Neurotoxicology最新文献

Doxorubicin (DOX)-induced chemobrain has been reported in several studies. Its main culprit is the induction of massive amounts of reactive oxygen species (ROS), hence triggering damage to brain tissues and thus leading to neuroinflammation. Biochanin A (BIO-A) is known to be an antioxidant, anti-inflammatory, and neuroprotective agent. An insilico study was designed to examine the potential neuroprotective effect of BIO-A. An invivo study was used to evaluate the modulatory effect of BIO-A on cognitive impairment engendered by DOX. The insilico investigation proved the putative neuroprotective effect of BIO-A. In the invivo study, BIO-A treatment counteracted DOX-induced memory deficits, as evidenced by improved spatial memory in rats compared to the DOX-only group. BIO-A also reversed DOX-triggered hippocampal neurodegeneration and neuroinflammation, supported by a significant decrease in tissue contents of NF-κB (p65) by 32% and NLRP3 by 36% versus the DOX-only group. BIO-A also abrogated DOX-induced neurodegneration, as evidenced by increasing SIRT1 content by 2-fold and BDNF content by 2-fold versus the DOX-only group in hippocampal tissues. In addition, BIO-A ameliorated DOX-augmented apoptosis in the hippocampus, as evidenced by lowering caspase-3 content in the hippocampus by 26% versus the DOX-only group. Regarding tauopathy, BIO-A reversed DOX-increased tauopathy by 35% versus the DOX-only group. The neuroprotectant miR-132 was increased by BIO-A in hippocampal tissues by 4-fold, contrary to the DOX-only group. Thus, BIO-A treatment modulated DOX-induced behavioral, histological, and molecular changes in the hippocampi of rats. Further studies are recommended to evaluate BIO-A in early clinical trials for the purpose of protection against chemobrain in cancer patients.

Benzo(a)pyrene (B[a]P) and its ultimate active metabolite, benzo(a)pyrene-7,8-dihydrodiol-9,10-epoxide (BPDE), are known to have neurotoxic effects that can damage hippocampal neurons and cause cognitive impairments. Ferroptosis, a form of programmed cell death distinct from apoptosis, is associated with multiple neurodegenerative conditions. Recently, we have found that BPDE triggers ferroptosis in hippocampal neurons, though the underlying molecular mechanism remains unclear. Here, we firstly identified ACSL3 as the target of BPDE-induced ferroptosis through transcriptomics, and then investigated its role in ferroptosis using gene transfection technology in HT22 cells and primary hippocampal neurons. Our results showed that BPDE treatment caused significant transcriptional changes in HT22 cells, notably decreasing ACSL3 expression, which was further validated in both HT22 cells and primary hippocampal neurons. Furthermore, overexpression of ACSL3 effectively rescued the ferroptosis induced by BPDE in HT22 cells and primary mouse hippocampal neurons, characterized by increased cell viability, enhanced glutathione and glutathione peroxidase activities, and reduced levels of intracellular free Fe²⁺, reactive oxygen species, and malondialdehyde. In summary, our findings demonstrated that BPDE induces ferroptosis in hippocampal neurons by inhibiting ACSL3 expression, providing new insights into the toxicological mechanisms underlying BPDE-induced neurotoxicity.

Although neonicotinoids were considered safe for mammals for many decades, recent research has proven that these insecticides can alter cholinergic functions by interacting with neuronal nicotinic acetylcholine (ACh) receptors (nAChRs). One such receptor is the heteromeric α4β2 nAChR, which exists under two different stoichiometries: high sensitivity and low sensitivity α4β2 nAChRs. To replace these insecticides, new classes of insecticides have been developed, such as, sulfoximine, sulfoxaflor, and the butenolide, flupyradifurone. In this study, we injected Xenopus laevis oocytes with 1:10 and 10:1 α4:β2 subunit RNA ratios, in order to express the high (α4)₂(β2)₃ and low sensitivity (α4)₃(β2)₂ nAChRs. Using the two-electrode voltage-clamp technique, we found that the low sensitivity (α4)₃(β2)₂ nAChRs were activated by all tested insecticides, whereas the high sensitivity (α4)₂(β2)₃ nAChR was only activated by ACh. Imidacloprid, sulfoxaflor and flupyradifurone confirmed their agonist effects by reducing the responses to the ACh EC₈₀ concentrations, for both low (α4)₃(β2)₂ and high sensitivity (α4)₂(β2)₃ stoichiometries. Clothianidin only inhibited ACh responses of the low sensitivity (α4)₃(β2)₂ stoichiometry. Mutation E226P in the α4 subunit of the low sensitivity (α4)₃(β2)₂ receptors inhibits the agonist potency of imidacloprid and flupyradifurone, whereas mutation L273T (in the β2 subunit) in the high sensitivity (α4)₂(β2)₃ nAChR leads to activation by all insecticides. Major agonist effects were found with the double mutation of the E226P in the α4 subunit, and the L273T in the β2 subunit of the high sensitivity (α4)₂(β2)₃ stoichiometry.

Parkinson's disease is one of the most prevalent neurodegenerative disorders worldwide. The kynurenine pathway associated with oxidative stress and neuroinflammation is recognized to contribute to its pathophysiology, although the exact mechanism is not fully elucidated. In neuroinflammation, IDO-1 catalyzes the conversion of tryptophan to neurotoxic QUIN through the kynurenine pathway. Consequently, QUIN increases oxidative stress via nNOS and NMDA, which causes neurodegeneration. Few studies have reported on the effect of different antiviral drugs in Parkinson's disease; the exact mechanism is still unknown. The antiviral acyclovir has been shown to have neuroprotective properties and can cross the blood-brain barrier. We examined acyclovir's effects and potential mechanisms in the 6-OHDA-induced in vitro model of Parkinson's disease in SH-SY5Y cells using biochemical, immunocytochemical, and in silico methods. MTT assay demonstrated that acyclovir significantly decreased cell mortality induced by the neurotoxic 6-OHDA at dosages of 3.2 µM, 6.4 µM, 12.8 µM, 25.6 µM, and 51.2 µM. In immunocytochemical analysis, acyclovir treatment decreased α-synuclein and TNF-α expressions in cells. In biochemical analyses, while IL-17A and TOS levels decreased depending on varying doses (1.6 µM, 3.2 µM, 6.4 µM, 12.8 µM), TAC levels increased. Using in silico analyses to investigate the mechanism showed that acyclovir docked with TNF-α, IL-17A, IDO-1, nNOS, α-synuclein, and NMDA. The findings demonstrated that acyclovir had neuroprotective effects by modulating the kynurenine pathway and decreasing neurodegeneration via QUIN inhibition in an in vitro Parkinson's disease model. Although the mechanisms of acyclovir's effects in Parkinson's disease are unclear, the results obtained from the experiments are encouraging.

Parkinson's disease (PD) is a common progressive neurodegenerative disease characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta (SNpc). Environmental and lifestyle factors, such as smoking and coffee drinking, have been associated with a decreased risk for PD. However, the biological mechanisms underlying protective effects on PD are still not fully understood. It has been suggested that non-nicotine components in cigarette smoke and non-caffeine components in coffee may contribute to this protective effect. The aim of this review was to explore candidate molecules and mechanisms behind the effects of smoking and coffee drinking on PD by integrating findings from previous studies. By cross-referencing an index of tobacco constituents and a list of coffee constituents with existing literature on natural compounds and their structural analogs that show inhibitory activities against monoamine oxidase B, catechol O-methyltransferase, and α-synuclein fibrillation, we have identified tobacco and coffee components that inhibit these targets. Furthermore, tobacco and coffee components potentially play roles in suppressing neuroinflammation, activating the Nrf2 pathway as natural activators, and altering the gut microbiome. This review suggests that the phenolic compounds from tobacco and coffee investigated may contribute to the low incidence of PD in smokers and coffee drinkers, showing moderate to strong potential as therapeutic interventions. The current review suggests that multifunctional molecules found in coffee and cigarette smoke may have potential neuroprotective effects, but none of the data indicates that multifunctionality is required for these effects. This review will deepen our understanding of how smoking and coffee drinking are linked to a reduced risk of PD and will also be important in elucidating the mechanisms underlying the protective effects of smoking and coffee drinking on PD.

Toxoplasmosis presents notable hazards in the context of pregnancy, impacting the health of the mother and the neurodevelopment of the fetus via immune reactions and possible vertical transmission. The maternal immune response from chronic Toxoplasma gondii (T. gondii) infection may negatively influence fetal neurodevelopment. This research evaluated the association between the seroprevalence of chronic T. gondii and cytomegalovirus infection in pregnant women and the neuropsychological development of their children at 12 months of age. A follow-up study evaluated women during the gestational period and their respective infants. The pregnant women were tested for the presence of antibodies to infectious agents: T. gondii, cytomegalovirus (CMV), syphilis, human immunodeficiency virus (HIV), hepatitis B and C. Detailed information about the newborns was extracted from medical records. At 12 ± 3 months of age, the infant's neurodevelopment was assessed using the Bayley-III Scales of Infant and Toddler Development by a trained specialist under the supervision of a neuropsychologist. A statistically significant association was found between maternal IgG anti-T. gondii levels and lower scores on the Bayley-III cognition scale, with a non-standardized β-coefficient of -0.078 (95 %-CI: -0.144 to -0.013), accounting for 35.1 % of the variation in this outcome. These results suggest that chronic maternal T. gondii infection, even without vertical transmission, may be associated with subtle changes in the child's cognitive development. Therefore, monitoring and early intervention are essential to identify and address possible delays in childhood neurodevelopment related to chronic maternal toxoplasmosis.

Bisphenol A (BPA) is an endocrine disruptor monomer that is widely used in the manufacturing of epoxy resins and polycarbonate plastics. Several lines of evidence indicate the function of the pre- or perinatally PI3K/AKT signaling pathway in the development of psychiatric disorders. The present study aimed to evaluate for the first time the effect of modifying the NMDAR/PSD-95-PTEN/AKT signaling pathway on behavioral and synaptic plasticity of early-life BPA exposure and its long-lasting influence on juvenile and adulthood stages of development. We investigated the effects of oral BPA doses of 50 and 125 mg/kg/day on the prefrontal cortex (PFC) and hippocampus of male Sprague Dawley rats from postnatal day (PND) 18-60 and PND 18-95, which correspond to juvenile and adolescent stages, respectively. Subsequently, we performed a series of rat behavioral tests, including the open field, elevated plus-maze, forced swimming, and Y-maze. Notably, neurotransmitter levels such as dopamine, serotonin, and gamma-aminobutyric acid, levels of postsynaptic density protein 95 and cAMP response element-binding protein, as well as mRNA levels of N-methyl-D-aspartate receptor subunits, fluctuated between reduction and elevation in the PFC and hippocampus. Furthermore, phosphatase and tensin (PTEN) mRNA and protein levels were upregulated in both brain areas, while PI3K, protein kinase B (AKT) and mammalian target of rapamycin (mTOR) mRNA and protein levels were decreased. Finally, our findings indicate that postnatal BPA exposure promotes long-term anxiety and depressive-like behaviors, as well as cognitive impairment, via modulation of the NMDAR/PSD-95-PTEN/AKT pathway. These findings could help to elucidate the potential developmental and neurobehavioral effects of early-life BPA exposure.

Objective: To explore the microstructural damage of white matter in acute diquat (DQ) poisoning patients using diffusion kurtosis imaging (DKI) and Tract-based Spatial Statistics (TBSS).

Methods: This study included 19 DQ poisoning patients and 19 age-matched controls. MRI was performed using a 3.0 T Philips Achieva scanner with sequences including 3D T1WI, T2WI, DWI, 3D T2WI-FLAIR, and DKI (3 b-values, 15 directions). DICOM to NIFTI image form conversion was done using MRIcron's Dcm2niigui, followed by motion and eddy current correction with FSL to create a brain mask. Scalar indicators (MK, AK, RK, FAK) were calculated with DKE software. TBSS was used for spatial normalization, skeletonization, and projection of DKI indices for group analysis with TFCE for multiple comparison correction (P < 0.025).

Results: After the screening and enrollment process, 19 DQ-poisoned patients and 19 healthy volunteers were analyzed. No significant age or sex differences were found between groups. For Mean Kurtosis (MK), the right corticospinal tract showed a significant difference with a mean difference of 0.21 (95 % CI: 0.15-0.27) and P = 0.000503. Axial Kurtosis (AK) in the left superior longitudinal fasciculus had a mean difference of 0.18 (95 % CI: 0.12-0.24) and P = 0.0024. Fractional Anisotropy of Kurtosis (FAK) in the right corticospinal tract showed a mean difference of 0.19 (95 % CI: 0.13-0.25) and P = 0.0000318. Axial Kurtosis (AK) positively correlated with blood drug levels (r = 0.52, P < 0.05). Seven patients developed subcortical leukodystrophy, mainly in the frontal parietal lobe, with possible insular lobe involvement.

Conclusions: DQ poisoning primarily damages the right corticospinal tract, right cingulate gyrus, and left superior longitudinal fasciculus, potentially causing movement and visual impairments. The injury involves demyelination and axonal degeneration, with asymmetrical damage between hemispheres. The left superior longitudinal fasciculus injury is dose-dependent, and unlike prior studies, dopaminergic nuclei were unaffected. The frontal parietal lobe is predominantly affected, with some insular lobe involvement in DQ poisoning patients.