Neurotoxicity Research最新文献

Melamine, an industrial chemical linked to neurotoxicity, prompted this study investigating taurine's neuroprotective effects in rat brains. The study examined the impact of taurine on brain metabolic enzymes, neurochemicals, autophagy-related proteins, and oxidative-inflammatory pathways. Twenty-eight rats were divided into four groups (seven rats per group): control (saline), taurine (100 mg/kg), melamine (50 mg/kg/day), and melamine plus taurine. Taurine administration (30 min post-melamine) continued daily for 28 days, starting on day 29 to day 56, which allowed for the assessment of its restorative effect against ongoing melamine-induced neurotoxicity. Non-spatial recognition memory was evaluated using the novel-object recognition memory test (NORT). Following this, brain neurochemical status, metabolic enzymes, autophagic proteins, and oxidative-inflammatory markers were assessed postmortem. Results demonstrated that taurine improved cognitive function in melamine-treated rats, as evidenced by increased exploration of novel objects in the NORT. Taurine protected against melamine-induced oxidative stress. Additionally, taurine reduce tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β expression, modulated mammalian target of rapamycin (mTOR) and beclin-1, restored brain metabolic enzyme activity, enhanced neurotransmitter levels, and prevented alterations in α-synuclein and paraoxonase 1 (PON1). In conclusion, taurine protects against melamine-induced neurotoxicity in rats by improving autophagic response, downregulating apoptosis and inflammation markers, inhibiting oxidative stress, and potentially restoring brain metabolic enzyme activities and neurotransmitter levels.

Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting complication that significantly reduces quality of life in cancer patients, with no effective preventive or therapeutic options currently available. There is increasing evidence that neuroinflammation plays a central role in OIPN initiation and progression. This review provides a critical and up-to-date analysis of recent studies on the molecular mechanisms of oxaliplatin-induced neuroinflammation, with a particular focus on the integration of mitochondrial dysfunction, immune-mediated inflammation, glial activation, microRNA dysregulation, and gut-nerve axis disruption. Recent findings demonstrate that oxaliplatin disrupts mitochondrial dynamics, increases oxidative stress, and impairs blood-nerve barrier integrity, triggering neuroinflammatory responses. Neuroinflammation in OIPN is mediated through the activation of several key signaling pathways, including MAPK, NF-κB, Wnt/β-catenin, TLR4, and mTOR, which lead to increased production of pro-inflammatory cytokines and activation of glial cells. Furthermore, emerging evidence has identified dysregulation of the gut-nerve axis and alterations in gut microbiota composition as contributing factors that exacerbate oxaliplatin-induced neuroinflammation and neuropathic pain. Various pharmacological and plant-derived compounds, such as naringin, baicalein, and puerarin, as well as selective inhibitors of inflammatory pathways, have shown promising neuroprotective effects in animal models by attenuating inflammatory responses and alleviating neuropathic symptoms. By synthesizing these converging lines of evidence, this review further outlines potential future directions, including the development of combination therapies targeting multiple inflammatory pathways, microbiome-based interventions, and the translation of preclinical findings into well-designed clinical trials.

Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease causing motor neuron loss. 90-95% of ALS cases are sporadic, and the interplay of genetic predispositions and environmental exposures is essential in ALS pathology. Several neurotoxic exposures, such as smoking, pesticides, and organic solvents, have been implicated as affecting the risk of ALS. However, it is unclear how these exposures impact specific cellular mechanisms and influence ALS risk. We investigated the potential mechanisms of toxicity of diesel exhaust, toluene, pesticides, and smoking on ALS pathology through a bioinformatics approach. We retrieved the gene sets targeted by these environmental exposures, and the gene sets involved in ALS-associated biological processes. We performed overlap analysis to assess the statistical significance of the overlap between the gene sets associated with environmental exposures and those linked to ALS. Response to oxidative stress, synaptic signaling, lipid metabolic process, cellular oxidant detoxification, and regulation of gliogenesis significantly overlapped with the gene sets targeted by each of the four environmental exposures. Contrarily, chaperone-mediated autophagy, DNA repair, and regulation of action potential, significantly overlapped only with the gene sets targeted by diesel exhaust, pesticides, and toluene, respectively. Finally, transport across the blood-brain barrier, vesicle-mediated transport, actin filament-based transport, autophagy, transport to the Golgi and subsequent modification of proteins, metabolism of lipids, regulation of neurotransmitter receptor levels, and axon guidance significantly overlapped only with the gene set targeted by tobacco smoke pollution. This study aims to investigate the molecular relationships between neurotoxic exposures and ALS by overlap analysis, providing a framework that can be applied to investigate other exposure-disease interactions.

Tetracycline-derived compounds with anti-inflammatory properties have demonstrated neuroprotective potential in preclinical models of Parkinson's disease. In this study, we investigated the efficacy of DDOX (4-dedimethylamino 12a-deoxydoxycycline), a novel non-antibiotic tetracycline derivative. We used an intrastriatal unilateral 6-hydroxydopamine (6-OHDA) lesion paradigm in rats, which leads to partial nigrostriatal dopaminergic denervation. Our goal was to assess whether DDOX could preserve nigrostriatal dopaminergic integrity, reduce lesion-associated glial responses in the striatum, and improve motor function. Daily administration of DDOX (20 mg/kg, subcutaneously), beginning five days prior to lesion and continuing for fifteen days post-lesion, significantly attenuated the loss of dopaminergic terminals in the dorsal striatum and that of dopaminergic cell bodies in the ventral substantia nigra, as indicated by tyrosine hydroxylase (TH) immunostaining analysis. DDOX also markedly suppressed lesion-induced glial responses in the striatum. Behavioral assessments revealed that DDOX preserved motor performance, as evidenced by improved forelimb use (stepping test), maintained coordination and balance (rotarod), and maintained spontaneous locomotion (open field - actimeter). Additionally, DDOX significantly diminished amphetamine-induced rotational asymmetry, suggesting preservation of dopaminergic tone. Notably, the extent of functional recovery exceeded the degree of TH-immunoreactive nerve terminal preservation, indicating that DDOX's benefits may extend beyond dopaminergic neuroprotection. Further studies are warranted to elucidate the underlying mechanisms of these effects and confirm DDOX's efficacy in other Parkinson's disease models.

Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under pathologic conditions like hypoxia. Moreover, the effect of STX on embryonic neural stem/progenitor cells (ENS/PCs) derived from the rat embryonic brain, which are highly vulnerable during early development, remains unexplored. Considering the pivotal role of hypoxia in numerous neuropathological situations, this study examined the impact of STX on rat ENS/PCs exposed to chemically induced hypoxia. ENS/PCs were isolated from rat embryos and subjected to hypoxia using 100 µM cobalt (II) chloride hexahydrate (CoCl₂0.6 H₂O) for 48 h. Cytotoxic activity of STX andCoCl2was assessed using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium (MTT) assay, while stem cell identity was confirmed via flow cytometry (Nestin, SOX2). STX (0.1 and 0.5 µM) was applied under both normoxic and hypoxic conditions. Expression levels of hypoxia-inducible factor 1-alpha (Hif1α) mRNA, autophagy markers (Beclin-1, microtubule-associated protein 1 light chain 3-II [LC3-II]), and pro-inflammatory proteins nuclear factor kappa B [NF-κB], Toll-like receptor 2 [TLR2], Toll-like receptor 4 [TLR4]) were assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques following STX treatment. Based on flow cytometric assays, over 70% of cultivated cells were positive for Nestin and SOX2. Hypoxia significantly reduced cell viability and proliferation, accompanied by increased Hif1α mRNA expression. Treatment with STX (0.1 µM and 0.5 µM) significantly reversed these changes, restoring cell viability and proliferation while reducing Hif1α levels. Hypoxia also elevated autophagy markers (Beclin-1, LC3-II) and pro-inflammatory proteins (NF-κB, TLR2, TLR4), which STX suppressed in a dose-dependent manner. This study provides novel evidence that STX mitigates hypoxia-induced neural damage by downregulating Hif1α and its downstream inflammatory and autophagic signaling pathways. The use of a clinically relevant cannabinoids mixture and a developmentally sensitive cell model underline the translational potential of balanced THC/CBD formulations in the treatment of hypoxia-related neurodegenerative and neurodevelopmental conditions.

Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes mellitus (T2DM). Metformin is considered the first line drug for treatment of T2DM and has a plethora of effects in the peripheral and nervous system. However, the neuroprotective mechanism of action of this drug is still under debate. In order to assess the effects of metformin in dementia, we investigated the optimal time to start metformin treatment in animals that were submitted to intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg) to induce a sporadic AD-like rodent model of dementia. We used two protocols of metformin administration: early metformin (50 mg/Kg/daily) treatment (2 days after STZ model induction, lasting 28 days) and late metformin (50 mg/Kg/daily) treatment (20 weeks after STZ model induction, lasting 28 days). Both time points improved cognitive behavior in STZ rats, as evaluated by the novel object recognition and Morris's water maze tasks. Moreover, both treatments reduced neuroinflammatory parameters, such as TLR4, RAGE, TNF-α and NF-κB protein expression, induced in STZ animals. Metformin downregulated the methylglyoxal/RAGE/NOX‑2 signaling pathway by restoring glyoxalase 1 activity and GSH levels, which are impaired in the STZ-induced dementia model. Our data contribute to understanding the neuroprotective role of metformin, particularly in conditions involving insulin resistance, such as diabetic encephalopathy and AD.

Bisphenol A (BPA), a widely prevalent environmental contaminant, has been linked to neuroinflammation; however, the molecular mechanisms underlying this effect remain unclear. In this study, we used molecular docking and molecular dynamics simulations to predict the interactions of BPA with key proteins in the cGAS-STING-NLRP3 signaling pathway, an innate immune axis implicated in neuroinflammatory diseases. BPA demonstrated higher predicted binding affinity to these proteins than the reference neurotoxicant rotenone, suggesting a potential to interact with and modulate this pathway. Molecular dynamics simulations indicated stable binding of BPA, with possible structural adaptations observed in cGAS and NLRP3 proteins, which may influence downstream inflammatory signaling. Since this pathway plays a role in neurodegeneration by sensing cytosolic DNA and activating the NLRP3 inflammasome and type I interferon responses, our computational findings raise the possibility of a previously unrecognized route for BPA-mediated neuroimmune modulation, distinct from oxidative stress or NF-κB activation. These predictions underscore the need for further experimental validation and provide a basis for future research into the mechanistic underpinnings and therapeutic targeting of BPA-induced neurotoxicity.

With the advent of medical technology and the sustenance of a longer lifespan, an increase in the number of age-related neurodegenerative diseases, including Parkinson's disease (PD), is inevitable. Although current treatments for PD provide remarkable symptomatic relief for a few years, their side effects, combined with the progression in neurodegeneration, pose an urgent challenge for development of more effective treatments for this devastating disease. The challenge is further exacerbated by the unknown etiology in most PD cases. Nonetheless, progress in early identification of the premorbid/prodromal symptoms as well as understanding processes leading to their manifestation may help provide novel preventive and/or intervention strategies. The triad of the best-characterized and inter-related symptoms of prodromal PD include hyposmia (decrease sense of smell), constipation, and major depressive disorder (MDD). Recent revelations indicate a crucial role for the gut microbiota (GM) not only in maintaining the integrity of the gastrointestinal system but also that of the central nervous system via its bidirectional relationship with the brain, commonly referred to as the gut-brain-axis (GBA). Moreover, neuroinflammation, underscored by microglial activation, is believed to play a critical role in neurodegenerative as well as neuropsychiatric disorders including MDD. Here, we delve into the primary roles of GM/GBA and microglia, as well as their interactions, with the aim of providing novel diagnostic and/or treatments in PD. Regarding the treatments, we mention potential use of pre- post- or pro-biotics, and nicotinic or toll-like receptor modulators.

Tyrosinemia type II (Richner-Hanhart syndrome) is a rare disorder caused by mutations in the TAT gene, leading to elevated blood tyrosine and impaired metabolism. It presents with oculocutaneous symptoms, retinal tyrosine crystals, and neurological issues. Elevated tyrosine disrupts brain metabolism, neurotransmitters, and neurotrophic factors, causing neuroinflammation and affecting brain function. The exact mechanism of neurological damage is unclear, and the impact of dietary intervention on cognition is uncertain. While rodent models are commonly used, zebrafish are emerging as a cost-effective, genetically similar alternative for studying tyrosinemia type II. Thus, this study aims to determine whether acute exposure of zebrafish to elevated tyrosine concentrations can reproduce early central nervous system alterations associated with tyrosinemia type II. Zebrafish were exposed via immersion to 1 mM or 2 mM tyrosine for 1-24 h, with a total of 180 animals used across assays. Behavioral analysis was conducted using the novel tank test, and cholinergic and oxidative stress markers were assessed. Brain tyrosine levels were measured centrally. Exposure to 1 mM tyrosine for 24 h resulted in the highest brain accumulation, suggesting a non-linear dose-response. Behavioral testing revealed decreased locomotor activity and exploratory behavior, and ChAT activity was reduced in both exposure groups. No significant changes were observed in oxidative stress or protein damage. These findings indicate that acute tyrosine exposure induces early behavioral and cholinergic alterations without detectable oxidative stress, supporting the use of zebrafish as a preliminary model to study early neurochemical disturbances such in tyrosinemia type II. Further studies should explore different life stages, sex-specific responses, chronic exposure, and precise tyrosine kinetics, including potential non-linear effects due to the LAT1 transporter, to clarify mechanisms underlying neurotoxicity and improve translational relevance.