified mutations are located in the N-terminal region of the protein and are associated with either early- or late-onset of the disease. Studies using model organisms, cell lines, and animal models identified several cellular effects associated with mutated forms of the protein. In addition, the clinical phenotypes of the disease in patients with different mutations vary in intensity. Interestingly, although each mutation is associated with the disease, the resulting α-synuclein aggregation rate and effect on cellular pathways are variable. In this review, we aim to summarize these interesting alterations in the protein and the associated pathophysiology of the disease following a single amino acid change.

Neuroprotective effects of statins in Parkinson's disease (PD) remain uncertain, and their activity in genetic α-synuclein (αSyn) disease models has been insufficiently characterized. We evaluated atorvastatin (ATO) in a mouse model with nigral overexpression of human A53T-mutant αSyn. Mice received ATO by oral gavage at 10 mg/kg/day for 5 weeks and were assessed using behavioral testing, neuropathological assessment, brain transcriptomics, and molecular docking. ATO inhibited cholesterol biosynthesis-related transcriptional programs and broadly remodeled lipid metabolism-associated networks, but did not lead to functional or histopathological benefit. ATO did not ameliorate motor deficits, restore dopaminergic markers, or reduce αSyn protein levels or pSer129-αSyn immunoreactivity. Transcriptomic analysis further showed that ATO failed to reverse the core disease-associated signature induced by A53T αSyn overexpression and instead increased SNCA mRNA. Targeted RNA-seq and western blot analyses showed no parallel increase in Prkn, Gba1, or Lamp2 transcript abundance or in PARKIN, GBA1, or LAMP2A protein expression. Molecular docking, used here as an exploratory structural comparison, suggested a relatively weak predicted interaction between ATO and αSyn when compared with several other statins and provided supportive context for the lack of efficacy. Overall, our findings indicate limited efficacy of ATO in this αSyn-driven setting and support further comparative evaluation of individual statins across complementary PD models.

Methamphetamine (MA) is a widely abused psychostimulant known to affect monoaminergic systems, with neurotoxic effects often associated with oxidative stress. The present study investigated the early effects of repeated neonatal MA exposure on dopamine (DA), noradrenaline (NA), and selected markers of oxidative status in the hippocampus and striatum of male rats. MA (5 mg/kg/day, s.c.; PND 1-12) significantly reduced DA levels in both brain regions on PND 12, while lipid peroxidation (TBARS) and antioxidant capacity remained unchanged. By PND 28, the early reduction in DA was no longer detectable, and neonatal MA exposure did not significantly affect body weight within either exposure paradigm. In the indirect-exposure paradigm, post-weaning isolation was associated with increased noradrenaline concentrations, whereas no corresponding housing effect was detected in the direct-injection paradigm; however, treatment × housing interactions were not significantThese findings indicate that early postnatal MA exposure induces transient alterations in dopaminergic neurotransmission without detectable changes in markers of lipid peroxidation, suggesting a normalization of DA levels during early adolescence. Overall, under the present experimental conditions, lipid peroxidation does not appear to be a major contributing mechanism to the observed neurochemical changes.

Sevoflurane (SEV) is widely used in clinical anesthesia, but its exposure is increasingly being linked to neurocognitive dysfunction, particularly in hippocampal neurons. TRIM14, an E3 ubiquitin ligase, is essential for regulating inflammation, apoptosis, and mitochondrial function; however, its involvement in SEV-induced neuronal damage remains unclear. In this study, we investigated the role of TRIM14 in SEV-induced hippocampal neuronal damage, focusing on mitochondrial dysfunction, iron homeostasis, and inflammation. The results show that TRIM14 knockdown significantly increased cell viability, restrained apoptosis, and suppressed inflammatory cytokines in SEV-treated neurons. However, it also alleviated mitochondrial dysfunction, mitigated ferroptosis, and regulated iron homeostasis. Furthermore, silencing TRIM14 suppressed the NF-κB and STAT3 axis. These findings suggest that TRIM14 contributes to SEV-induced neuronal damage.

Central nervous system (CNS) injuries are the leading cause of permanent disability and premature death in adults worldwide, with their incidence continuing to rise amid social development. These injuries not only severely impair the quality of life but also impose a heavy burden on the global public health system. Current clinical interventions, such as decompression and thrombolysis, can alleviate primary injury but fail to effectively reverse the secondary neuroinflammatory damage. Traditional anti-inflammatory therapies, which cannot block the upstream source of the inflammatory cascade, have led to repeated failures in global clinical translation research over the past decades. Gasdermins were first characterized in studies of systemic inflammatory diseases. These proteins form transmembrane pores to drive the release of proinflammatory factors and inflammatory cell death, serving as key mediators of host innate immunity. Recent studies have revealed that gasdermins play critical roles in regulating the initiation and amplification of neuroinflammation following CNS injury. To clarify the therapeutic potential of gasdermins as targets for injury repair, this review systematically summarizes the structure and function of gasdermins, as well as their cell-specific activation and regulatory mechanisms. We further elaborate on their pathological roles in these injuries and the corresponding therapeutic strategies, aiming to provide a theoretical reference for basic research and clinical translation in this field.

Iron is an essential micronutrient for brain development, participating in mitochondrial respiration, myelination, and neurotransmitter synthesis. However, previous studies have demonstrated that excessive iron during early postnatal life induces oxidative reactions, leading to mitochondrial dysfunction and synaptic failure. These alterations compromise energy metabolism and neuronal integrity, contributing to long-lasting cognitive dysfunction and increased brain vulnerability later in life. This study evaluated the effects of cannabidiol (CBD) and cannabigerol (CBG) on behavioral, neuroinflammatory, and blood-brain barrier (BBB) outcomes in rats exposed to early-life iron overload. Male Wistar rats received iron carbonyl (30 mg/kg, intragastrically) from postnatal day 12 to 14. At three months of age, they were treated intraperitoneally with CBD, CBG (both at 10 mg/kg), or vehicle for 21 days. Cognitive performance was assessed in the open field and object recognition tasks. We examined hippocampal levels of interleukin-1 beta (IL-1β), interleukin-6 (IL-6), tumor necrosis factor alpha (TNF-α), as proinflammatory markers, and occludin, a protein known to regulate BBB permeability. Iron-exposed animals showed impaired recognition memory, with elevated TNF-α and IL-1β, while CBD reversed memory deficits and reduced IL-1β in iron-treated animals, without affecting TNF-α. CBG restored memory, decreased IL-1β in both iron-treated and controls, and increased TNF-α in controls. Also, iron overload reduced occludin expression in vehicle-treated rats which was reversed by both CBD and CBG. These findings highlight inflammation and BBB disruption as mediators of iron-induced cognitive dysfunction and show that both phytocannabinoids act through distinct but complementary mechanisms, supporting their therapeutic potential in neuroinflammation linked to iron overload.

Non-nutritive sweeteners (NNS) are commonly used in the beverage, food, and pharmaceutical industries, however, their possible link to neuroinflammation remains a contentious issue. Hence, to investigate this potential association and identify the molecular pathways involved, targets of the most frequently consumed NNSs, namely sucralose, aspartame, acesulfame, cyclamate, and saccharin, were extracted from the STITCH, Super-PRED, STP, SEA and CTD databases, while neuroinflammatory targets were extracted from GeneCards, OMIM, and NCBI databases. A total of 124 targets were obtained by overlapping NNS and neuroinflammatory targets, of which 20 key targets, including CASP3, PPARγ, MTOR, and MMP9, were identified for further analysis. KEGG enrichment analysis suggested a significant association of these targets with pathways related to Alzheimer's disease and neuroactive ligand-receptor interaction. Gene Ontology analysis revealed enrichment in biological processes associated with inflammatory response and reactive oxygen species. The associated cellular components were primarily localised in the axon, dendrite, and synaptic membrane. Molecular docking followed by molecular dynamics simulations was performed to evaluate the stability of the NNS-key target complexes, revealing favourable binding affinities and stable interaction profiles. Gene expression analysis of these key targets predicted their differential regulation across four majorly recognised neuroinflammatory disorders, including Alzheimer's disease, multiple sclerosis, Parkinson's disease, and amyotrophic lateral sclerosis, with a significant up or downregulation of these key targets. Results of this study suggest that NNS may be associated with neuroinflammatory processes through these key targets and identified pathways, highlighting the need for improving the standards in food safety.

Alzheimer's disease (AD) is defined by the accumulation of extracellular amyloid-β plaques and intracellular neurofibrillary tangles, which drive neuronal and synaptic impairment. In AD, the accumulation of protein aggregates leads to neuroinflammation, increased oxidative stress, and mitochondrial damage, resulting in neuronal loss and cognitive impairment. Emerging evidence highlights that microRNAs (miRNAs) modulate AD-related pathological pathways and may offer opportunities for therapeutic intervention. In this study, we investigated the therapeutic potential of microRNA-29b (miR-29b) delivered via small extracellular vesicles (sEVs) in an in vitro neuroblastoma model of AD. Four experimental groups were established using SH-SY5Y neuroblastoma cells: (1) untreated control cells, (2) Aβ-treated cells to model AD-like pathology, (3) cells treated with unloaded sEVs, and (4) cells treated with miR-29b-loaded sEVs (sEV-miR-29b). To evaluate treatment effects, we assessed markers of oxidative stress (ROS, LDH, SOD, MDA, GPX1), neuroinflammation (BDNF, ICAM1, TNF-α, NfL, MIF, VEGFA, MCP-1), mitochondrial dysfunction (Cytc, TFAM, PINK1, DNM1L), synaptic integrity (CPLX2, ROR1), and AD pathology (Amyloid-β, Total Tau, pTau181, pTau217). Our findings demonstrate that treatment with sEV-miR-29b attenuated Aβ-induced oxidative stress, reduced pro-inflammatory signaling, and improved mitochondrial homeostasis compared with Aβ-only and sEV-only groups. Moreover, sEV-miR-29b treatment partially restored synaptic protein expression and decreased pathological tau phosphorylation. These results indicate that miR-29b plays a regulatory role in neuroinflammation, oxidative stress, and mitochondrial function, suggesting that sEV-mediated delivery of miR-29b represents a promising therapeutic strategy for modulating AD-related neurodegenerative mechanisms. This study highlights the potential of miR-29b-loaded sEVs as a therapeutic approach for AD.

Anxiety disorders are among the most common mental health conditions affecting women of reproductive age, and a significant proportion of pregnant women experience clinically relevant anxiety symptoms. In some cases, pharmacological treatment may be required to manage severe or persistent symptoms; however, concerns remain regarding the potential impact of prenatal exposure to anxiolytic medications on fetal brain development. The developing nervous system undergoes critical processes during gestation, including neuronal proliferation, migration, and synaptic formation, which may be sensitive to pharmacological influences. This review examines available clinical and preclinical evidence regarding the neurodevelopmental consequences of prenatal exposure to commonly used anxiolytic medications, especially benzodiazepines (BZDs) and azapirones (AZPs). Evidence from observational human studies has shown associations between prenatal exposure to BZDs and certain neonatal and neurodevelopmental outcomes. However, results remain inconsistent and may be influenced by confounding factors, including maternal psychiatric conditions, co-medication use, and environmental variables. In contrast, data on prenatal exposure to AZPs, especially buspirone, are relatively limited, with most of the available evidence coming from small cohorts and preclinical models. Experimental studies provide mechanistic insights suggesting that early-life exposure to anxiolytic agents may influence neurotransmitter systems, neuronal morphology, and behavioral development in offspring. However, translating findings from animal models to the human clinical context remains challenging. Overall, the current literature highlights substantial knowledge gaps regarding dose-dependent effects, critical developmental windows, and long-term neurobehavioral outcomes. Further well-controlled longitudinal and translational studies are needed to clarify the potential implications of prenatal exposure and to support evidence-based clinical decision-making during pregnancy.

Oxidative stress is an early and important feature of Alzheimer's disease (AD) that contributes to synaptic dysfunction and neurodegeneration. Soluble amyloid-β oligomers (AβOs) are major contributors to oxidative damage and have been shown to impair neuronal antioxidant defenses. The Nrf2/KEAP1 pathway is a central regulator of cellular redox homeostasis; however, its activity is compromised in AD, increasing neuronal vulnerability to oxidative stress. Metformin (Met), a widely used antidiabetic drug, has emerged as a potential modulator of antioxidant signaling pathways in the nervous system. In the present study, we investigated whether Met enhances antioxidant defenses in primary fetal rat hippocampal neurons exposed to AβOs. Neuronal cultures were treated with Met (2.5 mM for 24 h) prior to exposure to AβOs (500 nM for 6 h). We evaluated Nrf2 and KEAP1 protein levels, Nrf2 nuclear localization, antioxidant enzyme expression and activity, and lipid peroxidation. Met treatment promoted Nrf2 nuclear accumulation, preserved a favorable Nrf2/KEAP1 profile under amyloid stress, and enhanced the expression and activity of key antioxidant enzymes, including superoxide dismutase (SOD1 and SOD2), catalase (CAT), and glutathione peroxidase (GPx1/2). In addition, Met attenuated AβOs-induced lipid peroxidation, supporting its protective effects against amyloid-associated oxidative damage. Collectively, these findings indicate that Met strengthens neuronal antioxidant defenses and promotes redox resilience under amyloid-associated oxidative stress. Our results support modulation of the Nrf2/KEAP1 pathway as a mechanism contributing to the neuroprotective actions of Met and identify the coordinated enhancement of antioxidant defenses and reduction of lipid peroxidation as key components of neuronal redox resilience against AβOs-induced stress.

Tau is a crucial protein involved in many neurodegenerative diseases, including Alzheimer's disease. Natively, Tau is an unfolded protein found predominantly in axons that play a vital role in maintaining and stabilizing microtubules. Under pathological circumstances, Tau disengages from microtubules and forms insoluble intracellular filaments on its own, building neurofibrillary tangles in the brains of Alzheimer's patients. Although Tau exists in aggregates found in the brain and gut of Alzheimer's patients, the function of Tau in the brain is well studied, while the role of Tau in the gut needs further investigation. We have investigated the effects of Tau monomer, oligomer, and aggregates at 10 µM concentration via feeding them to the third instar larvae. To evaluate the genotoxicity, we did 4', 6-diamidino-2-phenylindole staining, while dichloro-dihydro-fluorescein diacetate staining was performed to assess cytotoxicity. Furthermore, we performed a TUNEL assay to detect apoptotic cells. Additionally, we carry out an NBT assay for biochemical estimation of reactive oxygen species by extracting hemolymph. Phenotypes were examined in different stages, i.e., larvae, pupae, and adult flies. Histological studies were performed on eye, gut tissue and reproductive organs of D. melanogaster to check the cytoskeletal alterations. The current study finds that the administration of monomer, oligomer, and aggregate forms causes genotoxicity, cytotoxicity, and cytoskeletal defects in D. melanogaster.