Non-cytotoxic nanomolar concentration of arctigenin protects neuronal cells from chemotherapy-induced ferroptosis by regulating SLC7A11-cystine-cysteine axis.

Neurotoxicity is a common side effect of certain types of therapeutic drugs, posing a major hurdle for their clinical application. Accumulating evidence suggests that ferroptosis is involved in the neurotoxicity induced by these drugs. Therefore, targeting ferroptosis is considered to be a reasonable approach to prevent such side effect. Arctigenin (ATG) is a major bioactive ingredient of Arctium lappa L., a popular medicinal plant in Asia, and has been reported to have multiple bioactivities including neuroprotection. However, the mechanisms underlying the neuroprotection of ATG has not been well elucidated. The purpose of this study was to investigate whether the neuroprotection of ATG was associated with its ability to protect neuronal cells from ferroptosis. Using neuronal cell ferroptosis model induced by either classic ferroptosis induces or therapeutic drugs, we demonstrated for the first time that ATG in the nanomolar concentration range effectively prevented neuronal cell ferroptosis induced by classic ferroptosis inducer sulfasalazine (SAS) and erastin (Era), or therapeutic drug oxaliplatin (OXA) and 5-fluorouracil (5-FU). Mechanistically, we uncovered that the anti-ferroptotic effect of ATG was attributed to its ability to activate SLC7A11-cystine-cysteine axis. The findings of the present study implicate that ATG holds great potential to be developed as a novel agent for preventing SLC7A11 inhibition-mediated neurotoxicity.

Clinical features and predictors of delayed neurological syndrome in carbon monoxide poisoning: the AMICO study. / Caracterización clínica y factores predictivos de desarrollo de síndrome neurológico tardío en la intoxicación por monóxido de carbono: estudio AMICO.

OBJECTIVES: To identify predictors for developing delayed neurological syndrome (DNS) after an initial episode of carbon monoxide (CO) poisoning in the interest of detecting patients most likely to develop DNS so that they can be followed. MATERIAL AND METHODS: Retrospective review of cases of CO poisoning treated in the past 10 years in the emergency departments of 4 hospitals in the AMICO study (Spanish acronym for the multicenter analysis of CO poisoning). We analyzed demographic characteristics of the patients and the clinical characteristics of the initial episode. The records of the cohort of patients with available follow-up information were reviewed to find cases of DNS. Data were analyzed by multivariant analysis to determine the relationship to characteristics of the initial exposure to CO. RESULTS: A total of 240 cases were identified. The median (interquartile range) age of the patients was 36.2 years (17.6-49.6 years); 108 patients (45.0%) were men, and the poisoning was accidental in 223 cases (92.9%). The median carboxyhemoglobin concentration on presentation was 12.7% (6.2%-18.7%). Follow-up details were available for 44 patients (18.3%). Eleven of those patients (25%) developed DNS. A low initial Glasgow Coma Scale score predicted the development of DNS with an odds ratio (OR) of 0.61 (95% CI, 0.41-0.92) and an area under the receiver operating characteristic curve of 0.876 (95% CI, 0.761-0.990) (P .001). CONCLUSION: The initial Glasgow Coma Scale score seems to be a clinical predictor of DNS after CO poisoning. We consider it important to establish follow-up protocols for patients with CO poisoning treated in hospital EDs.

OBJETIVO: Identificar factores pronósticos de desarrollo de síndrome neurológico tardío (SNT) después de un episodio inicial de intoxicación por monóxido de carbono (ICO), con el fin detectar precozmente a la población más susceptible y facilitar su acceso a un seguimiento específico. METODO: Revisión retrospectiva de todos los casos de ICO que acudieron a los servicios de urgencias (SU) de 4 hospitales durante los últimos 10 años. Se analizaron datos demográficos y características clínicas en el momento del episodio. En la cohorte de pacientes con datos de seguimiento disponibles, se evaluó la aparición de SNT y su relación con diferentes variables en la exposición inicial al CO a través de técnicas de análisis multivariante. RESULTADOS: Se identificaron 240 pacientes. La mediana de edad fue de 36,2 años (17,6-49,6). De ellos 108 (45,0%) eran hombres y 223 casos (92,9%) fueron accidentales. El nivel medio de COHb fue del 12,7% (6,2-18,7). En 44 (18,3%) episodios se disponía de datos de un seguimiento específico. En esta cohorte, 11 (25%) pacientes desarrollaron SNT. Una puntuación inicial más baja en la Escala Coma de Glasgow (GCS) (OR: 0,61, IC 95%: 0,41-0,92) fue predictor independiente del desarrollo del SNT, con un ABC en la curva COR de 0,876 (IC 95%: 0,761-0,990, p 0,001). CONCLUSIONES: Una puntuación inicial baja en la GCS parece ser un predictor clínico de desarrollo de SNT en la ICO. Dada la incidencia de SNT, consideramos fundamental establecer protocolos de seguimiento específico de estos pacientes tras su asistencia inicial en los SU.

AuNPs with Cynara scolymus leaf extracts rescue arsenic-induced neurobehavioral deficits and hippocampal tissue toxicity in Balb/c mice through D1R and D2R activation.

The present study was designed to evaluate whether AuNPs (gold nanoparticles) synthesized with the Cynara scolymus (CS) leaf exert protective and/or alleviative effects on arsenic (As)-induced hippocampal neurotoxicity in mice. Neurotoxicity in mice was developed by orally treating 10 mg/kg/day sodium arsenite (NaAsO2) for 21 days. 10 µg/g AuNPs, 1.6 g/kg CS, and 10 µg/g CS-AuNPs were administered orally simultaneously with 10 mg/kg As. CS and CS-AuNPs treatments showed down-regulation of TNF-α and IL-1ß levels. CS and CS-AuNPs also ameliorated apoptosis and reduced the alterations in the expression levels of D1 and D2 dopamine receptors induced by As. Simultaneous treatment with CS and CS-AuNPs improved As-induced learning, memory deficits, and motor coordination in mice assessed by water maze and locomotor tests, respectively. The results of this study provide evidence that CS-AuNPs demonstrated neuroprotective roles with antioxidant, anti-inflammatory, and anti-apoptotic effects, as well as improving D1 and D2 signaling, and eventually reversed neurobehavioral impairments.

The protective role of sesame oil against Parkinson's-like disease induced by manganese in rats.

Chronic exposure to manganese (Mn) results in motor dysfunction, biochemical and pathological alterations in the brain. Oxidative stress, inflammation, and dysfunction of dopaminergic and GABAergic systems stimulate activating transcription factor-6 (ATF-6) and protein kinase RNA-like ER kinase (PERK) leading to apoptosis. This study aimed to investigate the protective effect of sesame oil (SO) against Mn-induced neurotoxicity. Rats received 25 mg/kg MnCl2 and were concomitantly treated with 2.5, 5, or 8 ml/kg of SO for 5 weeks. Mn-induced motor dysfunction was indicated by significant decreases in the time taken by rats to fall during the rotarod test and in the number of movements observed during the open field test. Also, Mn resulted in neuronal degeneration as observed by histological staining. The striatal levels of lipid peroxides and reduced glutathione (oxidative stress markers), interleukin-6 and tumor necrosis factor-α (inflammatory markers) were significantly elevated. Mn significantly reduced the levels of dopamine and Bcl-2, while GABA, PERK, ATF-6, Bax, and caspase-3 were increased. Interestingly, all SO doses, especially at 8 ml/kg, significantly improved locomotor activity, biochemical deviations and reduced neuronal degeneration. In conclusion, SO may provide potential therapeutic benefits in enhancing motor performance and promoting neuronal survival in individuals highly exposed to Mn.

Attenuation of acrylamide-induced neurotoxicity by supplementation of sitagliptin in Wistar rats.

Objectives: Acrylamide (ACR) induces neurotoxicity in humans and animals through different mechanisms. Sitagliptin is a type-2 diabetes medication with neuroprotective properties. The effects of sitagliptin against neurotoxicity stimulated by ACR were examined. Materials and Methods: Male Wistar rats were classified as follows: 1. Control (normal saline, 11 days, IP), 2. ACR (50 mg/kg, 11 days, IP), 3. ACR (11 days, days 11-20 normal saline), 4-7. ACR+sitagliptin (5, 10, 20, and 40 mg/kg, 11 days, IP), 8. ACR+sitagliptin (10 mg/kg, days 6-11), 9. ACR+sitagliptin (10 mg/kg, days 6-20), 10. Sitagliptin (40 mg/kg, 11 days), 11. ACR+vitamin E (200 mg/kg, IP). Finally, the gait score was evaluated. Reduced glutathione (GSH) and malondialdehyde (MDA) levels were measured in cortex tissue. Also, IL-1ß, TNF-α, and caspase-3 levels were assessed in the cortex by western blotting. Results: ACR caused movement disorders, triggered oxidative stress, and raised TNF-α, IL-1ß, and caspase-3 cleaved levels. Supplementation of sitagliptin (10 mg/kg) along with ACR, in 3 protocols, reduced gait disorders compared to the ACR group. Receiving sitagliptin in all doses plus ACR and injection of sitagliptin (10 mg/kg) from days 6 to11 reduced the MDA level of cortex tissue. Sitagliptin (all doses) plus ACR increased the GSH level of the cortex tissue. Sitagliptin (10 mg/kg) with ACR dropped the amounts of TNF-α and caspase-3 cleaved proteins in cortex tissue but did not affect the IL-1ß level. Conclusion: Sitagliptin disclosed preventive and therapeutic effects on ACR neurotoxicity. Sitagliptin possesses antioxidant, anti-inflammatory, and anti-apoptotic properties and inhibits CR neurotoxicity in rats.

Sodium butyrate alleviates lead-induced neuroinflammation and improves cognitive and memory impairment through the ACSS2/H3K9ac/BDNF pathway.

Lead is an environmentally widespread neurotoxic pollutant. Although the neurotoxicity of lead has been found to be closely associated with metabolic disorders, the effects of short-chain fatty acids on the neurotoxicity of lead and its mechanisms have not yet been explored. In this study, the results of open field tests and Morris water maze tests demonstrated that chronic lead exposure caused learning and memory deficits and anxiety-like symptoms in mice. The serum butyric acid content of lead-treated mice decreased in a dose-dependent manner, and oral administration of butyrate significantly improved cognitive memory impairment and anxiety symptoms in lead-exposed mice. Moreover, butyrate alleviated neuroinflammation caused by lead exposure by inhibiting the STAT3 signaling in microglia. Butyrate also promoted the expression of acetyl-CoA synthetase ACSS2 in hippocampal neurons, thereby increasing the content of acetyl-CoA and restoring the expression of both histone H3K9ac and the downstream BDNF. We also found that the median butyric acid concentration in high-lead exposure humans was remarkably lower than that in the low-lead exposure humans (45.16 µg/L vs. 60.92 µg/L, P < 0.01), and that butyric acid significantly mediated the relationship of lead exposure with the Montreal cognitive assessment scores, with a contribution rate of 27.57 %. In conclusion, our results suggest that butyrate supplementation is a possible therapeutic strategy for lead-induced neurotoxicity.

The Protective Impact of Aronia melanocarpa L. Berries Extract against Prooxidative Cadmium Action in the Brain-A Study in an In Vivo Model of Current Environmental Human Exposure to This Harmful Element.

Cadmium (Cd) is a prooxidant that adversely affects human health, including the nervous system. As exposure of the general population to this heavy metal is inevitable, it is crucial to look for agents that can prevent the effects of its toxic action. An experimental model on female rats of current lifetime human exposure to cadmium (3-24-months' treatment with 1 or 5 mg Cd/kg diet) was used to test whether low-level and moderate intoxication can exert a prooxidative impact in the brain and whether supplementation with a 0.1% extract from the berries of Aronia melanocarpa L. (Michx.) Elliott (AE; chokeberry extract) can protect against this action. Numerous parameters of the non-enzymatic and enzymatic antioxidative barrier, as well as total antioxidative and oxidative status (TAS and TOS, respectively), were determined and the index of oxidative stress (OSI) was calculated. Moreover, chosen prooxidants (myeloperoxidase, xanthine oxidase, and hydrogen peroxide) and biomarkers of oxidative modifications of lipids, proteins, and deoxyribonucleic acid were assayed. Cadmium dysregulated the balance between oxidants and antioxidants in the brain and led to oxidative stress and oxidative injury of the cellular macromolecules, whereas the co-administration of AE alleviated these effects. To summarize, long-term, even low-level, cadmium exposure can pose a risk of failure of the nervous system by the induction of oxidative stress in the brain, whereas supplementation with products based on aronia berries seems to be an effective protective strategy.

Case report: Exploring chemoradiotherapy-induced leukoencephalopathy with 7T imaging and quantitative susceptibility mapping.

Chemotherapy and radiotherapy are widely used in the treatment of central nervous system tumors and acute lymphocytic leukemia even in the pediatric population. However, such treatments run the risk of a broad spectrum of cognitive and neurological deficits. Even though the correlation with cognitive decline is still not clear, neuroradiological defects linked to white matter injury and vasculopathies may be identified. Thanks to the use of 7T MRI it is possible to better define the vascular pattern of the brain lesions with the added advantage of identifying their characteristics and anatomical localization, which, however, are not evident with a conventional brain scan. Moreover, the use of Quantitative Susceptibility Mapping (QSM) makes it possible to discriminate between calcium deposits on vessels (chemo-radiation-induced) and hemoglobin deposition in radio-induced cavernomas, speculating, as a result, about the pathophysiology of iatrogenic brain damage. We describe the case of a 9 year-old boy with a T-type acute lymphoid leukemia who had previously been treated with polychemotherapy and high-dose RT. To better define the child's neuroradiological pattern, 7T MRI and QSM were performed in addition to conventional imaging examinations. Our case report suggests the potential usefulness of a QSM study to distinguish radio-induced vascular malformations from mineralizing microangiopathy.

Natural product Kaji-ichigoside F1 exhibits rapid antidepression via activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway.

BACKGROUND: Depression is a common and recurrent neuropsychiatric disorder. Recent studies have shown that the N-methyl-d-aspartate (NMDA) receptor (NMDAR) is involved in the pathophysiology of depression. Previous studies have found that Kaji-ichigoside F1 (KF1) has a protective effect against NMDA-induced neurotoxicity. However, the antidepressant mechanism of KF1 has not been confirmed yet. PURPOSE: In the present study, we aimed to evaluate the rapid antidepressant activity of KF1 and explore the underlying mechanism. STUDY DESIGN: First, we explored the effect of KF1 on NMDA-induced hippocampal neurons and the underlying mechanism. Second, depression was induced in C57BL/6 mice via chronic unpredictable mild stress (CUMS), and the immediate and persistent depression-like behavior was evaluated using the forced swimming test (FST) after a single administration of KF1. Third, the contributions of NMDA signaling to the antidepressant effect of KF1 were investigated using pharmacological interventions. Fourth, CUMS mice were treated with KF1 for 21 days, and then their depression-like behaviors and the underlying mechanism were further explored. METHODS: The FST was used to evaluate immediate and persistent depression-like behavior after a single administration of KF1 with or without NMDA pretreatment. The effect of KF1 on depressive-like behavior was investigated in CUMS mice by treating them with KF1 once daily for 21 days through the sucrose preference test, FST, open field test, and tail suspension test. Then, the effects of KF1 on the morphology and molecular and functional phenotypes of primary neuronal cells and hippocampus of mice were investigated by hematoxylin-eosin staining, Nissl staining, propidium iodide staining, TUNEL staining, Ca2+ imaging, JC-1 staining, ELISA, immunofluorescence analysis, RT-PCR, and Western blot. RESULTS: KF1 could effectively improve cellular viability, reduce apoptosis, inhibit the release of LDH and Ca2+, and increase the mitochondrial membrane potential and the number of dendritic spines numbers in hippocampal neurons. Moreover, behavioral tests showed that KF1 exerted acute and sustained antidepressant-like effects by reducing Glu-levels and ameliorating neuronal damage in the hippocampus. Additionally, in vivo and in vitro experiments revealed that PSD95, Syn1, α-amino-3­hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA), and brain-derived neurotrophic factor (BDNF) were upregulated at the protein level, and BDNF and AMPA were upregulated at the mRNA level. NR1 and NR2A showed the opposite trend. CONCLUSION: These results confirm that KF1 exerts rapid antidepressant effects mainly by activating the AMPA-BDNF-mTOR pathway and inhibiting the NMDAR-CaMKIIα pathway. This study serves as a new reference for discovering rapid antidepressants.

Acetylcholinesterase activity in muscle tissue of Norway lobster Nephrops norvegicus: Importance of body size, season, sex and naturally occurring metals.

The aim of the present study was to determine the levels of acetylcholinesterase (AChE) activity in the tail muscle tissue of wild populations of Nephrops norvegicus from the Northern Adriatic, and correlate it to body size, seasons, sex and the content of mercury, arsenic, cadmium, lead and copper. The animals of both sexes were collected in spring and autumn from two relatively distant fishing grounds. A marked variability of muscle AChE activity was found (0.49 to 11.22 nmol/min/mg prot.), displaying the opposite seasonal trend between two sampling sites. Small, but significant negative correlation has been found between AChE activity and carapace length (rs = - 0.35, p < 0.05). Data reported here provide an essential baseline for future studies of neurotoxicity in crustaceans. The study highlights the necessity for continuous monitoring of potentially toxic metals in edible marine species to avoid possible repercussions of seafood consumption on human health.

Testing the detoxification power of black cumin oil (Nigella sativa) over cypermethrin insecticide effects in rainbow trout (Oncorhynchus mykiss) at multiple scales.

This study investigated the curative effect of black cumin oil (Nigella sativa, NS), which is a phytotherapeutic agent against to cypermethrin (CYP), which is known to have adverse effects on rainbow trout (Oncorhynchus mykiss)'s behavioral changes, oxidative stress-mediated neurotoxicity, hematotoxicity and hepatotoxicity parameters.At the end of the trial period; (i) evaluation of critical swimming speed (Ucrit) (ii) hematology indices [white blood cell (WBC), red blood cell (RBC), hemoglobin (Hgb), hematocrit (Hct), mean cell volume (MCV), mean cell hemoglobin) (MCH), mean cell hemoglobin concentration (MCHC)] (iii) Elucidation of the mechanism of functional damage in brain tissue of O. mykiss by neurological parameter [acetylcholinesterase (AChE)] (iv) Evaluation of oxidative damage in oxidative stress-mediated neurotoxicity and hepatotoxicity in liver, gill and brain tissue of O. mykiss with antioxidant enzymes [(Superoxide dismutase (SOD), catalase (CAT), glutathione peroxidase (GPx), Glutathione (GSH)] and [(detection by means of malondialdehyde (MDA)] (v) Obtaining applicable data in the toxicological field using a multi-biomarker approach to investigate the modulation of NS administration via target markers in the physiological pathway of O. mykiss were aimed.As a result of CYP application, it was determined that the Ucrit value of O. mykiss decreased significantly. It was determined that the changes in the values of RBC, Hgb and Hct, which are among the hematology parameters examined in the blood tissue, were statistically significant (p < 0.05). It was determined that WBC value was inhibited by CYP application and NS tried to make a positive contribution to WBC. It was determined that the AChE activity of O. mykiss in the brain tissue had a statistically significant inhibition in the CYP-treated group (p < 0.05). SOD, CAT, GPx, enzyme activities were found to be inhibited by CYP application and were statistically significant (p < 0.05). Acute toxicity of CYP was determined by antioxidant enzyme biomarkers in gill tissue. In the results obtained; While inhibitions were determined in SOD, CAT, GPx activities compared to the control group, an induction occurred in MDA value.NS administration was noted to be an important modulator of the SOD-CAT system against CYP exposure at both concentrations. Thus, it can be said that it indirectly functions as an effective antioxidant through the NS receptor protein and structurally stimulates the synthesis and activity of antioxidative enzymes under oxidative stress.

Neuroactivity screening of botanical extracts using microelectrode array (MEA) recordings.

Toxicity testing of botanicals is challenging because of their chemical complexity and variability. Since botanicals may affect many different modes of action involved in neuronal function, we used microelectrode array (MEA) recordings of primary rat cortical cultures to screen 16 different botanical extracts for their effects on cell viability and neuronal network function in vitro. Our results demonstrate that extract materials (50 µg/mL) derived from goldenseal, milk thistle, tripterygium, and yohimbe decrease mitochondrial activity following 7 days exposure, indicative of cytotoxicity. Importantly, most botanical extracts alter neuronal network function following acute exposure. Extract materials (50 µg/mL) derived from aristolochia, ephedra, green tea, milk thistle, tripterygium, and usnea inhibit neuronal activity. Extracts of kava, kratom and yohimbe are particularly potent and induce a profound inhibition of neuronal activity at the low dose of 5 µg/mL. Extracts of blue cohosh, goldenseal and oleander cause intensification of the bursts. Aconite extract (5 µg/mL) evokes a clear hyperexcitation with a marked increase in the number of spikes and (network) bursts. The distinct activity patterns suggest that botanical extracts have diverse modes of action. Our combined data also highlight the applicability of MEA recordings for hazard identification and potency ranking of botanicals.

Efficacy and safety of traditional plant-based medicines for preventing chronic oxaliplatin-induced peripheral neurotoxicity in patients with colorectal cancer: A systematic review and meta-analysis with core herb contribution.

ETHNOPHARMACOLOGICAL RELEVANCE: Traditional plant-based medicines (TMs) have been widely used to prevent chronic oxaliplatin-induced peripheral neurotoxicity (OIPN). However, the prevention and safety of TMs for chronic OIPN remain ambiguous. Furthermore, diverse TM prescriptions and complicated components limit in-depth research on the mechanisms of TMs. AIM OF THIS STUDY: To determine core TMs and potential pharmacological pathways on the basis of a thorough investigation into the preventive benefits and safety of oral TMs for chronic OIPN in colorectal cancer (CRC). METHODS: A search of the PubMed, Cochrane, Embase, CNKI, VIP, and Wanfang databases for RCTs reporting on TMs for chronic OIPN was conducted through December 1, 2022. Subgroup analysis, sensitivity analysis and meta-regression were applied to assess the impacts of influencing variables. The assessment of Risk of Bias was relied on Cochrane Risk of Bias tool. The funnel plot, Egger's test, and the Trim and Fill method were applied to identify potential publication bias. Trial sequential analyses (TSA) were carried out by the TSA tool to increase the robustness. The assessment of the quality of evidence was according to the GRADE system. System pharmacology analysis was employed to screen core herbal combinations to elucidate possible mechanisms for preventing chronic OIPN in CRC. RESULTS: The pooled effect estimate with robustness increased by TSA analysis demonstrated that oral TMs appeared to significantly decrease the incidence of chronic OIPN (RR = 0.66, 95% CI (0.56, 0.78); P＜0.00001), leukocytopenia (RR = 0.65, 95% CI (0.54,0.79); P＜0.00001), and nausea and vomiting (RR = 0.72, 95% CI (0.61,0.84); P＜0.0001) as well as improve the Objective Response Rate (ORR) (RR = 1.31, 95% CI (1.09,1.56); P = 0.003). The incidence of severe chronic OIPN was revealed a significant reduction, particularly when chemotherapy was administered for periods of time shorter than six months (RR = 0.33, 95% CI (0.15,0.71); P = 0.005; actuation duration＜3 months; RR = 0.33, 95% CI (0.17,0.62); P = 0.0007; actuation duration≥3 months, ＜6 months). The considerable heterogeneity among studies may be attributable to the severity of dysfunction categorized by grade and accumulated dosage. Using core TMs consisting of Astragalus membranaceus (Fisch.) Bunge, Atractylodes Macrocephala Koidz., Poria cocos (Schw.) Wolf, and Codonopsis pilosula (Franch.) Nannf. To regulate nuclear factor-kappa B against inflammation caused by activation of microglia might be an approach to preventing chronic OIPN. CONCLUSIONS: TMs appear to be effective and safe in the prevention of chronic OIPN, especially severe chronic OIPN. Additionally, core TMs consisting of Astragalus membranaceus (Fisch.) Bunge, Atractylodes Macrocephala Koidz., Poria cocos (Schw.) Wolf, and Codonopsis pilosula (Franch.) Nannf were presumably responsible for reducing the incidence of chronic OIPN, and the mechanism may be related to relieving inflammation. However, quality-assured trials with long-term follow-up for exploring inflammatory factors and preliminary research on core TMs and pharmacological pathways are needed.

Identification of Antagonistic Action of Pyrrolizidine Alkaloids in Muscarinic Acetylcholine Receptor M1 by Computational Target Prediction Analysis.

Pyrrolizidine alkaloids (PAs) are one of the largest distributed classes of toxins in nature. They have a wide range of toxicity, such as hepatotoxicity, pulmonary toxicity, neuronal toxicity, and carcinogenesis. Yet, biological targets responsible for these effects are not well addressed. Using methods of computational biology for target identification, we tested more than 200 PAs. We used a machine-learning approach that applies structural similarity for target identification, ChemMapper, and SwissTargetPrediction. The predicted target with high probability was muscarinic acetylcholine receptor M1. The predicted interactions between this target and PAs were further studied by molecular docking-based binding energies using AutoDock and VinaLC, which revealed good binding affinities. The PAs are bound to the same binding pocket as pirenzepine, a known M1 antagonist. These results were confirmed by in vitro assays showing that PAs increased the levels of intracellular calcium. We conclude that PAs are potential acetylcholine receptor M1 antagonists. This elucidates for the first time the serious neuro-oncological toxicities exerted by PA consumption.

Alpha-Lipoic acid alleviates imidacloprid-induced neuro-behavioral deficits in rats via Nrf2/HO-1 pathway.

Imidacloprid (IMI), a widely used pesticide in agriculture and a potential food contaminant, poses significant health concerns. This study sought to comprehensively evaluate its neurotoxic effects while investigating the potential protective role of alpha-lipoic acid (ALA), a naturally occurring dietary antioxidant renowned for its capacity to combat oxidative stress, support cardiovascular health, and maintain optimal nerve function. In this study, 28 rats were divided evenly into four groups and administered oral treatments of corn oil, IMI, IMI + ALA, and ALA, respectively. The results of the study indicated that rats exposed to IMI exhibited significant neurobehavioral impairments, decreased levels of antioxidant enzymes and acetylcholinesterase activity, reduced expression of HO-1 and Nrf2, and increased levels of pro-inflammatory cytokines like IL-6 and TNF-α in their hippocampal tissues. Furthermore, histopathological analysis of the brain tissues, specifically cortex and hippocampus, from the IMI-treated group revealed varying degrees of neuronal degeneration. In contrast, rats co-administered ALA alongside IMI showed noticeable improvements in all the assessed toxicological parameters. This study underscores the vital significance of ALA as a potential therapeutic adjunct in mitigating the adverse neurobehavioral consequences of insecticide exposure. By harnessing the Nrf2/HO-1 pathway, ALA demonstrates its ability to shield against IMI-induced neurotoxicity, offering a promising avenue for enhancing public health and safety. As a result, our findings advocate for the incorporation of ALA as a daily dietary supplement to fortify resilience against oxidative stress-related neurobehavioral deficits linked to pesticide exposure, thereby advancing our understanding of neuroprotection strategies in the face of environmental challenges.

Nano-selenium alleviates cadmium-induced neurotoxicity in cerebrum via inhibiting gap junction protein connexin 43 phosphorylation.

Cadmium (Cd) as a ubiquitous toxic heavy metal is reported to affect the nervous system. Selenium (Se) has been shown to have antagonistic effects against heavy metal toxicity. In addition, it shows potential antioxidant and anti-inflammatory properties. Thus, the purpose of this study was to determine the possible mechanism of brain injury after high Cd exposure and the mitigation of Nano-selenium (Nano-Se) against Cd-induced brain injury. In this study, the Cd-treated group showed a decrease in the number of neurons in brain tissue, swelling of the endoplasmic reticulum and mitochondria, and the formation of autophagosomes. Nano-Se intervention restored Cd-caused alterations in neuronal morphology, endoplasmic reticulum, and mitochondrial structure, thereby reducing neuronal damage. Furthermore, we found that some differentially expressed genes were involved in cell junction and molecular functions. Subsequently, we selected eleven (11) related differentially expressed genes for verification. The qRT-PCR results revealed the same trend of results as determined by RNA-Seq. Our findings also showed that Nano-Se supplementation alleviated Cx43 phosphorylation induced by Cd exposure. Based on immunofluorescence colocalization it was demonstrated that higher expression of GFAP and lower expressions of Cx43 were restored by Nano-Se supplementation. In conclusion, the data presented in this study establish a direct association between the phosphorylation of Cx43 and the occurrence of autophagy and neuroinflammation. However, it is noteworthy that the introduction of Nano-Se supplementation has been observed to mitigate these alterations. These results elucidate the relieving effect of Nano-Se on Cd exposure-induced brain injury.

Aqueous leaf extract of Phyllanthus amarus protects against oxidative stress and misfiring of dopaminergic neurons in Paraquat-induced Parkinson's disease-like model of adult Wistar rats.

BACKGROUND OF THE STUDY: Phyllanthus amarus has high nutritional value and is beneficial in managing and treating diverse ailments. This study assessed the role of aqueous leaf extract of Phyllanthus amarus on Paraquat (PQ) induced neurotoxicity in the substantia nigra of Wistar rats. MATERIALS AND METHODS: The role of aqueous leaves extract of Phyllanthus amarus was assessed using an open field test (OFT) for motor activity, oxidative stress biomarkers [Catalase (CAT), and Superoxide Dismutase (SOD)], histological examination (H and E stained) for cytoarchitectural changes and immunohistochemical studies using tyrosine hydroxylase (TH) as a marker for dopaminergic neurons. Forty-two (42) rats were categorized into six groups (n = 7); group 1: control was administered 0.5 ml/kg distilled water, group 2: received 10 mg/kg PQ + 10 mg/kg L-dopa as reference drug, group 3; received 10 mg/kg PQ, while group 4: received 10 mg/kg PQ + 200 mg/kg P. amarus, group 5: received 10 mg/kg PQ + 300 mg/kg P. amarus, and group 6: received 10 mg/kg PQ + 400 mg/kg P. amarus respectively, for 14 days. All administrations were done orally; a significant difference was set at p < 0.05. RESULTS AND DISCUSSION: The study's open field test (OFT) revealed no motor activity deficit with Paraquat (PQ) exposure. Also, cytoarchitectural distortions were not observed with Paraquat (PQ) only treatment group compared to the control and other groups pretreated with P. amarus and L-dopa. Moreover, the Paraquat (PQ) only treatment group showed oxidative stress by significantly decreasing the antioxidant enzyme (SOD) compared to the control and L-dopa pretreated group. A significant decrease in tyrosine hydroxylase (TH) expressing dopaminergic neurons was also observed in Paraquat (PQ) only treatment. However, P. amarus treatment showed therapeutic properties by significantly increasing tyrosine hydroxylase (TH) expressing dopaminergic neuron levels relative to control. CONCLUSION: Aqueous leaf extract of Phyllanthus amarus possesses therapeutic properties against Paraquat (PQ) induced changes in the substantia nigra of Wistar rats.

Selenium alleviates modafinil-induced neurobehavioral toxicity in rat via PI3K/Akt/mTOR/GSK3B signaling pathway and suppression of oxidative stress and apoptosis: in vivo and in silico study.

Nonmedical use of modafinil (MOD) led to increased rates of overdose toxicity, road accidents, addiction, withdrawal, suicide, and mental illnesses. The current study aims to determine the probable MOD brain toxicity and elucidate the possible role of selenium (Se) in ameliorating the neurotoxicity in rat models. Fifty-four male Albino rats were randomly assigned into nine groups. The groups were G1 (control negative), G2 (Se0.1), G3 (Se0.2), G4 (MOD300), G5 (MOD600), G6 (Se0.1 + MOD300), G7 (Se0.2 + MOD300), G8 (Se0.1 + MOD600), and G9 (Se0.2 + MOD600). After finishing the experiment, blood and brain tissue were harvested for biochemical and histological investigation. Neurobehavior parameters were assessed. Tissue neurotransmitter levels and oxidative stress markers were assessed. Gene expression of PI3K/Akt/mTOR-GSK3B, orexin, and orexin receptor2 was measured by qRT-PCR. Histological and immunohistochemistry assessments, as well as molecular docking, were carried out. MOD-induced neurobehavioral toxicity exhibited by behavioral and cognitive function impairments, which are associated with decreased antioxidant activities, increased MDA levels, and decreases in neurotransmitter levels. Brain levels of mRNA expression of PI3K, Akt, and mTOR were decreased, while GS3K, orexin, and orexin receptors were significantly elevated. These disturbances were confirmed by histopathological brain changes with increased silver and Bax immunostaining and decreased crystal violet levels. MOD induced neurotoxic effects in a dose-dependent manner. Compared with the MOD groups, SE coadministration significantly attenuates MOD-induced toxic changes. Docking study shows the protective role of Se as an apoptosis inhibitor and inflammation inhibitor. In conclusion, Se could be used as a biologically effective antioxidant compound to protect from MOD neurobehavioral toxicity in Wistar rats by reversing behavioral alterations, inflammation, apoptosis, and oxidative injury.

Evaluation of neurological behavior alterations and metabolic changes in mice under chronic glyphosate exposure.

Glyphosate is a widely used active ingredient in agricultural herbicides, inhibiting the biosynthesis of aromatic amino acids in plants by targeting their shikimate pathway. Our gut microbiota also facilitates the shikimate pathway, making it a vulnerable target when encountering glyphosate. Dysbiosis in the gut microbiota may impair the gut-brain axis, bringing neurological outcomes. To evaluate the neurotoxicity and biochemical changes attributed to glyphosate, we exposed mice with the reference dose (RfD) set by the U.S. EPA (1.75 mg/Kg-BW/day) and its hundred-time-equivalence (175 mg/Kg-BW/day) chronically via drinking water, then compared a series of neurobehaviors and their fecal/serum metabolomic profile against the non-exposed vehicles (n = 10/dosing group). There was little alteration in the neurobehavior, including motor activities, social approach, and conditioned fear, under glyphosate exposure. Metabolomic differences attributed to glyphosate were observed in the feces, corresponding to 68 and 29 identified metabolites with dysregulation in the higher and lower dose groups, respectively, compared to the vehicle-control. There were less alterations observed in the serum metabolome. Under 175 mg/Kg-BW/day of glyphosate exposure, the aromatic amino acids (phenylalanine, tryptophan, and tyrosine) were reduced in the feces but not in the serum of mice. We further focused on how tryptophan metabolism was dysregulated based on the pathway analysis, and identified the indole-derivatives were more altered compared to the serotonin and kynurenine derivatives. Together, we obtained a three-dimensional data set that records neurobehavioral, fecal metabolic, and serum biomolecular dynamics caused by glyphosate exposure at two different doses. Our data showed that even under the high dose of glyphosate irrelevant to human exposure, there were little evidence that supported the impairment of the gut-brain axis.

Cerebral neurotoxicity of amino-modified polystyrene nanoplastics in mice and the protective effects of functional food Camellia pollen.

Accumulating evidence suggests that nanoplastics contribute to an increased risk of brain damage, however, the precise underlying mechanisms remain unclear. Here, we subjected mice to long-term exposure to amino-modified polystyrene nanoplastics (APS-NPs). These nanoplastics were detected in the mouse brain; coupled with the observed upregulation of Alzheimer's disease-associated genes (APP and MAPT). To further explore nanoplastic damage mechanisms and the corresponding protective strategies against these mechanisms in vitro, we used hCMEC/D3 and HT22 cells. Results showed that APS-NPs disrupted tight junction proteins (Occludin and ZO-1) via TLR2/MMP9 axis, resulting in blood-brain barrier permeation; this was significantly mitigated by functional food Camellia pollen treatment. APS-NPs initiated iNOS and nNOS upregulation within neurons resulting in Sirtuin 1 deacetylase inactivation and CBP acetyltransferase stimulation, ultimately leading to Ac-Tau formation. This process was attenuated by Camellia pollen, which also ameliorated the APS-NPs-induced neuronal apoptosis mediated by the p53/Bax/Bcl-2 axis. Network pharmacology analysis of Camellia pollen offered a further theoretical understanding of its potential applications in preventing and treating nervous system disorders, such as Alzheimer's disease. This study established that Camellia pollen protects the brain against APS-NPs-mediated blood-brain barrier damage and alleviates neuronal apoptosis and Alzheimer's disease-like neurotoxicity. This study elucidates the mechanisms underlying polystyrene-induced brain damage and can be used to inform future prevention and treatment strategies.