Neurotoxicity Research最新文献

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.

Mitochondrial dynamics, including fusion and fission, are essential for neural cell function and survival during central nervous system development. These processes are vital for eye formation, which requires high energy to support cellular events, such as proliferation, differentiation, and apoptosis. However, different conditions can disrupt the normal development of the eye, such as hyperhomocysteinemia (HHcy), a metabolic disorder characterized by elevated homocysteine (Hcy) levels. This study aimed to evaluate the effects of HHcy on eye development of Gallus domesticus. Fertilized eggs were treated with 20 µmol Hcy at embryonic day 2 (E2), with analyses conducted at E6 and E10 using a combination of survival analysis, transmission electron microscopy, flow cytometry for mitochondrial proteins and autophagy markers, and cell viability assay, providing a comprehensive evaluation of HHcy toxicity. A significant 40% reduction in the survival rate relative to control was observed in HHcy-treated embryos. Although eye diameter remained unchanged, ultrastructural analyses revealed mitochondrial damage, including membrane rupture, loss, and disorganization of the cristae, induced by the exposure at both embryonic ages. Analysis of proteins involved in mitochondrial dynamics showed increased Drp1 (fission) and decreased Mfn1 and Mfn2 (fusion) in HHcy-treated embryos. At E10, these changes were accompanied by an increased number of mitochondrial profiles and reduced mitochondrial area. HHcy also induced a reduction in cell viability, highlighting its cytotoxic effects, particularly on mitochondria. Additionally, increased cytoplasmic vesicles and autophagy were observed in HHcy-treated embryos. These findings indicate that mitochondria are key targets of HHcy, with mitochondrial dynamics and ultrastructural integrity significantly impaired by the exposure. These changes highlight the harmful effects of high Hcy levels on embryonic development and eye formation, providing insights into its pathogenic effects.

Retinoic Acid (RA) induces differentiation and regulates gene expression through three subtypes (α, β, γ) of the nuclear retinoid receptor heterodimer (RAR/RXR), which also function as transcription factors. Earlier, we reported the long intergenic noncoding RNAs (LINC-RBE and LINC-RSAS) induced by All-Trans Retinoic Acid (ATRA) in cultured primary hippocampal neurons from adult rat brain at transcriptional and post-transcriptional levels, respectively. In this study, we report that ~ 25% of the human neuroblastoma (SH-SY5Y) cells were differentiated by 1 µM ATRA-treatment within 72 h showing extension of neurites from spindle-shaped cells demonstrating neuronal differentiation. Expression of RARβ and interferon regulatory factor-1 (IRF-1) mRNAs was significantly upregulated up to 16xfold at 10 h and 2.6xfold at 8 h by 1 µM ATRA-treatment, respectively. This indicated activation of the RA-signaling pathway in these cells. With a transfection efficiency of ~ 40%, overexpression of LINC-RBE and LINC-RSAS caused ~ 34% and ~ 33% inhibition of cell proliferation, respectively, with an increase in cell death and ~ 10% reduction in number of cells in G1-phase of cell cycle. ATRA-treatment alone caused ~ 40% inhibition of cell proliferation, and induced ~ 66% of cells to G1-phase arrest. Combined effect of LINC-RSAS + ATRA further enhanced inhibition of cell proliferation by additional ~ 32%, whereas LINC-RBE, ATRA and LINC-RBE + ATRA showed similar effects indicating distinct effects and mechanisms of their actions. Moreover, overexpression of these lncRNAs led to fourfold increase in genomicDNA breakage/damage in these cells. Thus it showed an unique relationship between lncRNA and RA during neuronal differentiation, most likely involving regulation of gene expression.

Lethal organophosphate (OP) exposure leads to status epilepticus (SE), which, despite standard-of-care (SOC) therapy, is associated with acute mortality and long-term morbidities. Neuronal injury and inflammation are reported following OP-SE, and drugs targeted at these processes have produced beneficial outcomes. Verapamil (VPM) is a calcium-channel blocker used as an antihypertensive drug and has been shown to exhibit neuroprotective and anti-inflammatory actions in experimental models of CNS injuries. Here, we investigated the feasibility of an adjunctive intramuscular (i.m.) VPM therapy in OP Diisopropyl Fluorophosphate (DFP)-induced SE. We also investigated the safety and toxicity of i.m. VPM and compared its pharmacokinetic (PK) profile to oral (p.o.) administration. Rats were injected with DFP (4 mg/kg, s.c.). One minute later, SOC treatment consisting of atropine (0.5 mg/kg, i.m.) and pralidoxime chloride (2-PAM; 25 mg/kg, i.m.) were administered, and at 1-hour post-SE, midazolam (1.78 mg/kg, i.m.) was given. Rats that met the behavioral SE severity criteria (Racine 4-5) were randomized into two treatment groups: those receiving saline (SAL) or VPM (10 mg/kg, i.m. bid, 3 days). Histological analysis was conducted to assess neuronal injury and injection-site pathology. In a separate group of rats, PK studies were conducted on blood and brain homogenates treated once with saline or VPM (10 mg/kg, p.o. or i.m.). Our data demonstrated that following DFP-SE, i.m. VPM achieved higher blood and brain levels and exhibited a favorable PK profile compared to p.o. route. VPM therapy did not cause significant muscle pathology and produced a robust neuroprotective response. Neuroinflammatory markers and long-term behavioral outcomes were not included in this study. Our studies provide evidence that the i.m. route is an effective method for delivering VPM following SE, producing significant neuroprotective outcomes compared to treatment with the standard-of-care alone in OP-SE.

Novelty-seeking (NS) refers to the tendency of humans and animals to explore novel and unfamiliar stimuli and environments. It is a core feature of Attention Deficit Hyperactivity Disorder (ADHD) and associated with multiple psychiatric disorders. Recent researches indicated that NS behavior has an effect on reward-related learning. The hippocampus is a core brain region linked to reward-related learning and memory. However, how the hippocampal proteome modulates NS behavior remain largely elusive. In current study, we identified 165 differentially expressed proteins in the hippocampus between high and low novelty response mice with mass-spectrometry-based proteomics. Among these proteins, the over-expression of Tenascin-R (TNR) in high novelty response mice was verified with Western Blot and Immunofluorescence imaging. Moreover, systematic genetic analysis based on the BXD strains showed the expression of TNR is genetically cis-regulation. Further, gene co-expression analysis revealed that TNR has a negative connection with the expression of dopamine receptor D2 (DRD2) (P = 0.003, r = -0.298). And the knockdown of TNR enhanced the expression of DRD2 in vitro. Finally, we constructed a correlation network to exhibit the links among TNR gene variant, expression of TNR and DRD2, and NS related behaviors. Our study provides a novel hippocampal biomarker with preliminary insights into its association with the dopaminergic synaptic pathway. ROC analysis further confirms TNR's robust discriminatory power for distinguishing novel open field behavior, a key NS - related phenotype, which may be a new strategy for diagnosis of NS-related traits.

The coronavirus disease 2019 (COVID-19) pandemic has brought significant challenges to global health, not only due to respiratory symptoms but also due to its impact on psychiatric disorders. Understanding the biological mechanisms underlying psychiatric manifestations in individuals with COVID-19 is crucial. This study aimed to investigate potential alterations in caspase 3 and 8 levels, as well as brain-derived neurotrophic factor (BDNF) levels, in individuals with COVID-19. The association of these markers with mental health was also assessed. A cross-sectional study was conducted, including individuals with COVID-19 and those without the disease. The stress levels were higher in individuals with COVID-19. Caspase 3 and 8 and BDNF levels were increased in individuals with COVID-19 compared to individuals without COVID-19. No significant differences were found in caspase 3 and 8 and BDNF levels between moderate/severe and asymptomatic/mild symptoms of COVID-19. The results indicate that no significant differences were observed between the diagnosis of anxiety disorders and the levels of markers. However, higher caspase 3 levels in individuals without anxiety and COVID-19 were found. No significant associations between the diagnosis of major depressive disorder or psychiatric symptoms and caspase 3, caspase 8, and BDNF levels were found. The results indicate that, although caspase 3, caspase 8, and BDNF levels are increased in individuals with COVID-19, these elevations are not associated with the severity of COVID-19 symptoms or psychiatric conditions and symptoms in post-COVID-19. These findings suggest that severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may influence cellular activity and neurotrophic markers, but that other factors likely contribute to psychiatric disorders.