Model Of Neurotoxicity Research Articles

3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide derivatives: Design, Synthesis and Neuroprotectivity Potential Against 6-OHDA Induced Neurotoxicity Model

3-(1H-pyrazole-1-yl/1H-1,2,4-triazole-1-yl)-N-propananilide derivatives: Design, Synthesis and Neuroprotectivity Potential Against 6-OHDA Induced Neurotoxicity Model

Neuroprotective Effect of Resveratrol against Manganese-Induced Oxidative Stress and Matrix Metalloproteinase-9 in an "In Vivo" Model of Neurotoxicity.

Chronic exposure to manganese (Mn) leads to its accumulation in the central nervous system (CNS) and neurotoxicity with not well-known mechanisms. We investigated the involvement of matrix metalloproteinase (MMP)-2 and -9 in Mn neurotoxicity in an in vivo model of rats treated through an intraperitoneal injection, for 4 weeks, with 50 mg/kg of MnCl2 in the presence or in the absence of 30 mg/kg of resveratrol (RSV). A loss of weight was observed in Mn-treated rats compared with untreated and RSV-treated rats. A progressive recovery of body weight was detected in rats co-treated with Mn and RSV. The analysis of brain homogenates indicated that RSV counteracted the Mn-induced increase in MMP-9 levels and reactive oxygen species production as well as the Mn-induced decrease in superoxide dismutase activity and glutathione content. In conclusion, Mn exposure, resulting in MMP-9 induction with mechanisms related to oxidative stress, represents a risk factor for the development of CNS diseases.

Ameliorative role of diets fortified with Artocarpus altilis in a Drosophila melanogaster model of aluminum chloride-induced neurotoxicity

Backgrounds: Artocarpus altilis (breadfruit) belongs to the family Moraceae. Artocarpus altilis possesses antioxidative, anti-inflammatory, and anti-proliferative properties. Aluminum (Al) is extensively utilized for consumer products, cooking utensils, pharmaceuticals, and industries. Indication for the neurotoxicity of Al is investigated in various studies, notwithstanding the precise mechanisms of Al toxicity are yet to be fully elucidated, and, which requires novel therapy. In this study, we determined the ameliorative role of Artocarpus altilis on aluminum chloride-induced neurotoxicity in Drosophila melanogaster.MethodsVarying concentration of the extract were used to formulate diets for 6 groups of flies. Group 1 contained basal diet, group 2 contained basal diet and aluminium chloride (AlCl3), group 3 contained basal diet + 0.1% unseeded breadfruit (UBF), group 4 contained basal diet + 1% unseeded breadfruit, group 5 and 6 contained basal diet + AlCl3 + 0.1% and 1% unseeded breadfruit. Assays such as acetylcholinesterase activity, malondialdehyde (MDA) concentration level, catalase activity, and superoxide dismutase (SOD) activity were carried out after 7 days of exposure respectively.ResultsThe results showed low activity of acetylcholinesterase activity and MDA level and high catalase and SOD activity in the pretreated and post-treated flies with Artocarpus altilis compared to the normal and negative control respectively.ConclusionsTaken together, Artocarpus altilis is a promising prophylactic, antiacetylcholinesterase, and antioxidant plant in the prevention, management and treatment of neurodegenerative diseases.Graphical

Management of the Brain: Essential Oils as Promising Neuroinflammation Modulator in Neurodegenerative Diseases.

Neuroinflammation, a pivotal factor in the pathogenesis of various brain disorders, including neurodegenerative diseases, has become a focal point for therapeutic exploration. This review highlights neuroinflammatory mechanisms that hallmark neurodegenerative diseases and the potential benefits of essential oils in counteracting neuroinflammation and oxidative stress, thereby offering a novel strategy for managing and mitigating the impact of various brain disorders. Essential oils, derived from aromatic plants, have emerged as versatile compounds with a myriad of health benefits. Essential oils exhibit robust antioxidant activity, serving as scavengers of free radicals and contributing to cellular defense against oxidative stress. Furthermore, essential oils showcase anti-inflammatory properties, modulating immune responses and mitigating inflammatory processes implicated in various chronic diseases. The intricate mechanisms by which essential oils and phytomolecules exert their anti-inflammatory and antioxidant effects were explored, shedding light on their multifaceted properties. Notably, we discussed their ability to modulate diverse pathways crucial in maintaining oxidative homeostasis and suppressing inflammatory responses, and their capacity to rescue cognitive deficits observed in preclinical models of neurotoxicity and neurodegenerative diseases.

Protection Activity of 1,4-Naphthoquinones in Rotenone-Induced Models of Neurotoxicity.

The MTS cell viability test was used to screen a mini library of natural and synthetic 1,4-naphthoquinone derivatives (1,4-NQs) from marine sources. This screening identified two highly effective compounds, U-443 and U-573, which showed potential in protecting Neuro-2a neuroblastoma cells from the toxic effects of rotenone in an in vitro model of neurotoxicity. The selected 1,4-NQs demonstrated the capability to reduce oxidative stress by decreasing the levels of reactive oxygen species (ROS) and nitric oxide (NO) in Neuro-2a neuroblastoma cells and RAW 264.7 macrophage cells and displayed significant antioxidant properties in mouse brain homogenate. Normal mitochondrial function was restored and the mitochondrial membrane potential was also regained by 1,4-NQs after exposure to neurotoxins. Furthermore, at low concentrations, these compounds were found to significantly reduce levels of proinflammatory cytokines TNF and IL-1β and notably inhibit the activity of cyclooxygenase-2 (COX-2) in RAW 264.7 macrophages. The results of docking studies showed that the 1,4-NQs were bound to the active site of COX-2, analogically to a known inhibitor of this enzyme, SC-558. Both substances significantly improved the behavioral changes in female CD1 mice with rotenone-induced early stage of Parkinson's disease (PD) in vivo. It is proposed that the 1,4-NQs, U-443 and U-573, can protect neurons and microglia through their potent anti-ROS and anti-inflammatory activities.

Initial Molecular Mechanisms of the Pathogenesis of Parkinson's Disease in a Mouse Neurotoxic Model of the Earliest Preclinical Stage of This Disease.

Studying the initial molecular mechanisms of the pathogenesis of Parkinson's disease (PD), primarily in the nigrostriatal dopaminergic system, is one of the priorities in neurology. Of particular interest is elucidating these mechanisms in the preclinical stage of PD, which lasts decades before diagnosis and is therefore not available for study in patients. Therefore, our main goal was to study the initial molecular mechanisms of the pathogenesis of PD in the striatum, the key center for dopamine regulation in motor function, in a mouse model of the earliest preclinical stage of PD, from 1 to 24 h after the administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). It was shown that the content of tyrosine hydroxylase (TH), the first enzyme in dopamine synthesis, does not change within 6 h after the administration of MPTP, but decreases after 24 h. In turn, TH activity increases after 1 h, decreases after 3 h, remains at the control level after 6 h, and decreases 24 h after the administration of MPTP. The concentration of dopamine in the striatum gradually decreases after MPTP administration, despite a decrease in its degradation. The identified initial molecular mechanisms of PD pathogenesis are considered as potential targets for the development of preventive neuroprotective treatment.

Hybrid Fruits for Improving Health-A Comprehensive Review.

Several species of hybrid fruits, such as citrus, grapes, blueberries, apples, tomatoes, and lingonberries among others, have attracted scientific attention in recent years, especially due to their reported antioxidant and anti-inflammatory properties. The bagasse, leaves, bark, and seeds of these hybrid fruits have large amounts of polyphenols, such as flavonoids, which act as potent antioxidants. Several studies have been carried out in cellular models of neurotoxicity of the extract of these fruits, to document the beneficial effects for human health, as well as to prove its antiproliferative effect in cancer cells. In the present review, through a synthesis of existing information in the scientific literature, we demonstrate that hybrid fruits are a source of antioxidant and bioactive compounds, which act in the inhibition of diseases such as cancer, diabetes, and inflammatory and neurodegenerative diseases, and consequently improving human health.

Neurotoxic pesticides change respiratory parameters in early gill-breathing, but not in skin-breathing life-stages of zebrafish (Danio rerio)

Neurotoxic compounds can interfere with active gill ventilation in fish, which might lead to premature death in adult fish, but not in skin-breathing embryos of zebrafish, since these exclusively rely on passive diffusion across the skin. Regarding lethality, this respiratory failure syndrome (RFS) has been discussed as one of the main reasons for the higher sensitivity of adult fish in the acute fish toxicity test (AFT), if compared to embryos in the fish embryo toxicity test (FET). To further elucidate the relationship between the onset of gill respiration and death by a neurotoxic mode of action, a comparative study into oxygen consumption (MO2), breathing frequency (fv) and amplitude (fampl) was performed with 4 d old skin-breathing and 12 d old early gill-breathing zebrafish. Neurotoxic model substances with an LC50 FET/AFT ratio of > 10 were used: chlorpyrifos, permethrin, aldicarb, ziram, and fluoxetine. Exposure to hypoxia served as a positive control, whereas aniline was tested as an example of a narcotic substance interfering non-specifically with gill membranes. In 12 d old larvae, all substances caused an increase in MO2, fv and partly fampl, whereas effects were minor in 4 d old embryos. An increase of fv in 4 d old embryos following exposure to chlorpyrifos, aldicarb and hypoxia could not be correlated with an increased MO2 and might be attributed either to (1) to the successfully postponed decrease of arterial partial pressure of oxygen (PO2) through support of skin respiration by increased fv, (2) to an unspecific stimulation of the sphincter muscles at the base of the gill filaments, or (3) to the establishment of oxygen sensing for later stages. In gill-breathing 12 d old zebrafish, a concentration-dependent increase of fv was detected for aniline and chlorpyrifos, whereas for aldicarb, fluoxetine and permethrin, a decline of fv at higher substance concentrations was measured, most likely due to the onset of paralysis and/or fatigue of the gill filament sphincter muscles. Since alterations of fv serve to postpone the decrease in arterial PO2 and MO2 increased with decreasing fv, the respiratory failure syndrome could clearly be demonstrated in 12 d old zebrafish larvae. Passive respiration across the skin in zebrafish embryos could thus be confirmed as a probable reason for the lower sensitivity of early life-stages to neurotoxicants. Integration of respiratory markers into existing testing protocols with non-protected developmental stages such as embryos might help to not underestimate the toxicity of early life-stages of fish.

Effect of age on metabolomic changes in a model of paclitaxel-induced peripheral neurotoxicity.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is one of the most common dose-limiting side effects of paclitaxel (PTX) treatment. Many age-related changes have been hypothesized to underlie susceptibility to damage or impaired regeneration/repair after nerve injury. The results of these studies, however, are inconclusive and other potential biomarkers of nerve impairment need to be investigated. Twenty-four young (2 months) and 24 adult (9 months) Wistar male rats were randomized to either PTX treatment (10 mg/kg i.v. once/week for 4 weeks) or vehicle administration. Neurophysiological and behavioral tests were performed at baseline, after 4 weeks of treatment and 2-week follow-up. Skin biopsies and nerve specimens collected from sacrificed animals were examined for intraepidermal nerve fiber (IENF) density assessment and nerve morphology/morphometry. Blood and liver samples were collected for targeted metabolomics analysis. At the end of treatment, the neurophysiological studies revealed a reduction in sensory nerve action potential amplitude (p < .05) in the caudal nerve of young PTX-animals, and in both the digital and caudal nerve of adult PTX-animals (p < .05). A significant decrease in the mechanical threshold was observed only in young PTX-animals (p < .001), but not in adult PTX-ones. Nevertheless, both young and adult PTX-rats had reduced IENF density (p < .0001), which persisted at the end of follow-up period. Targeted metabolomics analysis showed significant differences in the plasma metabolite profiles between PTX-animals developing peripheral neuropathy and age-matched controls, with triglycerides, diglycerides, acylcarnitines, carnosine, long chain ceramides, sphingolipids, and bile acids playing a major role in the response to PTX administration. Our study identifies for the first time multiple related metabolic axes involved in PTX-induced peripheral neurotoxicity, and suggests age-related differences in CIPN manifestations and in the metabolic profile.

Neuroprotective effect of olive leaf extract in the mouse neuroblastoma cell line (NB2a): A good model to evaluate the neuroprotective effects of natural products

Chronic neurodegenerative diseases, such as Alzheimer's and Parkinson's diseases, whose prevalence increases with aging, cause serious health problems with inadequate treatment options. Long-term exposure to low doses of pesticides like chlorpyrifos has been linked to an increased risk of developing neurodegenerative diseases. This study assessed the effects of olive leaf extract (OLE) on cell viability and neurite outgrowth inhibition induced by chlorpyrifos (25 µM) using the mouse NB2a neuroblastoma cell line. High concentrations of OLE as 100 to 3000 µg/ml reduced cell viability, likely due to its anticancer properties. On the other hand, lower concentrations of OLE as 3, 10, 30 and 100 µg/ml significantly reversed the inhibition of neurite outgrowth caused by chlorpyrifos exposure, demonstrating a neuroprotective effect. In conclusion, the regular consumption of OLE may effectively slow or prevent the advancement of neurodegenerative diseases linked to long-term exposure to low-dose organophosphate pesticides. Furthermore, the chlorpyrifos-induced moderate neurotoxicity model can be employed as a valuable screening method for evaluating the neuroprotective potential of natural products, including various plant extracts.

Genomic studies of neudegeneration in Parkinson’s disease associated with glucocerebrosodase dysfunction on cell and animals models

Mutations in the glucocerebrosidase gene (GBA1), which encodes the lysosomal enzyme glucocerebrosidase (GCase), can cause Gaucher disease, an autosomal recessive disease, and increase the risk of Parkinson’s disease (PD). The risk of developing PD for carriers of homozygous and heterozygous GBA1 mutations increases by 8–10 times, but not all carriers develop PD during their lifetime. Additionally, GBA-associated PD (GBA-PD) represents 10 to 30% of all forms of parkinsonism. The development mechanism of GBA-PD remains unknown. A decrease in GCase activity and accumulation of lysosphingolipids in patients with GBA-PD was shown by us and other researchers [1, 2]. GCase dysfunction is thought to result in impaired autophagy and accumulation of the alpha-synuclein protein, which is a crucial process in neurodegeneration in PD. Several techniques based on modeling parkinsonism in mice with GCase dysfunction were used to study the impact of GCase dysfunction on DA neuron neurodegeneration [3, 4]. In this study, we evaluated GCase activity, lysosphingolipids level, and the degree of neurodegeneration in DA-neurons of the substantia nigra’s compact (SNc) and reticular part (SNr), as well as the levels of dopamine and alpha-synuclein (total and oligomeric) in the brains of mice with a double “soft” neurotoxic model induced by the introduction of the neurotoxin 1-methyl-4-phenyl-1. This is the first time such an evaluation has been made. The presymptomatic stage of parkinsonism induced by 2,3,6-tetrahydropyridine (MPTP) involved the double administration of 12 μg/kg at a 2-hour interval, in combination with a single injection of the selective GCase inhibitor conduritol-B-epoxide (CBE) at a dose of 100 mg/kg. Additionally, we compared the transcriptomes of primary macrophage cultures from GBA-PD patients [5] with the transcriptome of SN brain tissue in model mice. We demonstrated that a singular injection of CBE resulted in a 50% decrease in GCase activity in the mouse brain and an elevation in lysosphingolipid levels. Additionally, the introduction of both MPTP and CBE led to an increase in the level of oligomeric forms of alpha-synuclein in the striatum. Simultaneously, degeneration of DA neurons in SNc, assessed by tyrosine hybroxylase (TH) immunohistochemistry 14 days after injection, was comparable to MPTP and CBE (decreasing to 50 and 60%, respectively). The neurotoxic model, when combined, demonstrates a significantly greater reduction in dopamine concentration, accumulation of total alpha-synuclein in the striatum, and more severe neurodegeneration of DA neurons in SNr (70% compared to 45% with MPTP administration). A comparison of differential gene expression in primary macrophage cultures from patients with GBA-PD and controls revealed a reduction in the expression of genes associated with neurogenesis, such as JUNB, NR4A2, and EGR1. In both the GBA-PD patient group (TRIM13, BCL6) and the MPTP-induced parkinsonism mouse group with GCase dysfunction (MPTP+CBE), genes related to the PI3K-Akt-mTOR signaling pathway, which regulates autophagy, were found to be activated. These genes include Pdk4, Sgk, and Ppp2r3d. The data obtained indicates that dysfunctional GCase leads to the accumulation of toxic forms of alpha-synuclein and degeneration of DA neurons, similar to the effects of small doses of MPTP. Combining neurotoxins (MPTP+CBE) causes a greater accumulation of alpha-synuclein and a higher degree of neuron degeneration. Transcriptomic analysis conducted on GBA-PD patients’ cells and a combined neurotoxic mouse model (MPTP+CBE) brain revealed modifications in gene expression of autophagy regulation. Approaches focused on enhancing GCase activity and autophagy exhibit potential in developing neuroprotective agents.

Morphofunctional characterisation of axonal damage in different rat models of chemotherapy-induced peripheral neurotoxicity: The role of nerve excitability testing.

Chemotherapy-induced peripheral neurotoxicity (CIPN) is a common and long-lasting adverse event of several anticancer compounds, for which treatment has not yet been developed. To fill this gap, preclinical studies are warranted, exploiting highly translational outcome measure(s) to transfer data from bench to bedside. Nerve excitability testing (NET) enables to test in vivo axonal properties and can be used to monitor early changes leading to axonal damage. We tested NET use in two different CIPN rat models: oxaliplatin (OHP) and paclitaxel (PTX). Animals (female) were chronically treated with either PTX or OHP and compared to respective control animals. NET was performed as soon as the first injection was administered. At the end of the treatment, CIPN onset was verified via a multimodal and robust approach: nerve conduction studies, nerve morphometry, behavioural tests and intraepidermal nerve fibre density. NET showed the typical pattern of axonal hyperexcitability in the 72 h following the first OHP administration, whereas it showed precocious signs of axonal damage in PTX animals. At the end of the month of treatment, OHP animals showed a pattern compatible with a mild axonal sensory polyneuropathy. Instead, PTX cohort was characterised by a rather severe sensory axonal polyneuropathy with minor signs of motor involvement. NET after the first administration demonstrated the ongoing OHP-related channelopathy, whereas in PTX cohort it showed precocious signs of axonal damage. Therefore, NET could be suggested as an early surrogate marker in clinical trials, to detect precocious changes leading to axonal damage.

Curcumin-ZnO conjugated nanoparticles confer neuroprotection against ketamine-induced neurotoxicity.

Nanotechnology and its application to manipulate herbal compounds to design new neuroprotective agents to manage neurotoxicity has recently increased. Cur-ZnO conjugated nanoparticles were synthesized and used in an experimental model of ketamine-induced neurotoxicity. Cur-ZnO conjugated nanoparticles were chemically characterized, and the average crystalline size was determined. Forty-nine adult mice were divided into seven groups of seven animals each. Normal saline was given to control mice (group 1). Ketamine (25 mg/kg) was given to a second group. A third group of mice was given ketamine (25 mg/kg) in combination with curcumin (40 mg/kg), while mice in groups 4, 5, and 6 received ketamine (25 mg/kg) plus Cur-ZnO nanoparticles (10, 20, and 40 mg/kg). Group 7 received only ZnO (5 mg/kg). All doses were ip for 14 days. Hippocampal mitochondrial quadruple complex enzymes, oxidative stress, inflammation, and apoptotic characteristics were assessed. Cur-ZnO nanoparticles and curcumin decreased lipid peroxidation, GSSG content, IL-1β, TNF-α, and Bax levels while increasing GSH and antioxidant enzymes like GPx, GR, and SOD while increasing Bcl-2 level and mitochondrial quadruple complex enzymes in ketamine treatment groups. The neuroprotective properties of Cur-ZnO nanoparticles were efficient in preventing ketamine-induced neurotoxicity in the mouse brain. The nanoparticle form of curcumin (Cur-ZnO) required lower doses to produce neuroprotective effects against ketamine-induced toxicity than conventional curcumin.

Ethanol extract of Andrographis paniculata alleviates aluminum-induced neurotoxicity and cognitive impairment through regulating the p62-keap1-Nrf2 pathway

BackgroundAlzheimer’s disease (AD) is the most prevalent neurodegenerative and remains incurable. Aluminum is a potent neurotoxin associated with AD. The main pathological features of AD are extracellular amyloid-β protein deposition and intracellular hyperphosphorylated Tau protein. A body of evidence suggest that oxidative stress and autophagy are involved in the pathogenesis of AD. Andrographis paniculata (AP) is a native plant with anti-inflammatory, anti-oxidative stress, and regulation of autophagy properties. AP significantly alleviated cognitive impairments, reduced Aβ deposition and has neuroprotective effect. However, its effects on aluminum-induced AD model have not been studied much. In this study, we investigated whether AP protect against aluminum-induced neurotoxicity through regulation of p62-Kelch-like ECH-associated protein 1(Keap1)-Nuclear factor E2 related factor 2 (Nrf2) pathway and activation autophagy in vivo and in vitro.MethodsUPLC-ESI-qTOF-MS/MS was used to identify the chemical constituents of AP ethanol extract. The mice with cognitive deficit were established by injecting aluminum chloride and D-galactose, and treated with either AP extract (200, 400, or 600 mg/kg/d) or andrographolide (2 mg/kg/2d).The spatial memory ability was detected by Morris water maze, HE staining were used to detect in brain tissue,Oxidative stress indexs and SOD activity in both serum and brain tissue were detected by kit.The expression of p62-Nrf2 pathway proteins were measured via western blotting. Furthermore, the neurotoxicity model was induced by aluminum maltolate (700 µM) in PC12 cells. Following AP and andrographolide treatment, the cell viability was detected. The relevant mRNA and protein expressions were detected in cells transfected with the p62 siRNA.ResultsThe main active components of AP included andrographolide, neoandrographolide and deoxyandrographolide as identified. AP and andrographolide significantly improved the spatial memory ability of mice, attenuated pathological changes of hippocampal cells, reduced the level of malondialdehyde, and increased superoxide dismutase activity in serum or brain tissue as compared to model control. In addition, the Nrf2, p62 and LC3B-II proteins expression were increased, and p-Tau and Keap1 proteins were decreased in the hippocampus after AP and andrographolide treatment.Furthermore, AP increased aluminum maltolate-induced cell viability in PC12 cells. Silencing p62 could reverse the upregulation expression of Nrf2 and downregulation of Keap1 and Tau proteins induced by AP in aluminum maltolate-treated cells.ConclusionsAP had neuroprotective effects against aluminum -induced cognitive dysfunction or cytotoxicity, which was involved in the activation of the p62-keap1-Nrf2 pathway and may develop as therapeutic drugs for the treatment of AD. However, this study has certain limitations, further optimize the protocol or model and study the molecular mechanism of AP improving AD.

Preventive and therapeutic effects of azithromycin on acrylamide-induced neurotoxicity in rats

BackgroundAcrylamide (ACR) can induce neurotoxicity through different pathways, including oxidative stress and apoptosis. Azithromycin is well-known for its antioxidant and anti-apoptotic properties. ObjectiveTo evaluate the potential neuroprotective effect of azithromycin in an in vivo model of ACR-induced neurotoxicity, by investigating its impact on oxidative stress and apoptosis pathways. MethodsMale rats were divided into eleven groups at random (n = 6). 1:control (vehicle), 2:ACR (50 mg/kg, 11 days, I.P.), 3–7:ACR+ azithromycin (3.1, 6.25, 12.5, 25, 50 mg/kg, 11 days, I.P.), 8–9:ACR+ azithromycin (3.1, 6.25 mg/kg, from day 3–11), 10: ACR+ vitamin E (200 mg/kg, every other day, I.P.), 11. Azithromycin (50 mg/kg). Following the treatment period, a gait score examination was performed, and malondialdehyde (MDA), glutathione (GSH), Bcl-2-associated X protein (Bax)/B-cell lymphoma 2 (Bcl-2) ratio and caspase-3 levels in the cerebral cortex were measured. ResultsGait abnormality, a drop in GSH, and an increase in lipid peroxidation, Bax/Bcl-2 ratio, and caspase-3 levels were all significantly triggered by ACR in the cerebral cortex versus the control group. Azithromycin 3.1 and 6.25 mg/kg with ACR and azithromycin 6.25 mg/kg with ACR from day 3–11 ameliorated movement disorders caused by ACR. Azithromycin in all doses and both protocols along with ACR decreased the MDA level. Azithromycin (3.1, 6.25 mg/kg) along with ACR in both protocols increased the level of GSH, reduced the Bax/Bcl-2 ratio and caspase-3 amounts in the brain tissue versus the ACR group. ConclusionsAdministration of azithromycin had both preventive and therapeutic effects on ACR-induced neurotoxicity through its antioxidant and antiapoptotic properties.

The NADPH Oxidase Inhibitor, Mitoapocynin, Mitigates DFP-Induced Reactive Astrogliosis in a Rat Model of Organophosphate Neurotoxicity.

NADPH oxidase (NOX) is a primary mediator of superoxides, which promote oxidative stress, neurodegeneration, and neuroinflammation after diisopropylfluorophosphate (DFP) intoxication. Although orally administered mitoapocynin (MPO, 10 mg/kg), a mitochondrial-targeted NOX inhibitor, reduced oxidative stress and proinflammatory cytokines in the periphery, its efficacy in the brain regions of DFP-exposed rats was limited. In this study, we encapsulated MPO in polyanhydride nanoparticles (NPs) based on 1,6-bis(p-carboxyphenoxy) hexane (CPH) and sebacic anhydride (SA) for enhanced drug delivery to the brain and compared with a high oral dose of MPO (30 mg/kg). NOX2 (GP91phox) regulation and microglial (IBA1) morphology were analyzed to determine the efficacy of MPO-NP vs. MPO-oral in an 8-day study in the rat DFP model. Compared to the control, DFP-exposed animals exhibited significant upregulation of NOX2 and a reduced length and number of microglial processes, indicative of reactive microglia. Neither MPO treatment attenuated the DFP effect. Neurodegeneration (FJB+NeuN) was significantly greater in DFP-exposed groups regardless of treatment. Interestingly, neuronal loss in DFP+MPO-treated animals was not significantly different from the control. MPO-oral rescued inhibitory neuronal loss in the CA1 region of the hippocampus. Notably, MPO-NP and MPO-oral significantly reduced astrogliosis (absolute GFAP counts) and reactive gliosis (C3+GFAP). An analysis of inwardly rectifying potassium channels (Kir4.1) in astroglia revealed a significant reduction in the brain regions of the DFP+VEH group, but MPO had no effect. Overall, both NP-encapsulated and orally administered MPO had similar effects. Our findings demonstrate that MPO effectively mitigates DFP-induced reactive astrogliosis in several key brain regions and protects neurons in CA1, which may have long-term beneficial effects on spontaneous seizures and behavioral comorbidities. Long-term telemetry and behavioral studies and a different dosing regimen of MPO are required to understand its therapeutic potential.

Gardenia jasminoides J. Ellis extract attenuates memory impairment in rats with Alzheimer’s disease by suppressing NLRP3 inflammasome

Alzheimer’s disease (AD) is characterized by degeneration of the central nervous system. Recently, many studies have emphasized the beneficial role of Gardenia jasminoides J. Ellis extract (GJ-4) in neuroprotection, which is considered a potential drug for treating AD. However, the mechanism underlying its neuroprotective effects is obscure. This research intended to analyze the effectiveness of GJ-4 to induce neuronal protective role on a rat model of neurotoxicity and probe the potential mechanism. An AD model was established by intraperitoneal injection of aluminum chloride (AlCl3). Then, AlCl3-induced rats were administered 25 mg/kg and 50 mg/kg of GJ-4 orally. This study indicated that GJ-4 (25 and 50 mg/kg) mitigated AD-like behaviors, as evidenced by enhanced ambulation frequency, rearing frequency, and time spent in the target quadrant and decreased grooming frequency, defecation frequency, and escape latency in AlCl3-challenged rats. Also, GJ-4 at 25 and 50 mg/kg exerted an anti-apoptosis effect in the hippocampus of AlCl3-treated rats. Furthermore, GJ-4 (25 and 50 mg/kg) exhibited an anti-inflammatory effect in the hippocampus by repressing the activation of NOD-like receptor thermal protein domain associated protein 3 (NLRP3) inflammasome, further inhibiting the activation of Caspase 1, ASC, IL-1β, and IL-18 in AD hippocampus. Altogether, GJ-4 mitigated AlCl3-triggered impairment of learning and memory in AD rats via repressing NLRP3 inflammasome.

A Pediatric Rat Model of Organophosphate-Induced Refractory Status Epilepticus: Characterization of Long-Term Epileptic Seizure Activity, Neurologic Dysfunction and Neurodegeneration.

Children are highly vulnerable to the neurotoxic effects of organophosphates (OPs), which can cause neuronal developmental defects, including intellectual disability, autism, epilepsy, and related comorbidities. Unfortunately, no specific pediatric OP neurotoxicity model currently exists. In this study, we developed and characterized a pediatric rat model of status epilepticus (SE) induced by the OP diisopropylfluorophosphate (DFP) and examined its impact on long-term neurological outcomes. Postnatal day 21 rats were exposed to a DFP regimen with standard antidotes. Progressive behavioral deteriorations were assessed over a three-month period. Development of epileptic seizures, ictal discharges, high-frequency oscillations (HFOs), and interictal spikes were monitored by video-electroencephalography recordings. Histology-stereology analysis was performed to assess neurodegeneration, neuroinflammation, and morphologic abnormalities. DFP-exposed, post-SE animals exhibited significantly elevated levels of anxiety and depression than age-matched controls at 1, 2, and 3 months post-exposure. DFP-exposed animals displayed aggressive behavior and a marked decline in object recognition memory, as well as prominent impairment in spatial learning and memory. DFP-exposed animals had striking electrographic abnormalities with the occurrence of displayed epileptic seizures, ictal discharges, HFOs, and interictal spikes, suggesting chronic epilepsy. Neuropathological analysis showed substantially fewer principal neurons and inhibitory interneurons with a marked increase in reactive microglia and neuroinflammation in the hippocampus and other brain regions. DFP-exposed animals also exhibited mossy fiber sprouting indicating impaired network formations. Long-term epileptic seizures and neuropsychiatric functional deficits induced by DFP were consistent with neuropathological defects. Collectively, this pediatric model displays many hallmarks of chronic sequelae reminiscent of children exposed to OPs, suggesting that it will be a valuable tool for investigating pathologic mechanisms and potential treatment strategies to attenuate long-term OP neurotoxicity. SIGNIFICANCE STATEMENT: Millions of children are exposed to organophosphates (OPs) used in agriculture or chemical incidents. This study investigated the long-term impact of neonatal exposure to the OP chemical diisopropylfluorophosphate (DFP) on neurobehavioral and neurodevelopmental outcomes in adulthood. DFP exposure caused long-lasting behavioral abnormalities, epileptic seizures, and bilateral brain defects with an array of neurological sequelae seen in children's OP neurotoxicity. Thus, this model provides a novel tool to explore therapeutic interventions that mitigate long-term neurotoxic effects of children exposed to OP-induced seizures and status epilepticus.

Application of reduction and refinement principles in the evaluation of prodromal markers of Parkinson’s disease in a progressive neurotoxic mouse model using multi-tracer PET imaging

Not available.

Single-cell transcriptomics analysis of zebrafish brain reveals adverse effects of manganese on neurogenesis

Manganese (Mn) is considered as an important environmental risk factor for Parkinson's disease. Excessive exposure to Mn can damage various neural cells and affect the neurogenesis, resulting in neurological dysfunction. However, the specific mechanisms of Mn exposure affecting neurogenesis have not been well understood, including compositional changes and heterogeneity of various neural cells. Zebrafish have been successfully used as a neurotoxicity model due to its homology with mammals in several key regions of the brain, as well as its advantages such as small size. We performed single-cell RNA sequencing of zebrafish brains from normal and Mn-exposed groups. Our results suggested that low levels of Mn exposure activated neurogenesis in the zebrafish brain, including promoting the proliferation of neural progenitor cells and differentiation to newborn neurons and oligodendrocytes, while high levels of Mn exposure inhibited neurogenesis and neural function. Mn could affect neurogenesis through specific molecular pathways. In addition, Mn regulated intercellular communication and affected cellular communication in neural cells through specific signaling pathways. Taken together, our study elucidates the cellular composition of the zebrafish brain and adds to the understanding of the mechanisms involved in Mn-induced neurogenesis damage.