Polyglutamine disorders: Pathogenesis and potential drug interventions.

Polyglutamine/poly(Q) diseases are a group nine hereditary neurodegenerative disorders caused due to abnormally expanded stretches of CAG trinucleotide in functionally distinct genes. All human poly(Q) diseases are characterized by the formation of microscopically discernable poly(Q) positive aggregates, the inclusion bodies. These toxic inclusion bodies are responsible for the impairment of several cellular pathways such as autophagy, transcription, cell death, etc., that culminate in disease manifestation. Although, these diseases remain largely without treatment, extensive research has generated mounting evidences that various events of poly(Q) pathogenesis can be developed as potential drug targets. The present review article briefly discusses the key events of disease pathogenesis, model system-based investigations that support the development of effective therapeutic interventions against pathogenesis of human poly(Q) disorders, and a comprehensive list of pharmacological and bioactive compounds that have been experimentally shown to alleviate poly(Q)-mediated neurotoxicity. Interestingly, due to the common cause of pathogenesis, all poly(Q) diseases share etiology, thus, findings from one disease can be potentially extrapolated to other poly(Q) diseases as well.

Metabolomic modelling and neuroprotective effects of carvacrol against acrylamide toxicity in rat's brain and sciatic nerve.

The study aimed to investigate the harmful effects of acrylamide (AA), which forms in carbohydrate-rich foods at temperatures above 120°C, on the central and peripheral nervous systems and to evaluate the potential neuroprotective effects of carvacrol (CRV). Male Wistar Albino rats were subjected to AA (40 mg/kg/bw/day) and CRV (50 mg/kg/bw/day) for 15 days. Following the last administration, evaluations revealed disrupted gait, heightened thermal sensitivity and altered paw withdrawal thresholds in AA-exposed rats. Notably, AA reduced glutathione (GSH) and raised malondialdehyde (MDA) levels in both brain and sciatic nerve tissues. AA raised nuclear factor erythroid 2-related factor 2 (Nrf2), caspase 3 and nuclear factor κB (NF-κB) gene expressions while decreasing NR4A2. CRV co-administration mitigated gait abnormalities, elevated GSH levels and lowered MDA levels in both tissues. CRV also modulated gene expression, reducing Nrf2 and NF-κB while increasing NR4A2. Histopathological signs of AA-induced neurodegeneration and elevated glial fibrillary acidic protein levels observed in brain and sciatic nerve tissues were rectified with simultaneous administration of CRV, thereby demonstrating neuroprotective efficacy in both regions. This study is pioneering in demonstrating CRV's neuroprotective potential against AA-induced neurotoxicity in both central and peripheral nervous systems, effectively addressing limitations in the literature. In conclusion, the study revealed AA-induced neurodegeneration in the brain and sciatic nerve, with CRV significantly mitigating this neurotoxicity. This novel research underscores CRV's promise as a neuroprotective agent against AA-induced adverse effects in both the central and peripheral nervous systems.

BDNF specifically expressed in hippocampal neurons is involved in methylmercury neurotoxicity resistance.

Methylmercury (MeHg) causes selective neuronal damage to cerebrocortical neurons (CCNs) in the central nervous system, but not to hippocampal neurons (HiNs), which are highly vulnerable to neurodegenerative diseases. In our previous study using cultured rat neurons, we performed a comprehensive gene expression analysis and found that the brain-derived neurotrophic factor (BDNF), a neurotrophin (NT), was specifically expressed in HiNs. Therefore, to elucidate the causal factors of MeHg toxicity resistance in HiNs, we conducted a comparative study of the protein expression and function of several NTs, including BDNF, using CCNs showing vulnerability to MeHg toxicity and HiNs showing resistance. BDNF was specifically expressed in HiNs, whereas nerve growth factor was barely detectable in either neuron type. In addition, other NTs, NT3 and NT4/5, were expressed in small but nearly equal amounts in both neuron types. Furthermore, among the various pathways involved in MeHg neurotoxicity, the p44/42 MAPK pathway was specifically activated in HiNs, even without MeHg treatment. siRNAs were used to reduce NTs in both neuron types. Only a specific reduction in BDNF attenuated the resistance to MeHg toxicity and p44/42 MAPK activation in HiNs. In addition, the external addition of BDNF and NT4/5, which act on the same tyrosine receptor kinase (Trk), TrkB, suppressed MeHg neurotoxicity in both neuron types. These results suggest that BDNF, expressed specifically in HiNs, is involved in the resistance to MeHg neurotoxicity via TrkB. Additionally, the activation of the p44/42 MAPK pathway may contribute to the inhibitory effect of BDNF on MeHg neurotoxicity.

Notoginsenoside R1 attenuates bupivacaine induced neurotoxicity by activating Jak1/Stat3/Mcl1 pathway.

Bupivacaine, a common amide local anesthetic, can provide effective analgesia or pain relief but can also cause neurotoxicity, which remains a mounting concern in clinic and animal care. However, the precise underlying mechanisms have not been fully elucidated. A natural compound, notoginsenoside R1 (NG-R1) has been reported to exhibit a neuroprotective role in stress conditions. In this study, we explored the function and mechanism of NG-R1 in alleviating bupivacaine-induced neurotoxicity in mouse hippocampal neuronal (HT-22) and mouse neuroblastoma (Neuro-2a) cell lines. Our results exhibited that NG-R1 treatment can significantly rescue the decline of cell survival induced by bupivacaine. Tunel staining and western blotting showed that NG-R1 could attenuate BPV­induced cell apoptosis. Besides, we focused on Mcl1 as a potential target as it showed opposite expression tendency in response to NG-R1 and bupivacaine exposure. Mcl1 knockdown blocked the inhibitory effect of NG-R1 on cell apoptosis against bupivacaine treatment. Intriguingly, we found that NG-R1 can upregulate Mcl1 transcription by activating Stat3 and promote its nuclear translocation. In addition, NG-R1 can also promote Jak1 phosphorylation and docking analysis provide a predicted model for interaction between NG-R1 and phosphorylated Jak1. Taken together, our results demonstrated that NG-R1 can attenuate bupivacaine induced neurotoxicity by activating Jak1/Stat3/Mcl1 pathway.

Parkinson's disease-derived α-synuclein assemblies combined with chronic-type inflammatory cues promote a neurotoxic microglial phenotype.

Parkinson's disease (PD) is a common age-related neurodegenerative disorder characterized by the aggregation of α-Synuclein (αSYN) building up intraneuronal inclusions termed Lewy pathology. Mounting evidence suggests that neuron-released αSYN aggregates could be central to microglial activation, which in turn mounts and orchestrates neuroinflammatory processes potentially harmful to neurons. Therefore, understanding the mechanisms that drive microglial cell activation, polarization and function in PD might have important therapeutic implications. Here, using primary microglia, we investigated the inflammatory potential of pure αSYN fibrils derived from PD patients. We further explored and characterized microglial cell responses to a chronic-type inflammatory stimulation combining PD patient-derived αSYN fibrils (FPD), Tumor necrosis factor-α (TNFα) and prostaglandin E2 (PGE2) (TPFPD). We showed that FPD hold stronger inflammatory potency than pure αSYN fibrils generated de novo. When combined with TNFα and PGE2, FPD polarizes microglia toward a particular functional phenotype departing from FPD-treated cells and featuring lower inflammatory cytokine and higher glutamate release. Whereas metabolomic studies showed that TPFPD-exposed microglia were closely related to classically activated M1 proinflammatory cells, notably with similar tricarboxylic acid cycle disruption, transcriptomic analysis revealed that TPFPD-activated microglia assume a unique molecular signature highlighting upregulation of genes involved in glutathione and iron metabolisms. In particular, TPFPD-specific upregulation of Slc7a11 (which encodes the cystine-glutamate antiporter xCT) was consistent with the increased glutamate response and cytotoxic activity of these cells toward midbrain dopaminergic neurons in vitro. Together, these data further extend the structure-pathological relationship of αSYN fibrillar polymorphs to their innate immune properties and demonstrate that PD-derived αSYN fibrils, TNFα and PGE2 act in concert to drive microglial cell activation toward a specific and highly neurotoxic chronic-type inflammatory phenotype characterized by robust glutamate release and iron retention.

Clozapine-N-oxide protects dopaminergic neurons against rotenone-induced neurotoxicity by preventing ferritinophagy-mediated ferroptosis.

Parkinson's disease (PD) is the second most common neurodegenerative disorder, yet treatment options are limited. Clozapine (CLZ), an antipsychotic used for schizophrenia, has potential as a PD treatment. CLZ and its metabolite, Clozapine-N-Oxide (CNO), show neuroprotective effects on dopaminergic neurons, with mechanisms needing further investigation. This study aimed to confirm the neuroprotective effects of CLZ and CNO in a rotenone-induced mouse model and further explore the underlying mechanisms of CNO-afforded protection. Gait pattern and rotarod activity evaluations showed motor impairments in rotenone-exposed mice, with CLZ or CNO administration ameliorating behavioral deficits. Cell counts and biochemical analysis demonstrated CLZ and CNO's effectiveness in reducing rotenone-induced neurodegeneration of dopaminergic neurons in the nigrostriatal system in mice. Mechanistic investigations revealed that CNO suppressed rotenone-induced ferroptosis of dopaminergic neurons by rectifying iron imbalances, curtailing lipid peroxidation, and mitigating mitochondrial morphological changes. CNO also reversed autolysosome and ferritinophagic activation in rotenone-exposed mice. SH-SY5Y cell cultures validated these findings, indicating ferritinophage involvement, where CNO-afforded protection was diminished by ferritinophagy enhancers. Furthermore, knockdown of NCOA4, a crucial cargo receptor for ferritin degradation in ferritinophagy, hampered rotenone-induced ferroptosis and NCOA4 overexpression countered the anti-ferroptotic effects of CNO. Whereas, iron-chelating agents and ferroptosis enhancers had no effect on the anti-ferritinophagic effects of CNO in rotenone-treated cells. In summary, CNO shielded dopaminergic neurons in the rotenone-induced PD model by modulating NCOA4-mediated ferritinophagy, highlighting a potential therapeutic pathway for PD treatment. This research provided insights into the role of NCOA4 in ferroptosis and suggested new approaches for PD therapy.

Artemisinin protects dopaminergic neurons against 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-induced neurotoxicity in a mouse model of Parkinson's disease.

Artemisinin is an antimalarial drug that has been used for almost half a century. However, the anti-Parkinson's disease (PD) effects of artemisinin with respect to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced oxidative stress have not yet been investigated while focusing on NF-E2-related factor 2 (Nrf2) signaling. Thus, we sought to assess the behavioral and oxidative mechanistic effects of artemisinin on MPTP-induced toxicity via the Nrf2 signaling pathway. We explored this through immunohistochemical assays, ELISA, in differentiated PC12 cells treated with siRNA, and with a PD mouse model. Artemisinin increased Nrf2 DNA-binding activity and HO-1 and NQO1 expression. Artemisinin treatment protected cells against MPP+ -induced neuronal death signaling, including NADH dehydrogenase activity, reactive oxygen species, mitochondrial membrane potential, and cleaved caspase-3. Moreover, it protected cells against MPTP-induced behavioral impairments and significantly reduced dopaminergic neuronal loss. Additionally, Nrf2 pre-inhibition using ML385 neutralized the inhibitory effects of artemisinin on dopaminergic neuronal damage and behavioral impairments induced by MPTP. Our results suggest that artemisinin inhibits MPTP-induced behavioral and neurotoxic effects in mice. This provides a foundation for further research to evaluate artemisinin as a potential therapeutic agent for PD.

Hesperidin counteracts chlorpyrifos-induced neurotoxicity by regulating oxidative stress, inflammation, and apoptosis in rats.

Chlorpyrifos (CPF), considered one of the most potent organophosphates, causes a variety of human disorders including neurotoxicity. The current study was designed to evaluate the efficacy of hesperidin (HSP) in ameliorating CPF-induced neurotoxicity in rats. In the study, rats were treated with HSP (orally, 50 and 100 mg/kg) 30 min after giving CPF (orally, 6.75 mg/kg) for 28 consecutive days. Molecular, biochemical, and histological methods were used to investigate cholinergic enzymes, oxidative stress, inflammation, and apoptosis in the brain tissue. CPF intoxication resulted in inhibition of acetylcholinesterase (AChE) and butrylcholinesterase (BChE) enzymes, reduced antioxidant status [superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx) and glutathione (GSH)], and elevation of malondialdehyde (MDA) levels and carbonic anhydrase (CA) activities. CPF increased histopathological changes and immunohistochemical expressions of 8-OHdG in brain tissue. CPF also increased levels of glial fibrillary acidic protein (GFAP) and nuclear factor kappa B (NF-κB) while decreased levels of nuclear factor erythroid 2-related factor 2 (Nrf-2), heme oxygenase-1 (HO-1) and peroxisome proliferator-activated receptor gamma coactivator-1 alpha (PGC-1α). Furthermore, CPF increased mRNA transcript levels of caspase-3, Bax, PARP-1, and VEGF, which are associated with apoptosis and endothelial damage in rat brain tissues. HSP treatment was found to protect brain tissue by reducing CPF-induced neurotoxicity. Overall, this study supports that HSP can be used to reduce CPF-induced neurotoxicity.

Transfer of massive mitochondria from astrocytes reduce propofol neurotoxicity.

Studies have shown that propofol-induced neurotoxicity is mediated by disruption of mitochondrial fission and fusion, leading to an imbalance in energy supply for developing neurons. Healthy mitochondria released from astrocytes migrate to compromised neurons to mitigate propofol-induced neurotoxicity, yet the precise mechanisms involved require further clarification. In our investigation, primary neurons were incubated with propofol, which decreased ATP synthesis and mitochondrial membrane potential, increased ROS generation and neuronal apoptosis. Notably, astrocytes did not respond to the deleterious effects of propofol. The culture medium of neurons or astrocytes incubated with propofol was collected. It was found that mitochondrial ratio was decreased and mitochondrial function was impaired. Non-contact co-culture of neuro-astrocytes facilitated transcellular mitochondrial transfer in both physiological and propofol interventions, but failed to reverse propofol-induced neurotoxicity. The more pronounced damage to neuronal mitochondria induced by propofol compared to that in astrocytes alludes to secondary injury. Damaged neurons incubated with large, functional extracellular mitochondria derived from astrocytes demonstrates transfer of mitochondria to neurons, effectively reversing propofol-induced neurotoxicity. This discovery presents a novel mitochondrial transfer of neuro-astrocytes crosstalk that contributes to neuroprotection and neurological recovery in neurotoxicity.

Sevoflurane anesthesia reduces the expression of inflammatory response genes and ß-site amyloid precursor protein-cleaving enzyme in hippocampi of diabetic mice.

Diabetes and inhaled anesthesia are associated with an increased likelihood of developing postoperative cognitive dysfunction in humans and animal models, but the mechanisms are unclear. This study aimed to investigate the effect and mechanism of sevoflurane anesthesia on cognitive function in diabetic (DM) mice. Spontaneously diabetic db/db and control db/m mice were subject to sevoflurane anesthesia or allowed to breathe air, respectively. The Morris water maze test as spatial learning and novel object recognition test as recognition memory were performed. The expression of inflammatory cytokines and neurotoxicity-related genes in the hippocampus of four groups was measured using real-time PCR. The expression level of neurotoxicity and neuroprotection-related proteins in DM mice hippocampus were estimated using Western blot assay. It is found that DM mice developed cognitive impairment; however, the cognitive impairment was not exacerbated in sevoflurane-exposed mice. Sevoflurane anesthesia led to a decrease in mRNA levels of inflammatory cytokines in DM mice hippocampi, including interleukin 17 (IL-17), C-C motif chemokine (CCL20), CCL7 as well as high mobility group box 1 and beta-site amyloid-ß cleaving enzyme 1; and no effect was observed on the expression of neurotoxicity genes, including amyloid precursor protein, choline O-acetyltransferase, tumor necrosis factor, alpha-induced protein 1, B-cell lymphoma 2 and estrogen receptor 2. In addition, we observed elevated phosphorylation of cAMP response element-binding protein in DM mice exposed to sevoflurane anesthesia. In conclusion, sevoflurane did not exacerbate DM-associated cognitive impairment.

An adverse outcome pathway-based approach to assess the neurotoxicity by combined exposure to current-use pesticides.

Exposure to multiple pesticides in daily life has become an important public health concern. However, the combined effects of pesticide mixtures have not been fully elucidated by the conventional toxicological testing used for individual chemicals. Grouping of chemicals by mode of action using common key events (KEs) in the adverse outcome pathway (AOP) as endpoints could be applied for efficient risk assessment of combined exposure to multiple chemicals. The purpose of this study was to investigate whether exposure to multiple pesticides has synergistic neurotoxic effects on mammalian nervous systems. According to the AOP-based approach, we evaluated the effects of 10 current-use pesticides (4 neonicotinoids, 4 pyrethroids and 2 phenylpyrazoles) on the common KEs in AOPs for neurotoxicity, such as KEs involving mitochondrial and proteolytic functions, in a mammalian neuronal cell model. Our data showed that several pyrethroids and phenylpyrazoles partly shared the effects on several common KEs, including decreases in mitochondrial membrane potential and proteasome activity and increases in autophagy activity. Furthermore, we also found that combined exposure to a type-I pyrethroid permethrin or a type-II pyrethroid deltamethrin and the phenylpyrazole fipronil decreased the cell viability and the benchmark doses much more than either single exposure, indicating that the pair exhibited synergistic effects, since the combination indexes were less than 1. These findings revealed that novel pairs of different classes of pesticides with similar effects on common KEs exhibited synergistic neurotoxicity and provide new insights into the risk assessment of combined exposure to multiple chemicals.

Attenuation of Vanadium-Induced Neurotoxicity in Rat Hippocampal Slices (In Vitro) and Mice (In Vivo) by ZA-II-05, a Novel NMDA-Receptor Antagonist.

Exposure to heavy metals, such as vanadium, poses an ongoing environmental and health threat, heightening the risk of neurodegenerative disorders. While several compounds have shown promise in mitigating vanadium toxicity, their efficacy is limited. Effective strategies involve targeting specific subunits of the NMDA receptor, a glutamate receptor linked to neurodegenerative conditions. The potential neuroprotective effects of ZA-II-05, an NMDA receptor antagonist, against vanadium-induced neurotoxicity were explored in this study. Organotypic rat hippocampal slices, and live mice, were used as models to comprehensively evaluate the compound's impact. Targeted in vivo fluorescence analyses of the hippocampal slices using propidium iodide as a marker for cell death was utilized. The in vivo study involved five dams, each with eight pups, which were randomly assigned to five experimental groups (n = 8 pups). After administering treatments intraperitoneally over six months, various brain regions were assessed for neuropathologies using different immunohistochemical markers. High fluorescence intensity was observed in the hippocampal slices treated with vanadium, signifying cell death. Vanadium-exposed mice exhibited demyelination, microgliosis, and neuronal cell loss. Significantly, treatment with ZA-II-05 resulted in reduced cellular death in the rat hippocampal slices and preserved cellular integrity and morphological architecture in different anatomical regions, suggesting its potential in countering vanadium-induced neurotoxicity.

Identification of core genes, critical signaling pathways, and potential drugs for countering BPA-induced hippocampal neurotoxicity in male mice.

Although the neurotoxicity of the common chemical bisphenol A (BPA) to the mouse hippocampus has been often reported, the mechanism underlying BPA-induced depression-like behavior in mice remains unclear. We evaluated BPA's role in inducing depressive-like behavior by exposing male mice to different BPA concentrations (0, 0.01, 0.1, and 1 µg/mL) and using the forced swimming test (FST) and tail suspension test (TST). We aimed to identify critical gene and anti-BPA-neurotoxicity compounds using RNA sequencing combined with bioinformatics analysis. Our results showed that 1 µg/mL BPA exposure increased mouse immobility during the FST and TST. Based on BPA-induced hippocampal transcriptome changes, we identified NADH: ubiquinone oxidoreductase subunit AB1 (Ndufab1) as a critical and potential therapeutic target gene, and Ndufab1 mRNA and protein levels were downregulated in the BPA-exposed groups. Furthermore, molecular docking identified phenelzine as a compound that could counteract BPA-related neurotoxicity. Conclusively, our analyses confirmed that BPA triggers depressive behavior in male mice by downregulating Ndufab1 expression and suggested that phenelzine might reduce BPA-induced neurotoxicity.

Identification of neurotoxicology (NT)/developmental neurotoxicology (DNT) adverse outcome pathways and key event linkages with in vitro DNT screening assays.

There is a need to assess compounds reliably and quickly for neurotoxicity (NT) and developmental neurotoxicity (DNT). Adverse outcome pathways (AOPs) enable the mapping of molecular events to an apical endpoint in a chemical agnostic manner and have begun to be applied in NT and DNT testing frameworks. We assessed the status of NT/DNT AOPs in the AOP-Wiki (ca. 2/1/23; https://aopwiki.org/), to characterize the state of AOP development, identify strengths and knowledge gaps, elucidate areas for improvement, and describe areas for future focus. AOPs in the Wiki database were assessed for inclusion of NT/DNT molecular events and endpoints, AOP development and endorsement, as well as the linkages of key neurodevelopmental processes with in vitro new approach methods (NAMs). This review found that 41 AOPs have been proposed detailing NT/DNT, of which eight were endorsed by working parties in OECD. Further, this review determined that learning and memory is included as an adverse outcome in eight NT/DNT AOPS, often without distinction regarding the varying forms of learning and memory, regional specification, temporal dynamics, or acquisition mechanisms involved. There is also an overlap with key events (KEs) and in vitro NAMs, which synaptogenesis appeared as a common process. Overall, progress on NT/DNT AOPs could be expanded, adding in modes of action that are missing, improvement in defining apical endpoints, as well as utilizing NAMs further to develop AOPs and identify gaps in current knowledge.

Quantitative proteomics reveals the neurotoxicity of trimethyltin chloride on mitochondria in the hippocampus of mice.

Trimethyltin chloride (TMT) is a potent neurotoxin widely used as a constituent of polyvinyl chloride plastic in the industrial and agricultural fields. However, the underlying mechanisms by which TMT leads to neurotoxicity remain elusive. In the present study, we constructed a dose and time dependent neurotoxic mouse model of TMT exposure to explore the molecular mechanisms involved in TMT-induced neurological damage. Based on this model, the cognitive ability of TMT exposed mice was assessed by the Morris water maze test and a passive avoidance task. The ultrastructure of hippocampus was analyzed by the transmission electron microscope. Subsequently, proteomics integrated with bioinformatics and experimental verification were employed to reveal potential mechanisms of TMT-induced neurotoxicity. Gene ontology (GO) and pathway enrichment analysis were done by using Metascape and GeneCards database respectively. Our results demonstrated that TMT-exposed mice exhibited cognitive disorder, and mitochondrial respiratory chain abnormality of the hippocampus. Proteomics data showed that a total of 7303 proteins were identified in hippocampus of mice of which 224 ones displayed a 1.5-fold increase or decrease in TMT exposed mice compared with controls. Further analysis indicated that these proteins were mainly involved in tricarboxylic acid (TCA) cycle and respiratory electron transport, proteasome degradation, and multiple metabolic pathways as well as inflammatory signaling pathways. Some proteins, including succinate-CoA ligase subunit (Suclg1), NADH dehydrogenase subunit 5 (Nd5), NADH dehydrogenase [ubiquinone] 1 alpha subcomplex subunit 4-like 2 (Ndufa4l2) and cytochrome c oxidase assembly factor 7 (Coa7), which were closely related to mitochondrial respiratory electron transport, showed TMT dose and time dependent changes in the hippocampus of mice. Moreover, apoptotic molecules Bax and cleaved caspase-3 were up-regulated, while anti-apoptotic Bcl-2 was down-regulated compared with controls. In conclusion, our findings suggest that impairment of mitochondrial respiratory chain transport and promotion of apoptosis are the potential mechanisms of TMT induced hippocampus toxicity in mice.

Linalool attenuates hypothalamus proteome disturbance facilitated by methamphetamine induced neurotoxicity in rats.

BACKGROUND: One of the most powerful stimulants of the central nervous system is methamphetamine (METH). Linalool has a neuroprotective effect against ischemia injury by reducing oxidative stress and apoptosis. The present study investigated whether linalool can reverse the hypothalamus neurotoxicity and proteome disturbance in METH-treated rats. BRIEF METHOD: A total of 36 male albino rats were split into two equal groups (normal and METH-treated). Three equal subgroups of normal rats were created; Control, Linalool (25 mg/kg), and Linalool (50 mg/kg); Normal rats were given daily oral doses of 1 ml of distilled water, 25 mg/kg linalool, and 50 mg/kg of linalool, respectively. METH groups were divided into 3 equal subgroups; METH-treated rats, Linalool (25 mg/kg)+METH-treated, and Linalool (50 mg/kg)+METH-treated subgroups; METH-treated rats received daily and oral doses of 1 ml distilled water, 25 mg/kg linalool, and 50 mg/kg of linalool, respectively. RESULTS: According to the data obtained, METH caused a decrease of the sucrose preference test, travel distance test, and center square entries test, superoxide dismutase, glutathione peroxidase, catalase, NADPH oxidase, interleukin-10 but a rise in the center square duration test, tail suspension test, and forced swimming test, malondialdehyde, conjugated dienes, oxidative index, serotonin, dopamine, norepinephrine, γ-aminobutyric acid, tumour necrosis factor-α, interleukin-1ß, interleukin-6 levels. When compared to the control group, rats treated with METH had lower sodium/potassium ATPase activity and missing of prothrombin, fibrinogen, and ceruloplasmin protein bands in the hypothalamus. In METH-treated rats, daily and oral co-administration with linalool brought all these parameters back to values that were close to control. SIGNIFICANCE: According to obtained data, linalool could protect the hypothalamus against METH-induced neurotoxicity and proteome disturbance probably by modifying oxidative stress, neurotransmitters, inflammation, sodium/potassium-ATPase activity, proteome disturbance, and tissue histology in METH-treated rats where higher dose of linalool was more efficient than lower dose.

In situ PEGylation of CAR T cells alleviates cytokine release syndrome and neurotoxicity.

Chimeric antigen receptor T (CAR T) cell immunotherapy is successful at treating many cancers. However, it often induces life-threatening cytokine release syndrome (CRS) and neurotoxicity. Here, we show that in situ conjugation of polyethylene glycol (PEG) to the surface of CAR T cells ('PEGylation') creates a polymeric spacer that blocks cell-to-cell interactions between CAR T cells, tumour cells and monocytes. Such blockage hinders intensive tumour lysing and monocyte activation by CAR T cells and, consequently, decreases the secretion of toxic cytokines and alleviates CRS-related symptoms. Over time, the slow expansion of CAR T cells decreases PEG surface density and restores CAR T cell-tumour-cell interactions to induce potent tumour killing. This occurs before the restoration of CAR T cell-monocyte interactions, opening a therapeutic window for tumour killing by CAR T cells before monocyte overactivation. Lethal neurotoxicity is also lower when compared with treatment with the therapeutic antibody tocilizumab, demonstrating that in situ PEGylation of CAR T cells provides a materials-based strategy for safer cellular immunotherapy.

Deletion of IL-1ß exacerbates acrylamide-induced neurotoxicity in mice.

Acrylamide is a neurotoxicant in human and experimental animals. Interleukin-1ß (IL-1ß) is a proinflammatory cytokine known as a critical component of brain reaction to any insult or neurodegenerative pathologies, though its role in electrophile-induced neurotoxicity remains elusive. The aim of this study was to investigate the role of IL-1ß in acrylamide-induced neurotoxicity in mice. Ten-week-old male wild-type and IL-1ß knock-out mice were allocated into 3 groups each and exposed to acrylamide at 0, 12.5, 25 mg/kg body weight by oral gavage for 28 days. Compared with wild-type mice, the results showed a significant increase in landing foot spread test and a significant decrease in density of cortical noradrenergic axons in IL-1ß KO mice exposed to acrylamide at 25 mg/kg body weight. Exposure to acrylamide at 25 mg/kg significantly increased cortical gene expression of Gclc, Gpx1, and Gpx4 in wild-type mice but decreased them in IL-1ß KO mice. The same exposure level significantly increased total glutathione and oxidized glutathione (GSSG) in the cerebellum of wild-type mice but neither changed total glutathione nor decreased GSSG in the cerebellum of IL-1ß KO mice. The basal level of malondialdehyde in the cerebellum was higher in IL-1ß KO mice than in wild-type mice. The results suggest that IL-1ß protects the mouse brain against acrylamide-induced neurotoxicity, probably through suppression of oxidative stress by glutathione synthesis and peroxidation. This unexpected result provides new insight on the protective role of IL-1ß in acrylamide-induced neurotoxicity.

An Increase in Peroxiredoxin 6 Expression Induces Neurotoxic A1 Astrocytes in the Lumbar Spinal Cord of Amyotrophic Lateral Sclerosis Mice Model.

Amyotrophic lateral sclerosis (ALS) is a severe neurodegenerative disease with selective degeneration of motor neurons. It has been reported that an increase in the levels of inflammatory cytokines and glial cells such as reactive astrocytes is closely involved in the pathological progression of ALS. Recently, the levels of neuropathic cytotoxic (A1) astrocytes among reactive astrocytes have reportedly increased in the central nervous system of ALS mice, which induce motor neuron degeneration through the production of inflammatory cytokines and secretion of neuropathic factors. Hence, elucidating the induction mechanism of A1 astrocytes in ALS is important to understand the mechanism of disease progression in ALS. In this study, we observed that the expression of peroxiredoxin 6 (PRDX6), a member of the peroxiredoxin family, was markedly upregulated in astrocytes of the lumbar spinal cord of SOD1G93A mice model for ALS. Additionally, when PRDX6 was transiently transfected into the mouse astrocyte cell line C8-D1A and human astrocytoma cell line U-251 MG, the mRNA expression of complement C3 (a marker for A1 astrocyte phenotype) and inflammatory cytokines was increased. Furthermore, the mRNA expression of C3 and inflammatory cytokine was increased in C8-D1A and U-251 MG cells stably expressing PRDX6, and the increased mRNA expression was significantly suppressed by MJ33 (lithium[1-hexadecoxy-3-(2,2,2-trifluoroethoxy) propan-2-yl] methyl phosphate), an inhibitor of the phospholipase A2 activity of PRDX6. Our results suggest that the expression of PRDX6 in astrocytes plays an important role in the induction of A1 astrocytes and expression of inflammatory cytokines in the ALS mice model.

Bee venom (Apis mellifera L.) rescues zinc oxide nanoparticles induced neurobehavioral and neurotoxic impact via controlling neurofilament and GAP-43 in rat brain.

This study investigated the possible beneficial role of the bee venom (BV, Apis mellifera L.) against zinc oxide nanoparticles (ZNPs)-induced neurobehavioral and neurotoxic impacts in rats. Fifty male Sprague Dawley rats were alienated into five groups. Three groups were intraperitoneally injected distilled water (C 28D group), ZNPs (100 mg/kg b.wt) (ZNPs group), or ZNPs (100 mg/kg.wt) and BV (1 mg/ kg.bwt) (ZNPs + BV group) for 28 days. One group was intraperitoneally injected with 1 mL of distilled water for 56 days (C 56D group). The last group was intraperitoneally injected with ZNPs for 28 days, then BV for another 28 days at the same earlier doses and duration (ZNPs/BV group). Depression, anxiety, locomotor activity, spatial learning, and memory were evaluated using the forced swimming test, elevated plus maze, open field test, and Morris water maze test, respectively. The brain contents of dopamine, serotonin, total antioxidant capacity (TAC), malondialdehyde (MDA), and Zn were estimated. The histopathological changes and immunoexpressions of neurofilament and GAP-43 protein in the brain tissues were followed. The results displayed that BV significantly decreased the ZNPs-induced depression, anxiety, memory impairment, and spatial learning disorders. Moreover, the ZNPs-induced increment in serotonin and dopamine levels and Zn content was significantly suppressed by BV. Besides, BV significantly restored the depleted TAC but minimized the augmented MDA brain content associated with ZNPs exposure. Likewise, the neurodegenerative changes induced by ZNPs were significantly abolished by BV. Also, the increased neurofilament and GAP-43 immunoexpression due to ZNPs exposure were alleviated with BV. Of note, BV achieved better results in the ZNPs + BV group than in the ZNPs/BV group. Conclusively, these results demonstrated that BV could be employed as a biologically effective therapy to mitigate the neurotoxic and neurobehavioral effects of ZNPs, particularly when used during ZNPs exposure.