Neurotoxicity Research最新文献

Neural tube defects (NTDs) are severe congenital anomalies affecting 1-2 infants per 1000 births, and are influenced by genetic and environmental factors, with DNA hypomethylation and methylation cycle suppression being key causes. In our earlier investigation, decitabine (DCT) caused multiple NTDs in embryonic zebrafish, supporting this hypothesis. Recent research has emphasized the importance of myo-inositol (MI) in embryonic development and its efficacy in reducing the risk of neural tube defects, even in cases resistant to folate. We aimed to examine the effect of MI on DCT-induced NTDs in an embryonic zebrafish model. The embryos were exposed to 1 mM DCT alone, 50 µM MI with 1 mM DCT, 100 µM MI with 1 mM DCT, and a control group for comparison. The development, hatching, mortality rates, neural tube malformations, and neural tube patterning of developing embryos were monitored and recorded. Exposure to MI significantly reduced the incidence of NTDs in developing embryos. At concentrations of 50 µM and 100 µM, MI provided 35% and 30% protection against DCT-induced neural tube malformation, respectively. Multiple NTDs were significantly reduced in the MI groups, with 1 mM DCT causing 95% defects, 50 µM MI with 1 mM DCT causing 50%, and 100 µM MI with 1 mM DCT causing 55% defects. The DCT-induced hatching delay was also reversed by MI treatment. Alizarin red staining and histopathological observations supported these observations. In the context of neural tube development, the protective effects of MI against DCT-induced NTDs could be attributed to its potential role in epigenetic regulation, which may influence genetic expression.

The antidiabetic drug metformin possesses antioxidant and cell protective effects including in neuronal cells, suggesting its potential use for treating neurodegenerative diseases. This study aimed to assess metformin's effects on viability and antioxidant activity in human-induced pluripotent stem cell (hiPSC)-derived neurons under varying concentrations and stress conditions. Six lines of hiPSC-derived neuronal progenitors derived from healthy human iPSCs were treated with metformin (1-500 µM) on day 18 of differentiation. For mature neurons (day 30), three concentrations (10 µM, 50 µM, and 100 µM) were used to assess cytotoxicity. MG132 proteasomal inhibitor and sodium arsenite (NaArs) were used to investigate oxidative stress, and 50 µM of metformin was tested for its protective effects against oxidative stress in hiPSC-derived neurons. Metformin treatment did not affect cell viability, neuronal differentiation, or trigger reactive oxygen species (ROS) generation in healthy hiPSC-derived motor neurons. Additionally, mitochondrial membrane potential (MMP) loss was not observed at 50 µM metformin. Metformin effectively protected neurons from stress agents and elevated the expression of antioxidant genes when treated with MG132. However, an interplay between MG132 and metformin resulted in lower expression of Nrf2 and NQO1 compared to the MG132 group alone, indicating reduced JC-1 aggregate levels due to MG132 proteasomal inhibition. Metformin upregulated antioxidant genes in hiPSC-derived neurons under stress conditions and protected the cells from oxidative damage.

Trimethyltin chloride (TMT) is a neurotoxicant that damages the central nervous system (CNS) and triggers neurodegeneration. This study used multi-omic data, including transcriptomics and proteomics of the rat hippocampus, to identify differentially expressed genes and proteins in TMT-induced neurotoxicity over time, related to neuro-axonal damage marked by plasma Neurofilament Light (NfL) levels. Data were collected at 12, 24, 48, 72, and 168 h post-TMT administration. NfL levels surged at 72 and 168 h, confirming neuro-axonal damage. Transcripts of genes in the chemokine signaling pathway (Cxcl10, Cxcl12, Cxcl14, Cxcl16), apoptosis pathway (Caspase-3, PARP1, CTSD), and TNF signaling pathway (TNFR1, MMP9, ICAM-1, TRAF3) showed significant differential expression starting from 48 h, preceding the NfL increase, suggesting their roles in neuro-axonal damage. Additionally, 11 Alzheimer's disease-related proteins, with significant changes from 72 to 168 h, were detected only in the proteomic dataset, indicating post-translational modifications might be crucial in neurotoxicity. Pathway analysis revealed that neurodegeneration and Alzheimer's disease pathways were among the top 15 affected by TMT-induced gene regulation, aligning with the involvement of TNF signaling, apoptosis, and chemokine signaling in neurodegeneration. This research highlighted the value of longitudinal omics studies, combined with pathway enrichment, gene-disease association, and neuro-axonal damage biomarker analyses, to elucidate neurotoxicant-induced neurodegeneration. Findings from this study could enhance the understanding of TMT-induced neurotoxicity, potentially informing future therapeutic strategies and preventive measures.

Aminopyrimidine compounds have been gaining traction in the field of drug discovery in recent years due to their emergence as multi-targeted molecules. This makes them perfect candidates as agents for cognitive improvement, as cognitive decline is a multifaceted condition. We aim to evaluate their potential for memory enhancement, specifically through their cholinergic properties. This work examines the properties of seven aminopyrimidine derivatives and their effects on memory acquisition and retention. These compounds were administered to NMRI mice after the induction of amnesia by scopolamine, and memory impairment and improvement were assessed using passive avoidance and spontaneous alternation tests with the drug donepezil as the positive control group. These compounds were also analyzed using docking and ADME prediction studies to determine potential affinity to the acetylcholinesterase enzyme, and characterize pharmacokinetic properties, respectively. Additionally, in vitro inhibition of cholinesterase was evaluated. Results showed that three of the seven compounds significantly increased cognition in both behavioral tests. Software analysis suggested allosteric inhibition or modulation of acetylcholinesterase, signifying the potential of these compounds for further optimization and eventual utilization for treatment of cognitive impairment cases.

The global rise in obesity and overweight over the past few decades has led to numerous associated disorders, including cognitive deficits. This study evaluate investigates the effects of Naringin (Nar) on memory and learning, anxiety-like behaviors, brain-derived neurotrophic factor (BDNF), cAMP responsive element binding protein (CREB), acetylcholinesterase (AChE) activity, and neuronal density in the CA₁/CA₃ subfields of the hippocampus in an MSG-induced obese obesity rat model. Forty-eight male Wistar rat pups were randomly divided into four groups: Control, MSG, MSG + Nar50, and MSG + Nar100. MSG (4 g/kg BW) was administered subcutaneously in the cervical region from PND 2 to PND10, while Nar (50 mg/kg BW and 100 mg/kg BW) was administered orally from PND30 to PND42. After the treatment period, cognitive (working memory and passive avoidance) and anxiety-related tests (elevated plus maze and novelty-suppressed feeding test) were performed. Subsequently, hippocampal protein level of BDNF and CREB/BDNF gene expression, AChE activity and neuronal density in the CA₁ and CA₃ regions of the hippocampus were measured. Relative to the MSG group, the Nar-treated rats demonstrated improvements in spatial working memory, reduced anxiety-related behaviors, elevated hippocampal CREB and BDNF genes and BDNF protein levels, and reduced AChE activity. Additionally, Nar treatment increased neuronal density in the CA₁/CA₃ subfields of the hippocampus. These findings suggest that Nar enhances cognitive function and mitigates anxiety in MSG-induced obese rats by modulating CREB/BDNF signaling pathway, inhibiting AChE, and exerting neuroprotective effects in the hippocampus.

Early parental care is critical for the development of cortico-limbic circuits regulating stress responses and emotional well-being. Conversely, infant maltreatment can increase susceptibility to mood disorders-such as anxiety and depression-and impair stress-coping abilities. Here, we employed the Scarcity-Adversity Model (SAM) in rats, limiting nesting resources from postnatal days 8-12, to examine its effects on maternal and adult offspring behavior. SAM-exposed mothers exhibited fragmented care and increased violence towards pups. By postpartum day (PPD) 13, maternal fecal corticosterone metabolites (FCM) were elevated, indicating heightened stress. At weaning, SAM dams also showed increased anxiety-like behavior in the Elevated Plus Maze (EPM), suggesting significant emotional alterations. In adulthood, SAM-exposed offspring underwent anxiogenic tests. Both male and female SAM offspring showed increased latency to enter open arms and reduced risk-assessment in the EPM, though females displayed anxiolytic-like behavior in the Light-Dark Box. Male SAM rats had reduced locomotion in the Open Field, earlier onset and increased immobility in the Forced Swim, and increased latency to groom in the Sucrose Splash. When exposed to acute stress, male SAM rats had lower FCM levels, consistent with their passive stress reactivity. These findings confirm SAM induces long-lasting, sex-specific changes in risk-taking, novelty responsiveness, and stress reactions, underscoring the importance of early nurturing in promoting well-being and reducing psychopathological risk.

Dopamine (DA) has long been considered a major factor in the development of Parkinson's disease (PD). Ethanol (EtOH) and nicotine (Nic), either alone or in combination, have been shown to affect nigrostriatal dopaminergic neuronal activity. Here, we investigate whether EtOH and Nic alone or in co-exposure can restore the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced depletion of dopamine (DA), DA metabolites, and tyrosine hydroxylase (TH) in the striatum and hippocampus of C57BL/6N mice. MPTP-treated mice were treated intraperitoneally with saline (control), EtOH (1.0-3.0 g/kg), Nic (0.5-2.0 mg/kg), or a combination of EtOH and Nic. Brain samples were collected 1 h after treatment. DA and its metabolites 3,4-dihydroxyphenylacetic acid (DOPAC), 3-methoxytyramine (3-MT), and homovanillic acid (HVA) were measured by HPLC-ECD, while TH protein content and TH phosphorylation at Ser31 (pSer31 TH) were quantified by Western blot. EtOH (2.0 and 3.0 g/kg) alone reversed the effects of MPTP treatment in both studied brain regions, as evidenced by an increase in DA, DOPAC, and HVA contents, TH protein, and pSer31 TH compared to the MPTP group, indicating restorative effects on DA neurons in the MPTP model. Likewise, Nic (1.0 and 2.0 mg/kg) alone reversed MPTP treatment effects, with treated mice showing increased DA, DOPAC, and HVA contents, TH protein, and pSer31 TH compared to MPTP mice. Co-administration of EtOH (2.0 g/kg) and Nic (1.0 mg/kg) further increased DA, DOPAC and HVA tissue contents, TH protein, and pSer31 TH, indicating an additive effect. These results show that moderate to high doses of EtOH and Nic induce similar increases in brain DA and TH via TH phosphorylation activation in MPTP model mice. EtOH and Nic showed an additive effect in combination, suggesting that their co-application could be a potent therapeutic strategy for treating PD.

Tau is a neuronal protein that confers stability to microtubules; however, its hyperphosphorylation and accumulation can lead to an impairment of protein degradation pathways, such as autophagy. Autophagy is a lysosomal catabolic process responsible for degrading cytosolic components, being essential for cellular homeostasis and survival. In this context, autophagy modulation has been postulated as a possible therapeutic target for the treatment of neurodegenerative diseases. Studies point to the modulatory and neuroprotective role of the cannabinoid system in neurodegenerative models and here it was investigated the effects of cannabidiol (CBD) on autophagy in a human neuroblastoma strain (SH-SY5Y) that overexpresses the EGFP-Tau WT (Wild Type) protein in an inducible Tet-On system way. The results demonstrated that CBD (100 nM and 10 µM) decreased the expression of AT8 and total tau proteins, activating autophagy, evidenced by increased expression of light chain 3-II (LC3-II) protein and formation of autophagosomes. Furthermore, the cannabinoid compounds CBD, ACEA (CB1 agonist) and GW-405,833 (CB2 agonist) decreased the fluorescence intensity of EGFP-Tau WT; and when chloroquine, an autophagic blocker, was used, there was a reversal in the fluorescence intensity of EGFP-Tau WT with CBD (1 and 10 µM) and GW-405,833 (2 µM), demonstrating the possible participation of autophagy in these groups. Thus, it was possible to conclude that CBD induced autophagy in EGFP-Tau WT cells which increased tau degradation, showing its possible neuroprotective role. Hence, this study may contribute to a better understanding of how cannabinoids can modulate autophagy and present a potential therapeutic target in a neurodegeneration model.

Resveratrol, a natural polyphenol, has shown promising neuroprotective effects in several in vivo and in vitro experimental models. However, the mechanisms by which resveratrol mediates these effects are not fully understood. Glutamate is the major excitatory neurotransmitter in the brain; however, excessive extracellular glutamate levels can affect neural activity in several neurological diseases. Astrocytes are the glial cells that maintain brain homeostasis and can attenuate excitotoxicity by actively participating in glutamate neurotransmission. This study aimed to investigate the glioprotective effects of resveratrol against glutamate-induced cellular dysfunction in hippocampal slices and primary astrocyte cultures, with a focus on the role of heme-oxygenase 1 (HO-1). Glutamate impaired glutamate uptake activity through a glutamate receptor-dependent mechanism, in addition to altering other important astroglial parameters, including glutamine synthetase activity, glutathione levels and cystine uptake, which were normalized by resveratrol. Resveratrol also prevented glutamate-induced disruption in antioxidant defenses, as well as in trophic and inflammatory functions, including the nuclear factor κB (NFκB) transcriptional activity. Most of the effects of resveratrol, mainly in astrocytes, were dependent on the HO-1 signaling pathway, as they were abrogated when HO-1 was pharmacologically inhibited. Resveratrol also increased HO-1 mRNA expression and its transcriptional regulator, nuclear factor erythroid-derived 2-like 2 (Nrf2). Finally, resveratrol prevented glutamate-induced p21 senescence marker, indicating an anti-aging effect. Therefore, we demonstrated that the activation of the Nrf2/HO-1 system in astrocytes by resveratrol represents an astrocyte-targeted neuroprotective mechanism in neurodegeneration, with glutamate excitotoxicity, oxidative stress, and neuroinflammation as common neurochemical alterations.