Neurotox Res [JOURNAL]
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200 papers
Modulation of NMDA Receptor and TRPM4 Activity in Hippocampal Neurons with the NMDA Receptor/TRPM4 Interface Inhibitor Brophenexin.
Casby J, Allen RK, Marron Fernandez de Velasco E … +1 more , Thayer SA
Neurotox Res · 2026 Mar · PMID 41790165 · Full text
Excitotoxic signaling mediated by N-methyl-D-aspartate receptors (NMDARs) is inhibited by NMDAR/TRPM4 complex inhibitors such as brophenexin (BPN). We used rat hippocampal neurons grown in culture to determine the effect...
Excitotoxic signaling mediated by N-methyl-D-aspartate receptors (NMDARs) is inhibited by NMDAR/TRPM4 complex inhibitors such as brophenexin (BPN). We used rat hippocampal neurons grown in culture to determine the effects of BPN on NMDAR and TRPM4 function. NMDA evoked concentration-dependent increases in intracellular Ca2+ that were inhibited by 10 µM BPN in a non-competitive manner. In contrast, the TRPM4 inhibitor 4-chloro-2-(2-(naphthalene-1-yloxy) acetamido) benzoic acid (NBA) increased the potency of NMDA at 22 °C. BPN inhibition of NMDAR-mediated increases in Ca2+ was fully reversible and recovered by rapid (30 s) and slow (90 min) processes. The rapid phase of recovery from BPN inhibition was mediated by trafficking through recycling endosomes as indicated by blockade of this phase with bafilomycin A1 an agent that prevents endosomal acidification. The full recovery of NMDAR function observed 90 min after washout of BPN was not affected by this treatment. Immunocytochemistry experiments suggested that BPN did not directly alter NMDAR trafficking but instead changes in surface and internal GluN2B immunoreactivity were likely homeostatic responses to inhibition of NMDAR function by BPN. In the presence of MK-801 to block NMDARs, 10 µM NBA inhibited spontaneous network-driven Ca2+ spiking by 74 ± 11% whereas 10 µM BPN reduced activity by 49 ± 6%. Thus, BPN inhibits TRPM4-dependent activity. In summary, BPN is a non-competitive, fully reversible inhibitor of NMDAR-mediated Ca2+ influx and produces a modest inhibition of TRPM4 function. Functional inhibition of these ion channels likely contributes to the neuroprotective properties of NMDAR/TRPM4 interface inhibitors.
Investigating brain-derived neurotrophic factor (BDNF) changes in three main rodent models of autism spectrum disorder (ASD): a systematic review.
Jalalian-Javadpour M, Khaledian M, Moradi H … +4 more , Behnoud H, Sajjadi M, Yekta BG, Vaseghi S
Neurotox Res · 2026 Feb · PMID 41746531 · Publisher ↗
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments, and repetitive and aggressive behaviors. The pathophysiology of ASD still remains unclear, while the population with AS...
Autism spectrum disorder (ASD) is a neurodevelopmental disorder characterized by social impairments, and repetitive and aggressive behaviors. The pathophysiology of ASD still remains unclear, while the population with ASD is 1/36 in children in the USA in 2024. Evidence suggests a wide range of inconsistent changes in brain-derived neurotrophic factor (BDNF), the most important neurotrophin in the central nervous system, in ASD. The present systematic review investigated studies that examined BDNF levels in three main ASD-like models in rodents [induced by valproic acid (VPA) and propionic acid (PPA), and in the BTBR mouse strain] in accord with PRISMA guidelines and in PubMed database. Forty-two studies were included. Most studies used male rats/mice. The results showed ASD model induced by VPA often leads to decreased BDNF, although unchanged or increased BDNF levels were also reported. ASD model induced by PPA leads to both increased and decreased BDNF. BDNF changes in BTBR mouse strain were also inconsistent. We found that the type of molecular assay appears to be important in evaluating BDNF. Also, few evidence showed a role for postnatal day and sex difference in BDNF changes in ASD-like rodent models. In addition, some studies have shown the potential role of the brain region in BDNF changes in different ASD-like models. In conclusion, it was suggested that inconsistencies in BDNF changes in rodent models of ASD may be related to the type of the molecular assay, the brain region, ASD model, sex, or even the postnatal day. However, evidence is still insufficient.
Niacin Protects iPSC-Derived Neurons from Chemotherapy-Induced Toxicity.
Ababneh NA, Gharandouq MH, Ismail MA … +10 more , AlDiqs R, Hamdan O, Musa Q, Barham R, Sarhan M, Al Shboul S, Masri AT, Abuhammad A, Awidi A, Saleh T
Neurotox Res · 2026 Feb · PMID 41724856 · Publisher ↗
Neurotoxicity remains a major dose-limiting adverse effect of cancer therapy. Previous studies have indicated that niacin can promote neuroprotective effects primarily through antioxidative mechanisms. In this study, we...
Neurotoxicity remains a major dose-limiting adverse effect of cancer therapy. Previous studies have indicated that niacin can promote neuroprotective effects primarily through antioxidative mechanisms. In this study, we investigated the neuroprotective role of niacin on human induced pluripotent stem cell-derived motor neurons (iPSC-MNs) subjected to three neurotoxic chemotherapeutic agents: cisplatin, methotrexate, and 5-fluorouracil. Our findings revealed that niacin significantly enhanced neuronal viability, as evidenced by MTT and LDH assays, with the most pronounced protection observed in 5-fluorouracil–treated iPSC-MNs. Moreover, niacin markedly reduced reactive oxygen species (ROS) generation across all chemotherapy treatment conditions. Additionally, niacin mitigated mitochondrial membrane potential (MMP) decrease and promoted ATP production, indicating its ability to counteract chemotherapy-induced mitochondrial dysfunction. Collectively, our results highlight the potential of niacin as a form of supportive therapy for the protection of neurons against CIN and demonstrate the utility of iPSC-derived neurons as a relevant model for investigating various forms of CIN including chemotherapy-induced peripheral neuropathy (CIPN) or cognitive impairment (CICI).
Long-Term Effects of Arsenic Poisoning during Infancy Due to Contaminated Milk Powder: A Systematic Review.
Saad K, Odat RM, Mansour A … +15 more , Elbataa A, Kikhia AA, Haddad S, Kouta MZ, Nada MG, Alessawy L, Melad RR, Hassan I, Heiba AH, Aly SE, Abdel-Sadek ZM, Hussein WM, Altamimi I, Temsah MH, Elgenidi A
Neurotox Res · 2026 Feb · PMID 41665811 · Publisher ↗
Arsenic is a prevalent and significant cause of poisoning worldwide, leading to both acute and chronic toxicity. The life-threatening nature of arsenic toxicity is evident in its link to fatal health conditions in differ...
Arsenic is a prevalent and significant cause of poisoning worldwide, leading to both acute and chronic toxicity. The life-threatening nature of arsenic toxicity is evident in its link to fatal health conditions in different parts and systems of the body. We aimed to conduct a systematic review of the existing literature on long-term health outcomes following arsenic poisoning during infancy. Following the PRISMA 2020 guidelines, we systematically searched the PubMed, Embase, Scopus, Cochrane, and Web of Science databases from their inception up to May 2025. The final selection included seven studies that met the inclusion criteria, with a total of 15,701 participants. A risk assessment of arsenic exposure through powdered milk was done, and a quality assessment was performed. Seven studies were included. Arsenic poisoning due to contaminated milk powder has many effects on multiple organs. This review synthesizes evidence demonstrating that arsenic poisoning during infancy is associated with increased all-cause mortality, primarily attributable to malignancies, neurological disorders, and persistent alterations in somatic development. Exposed individuals exhibited reduced adult height, elevated serum alkaline phosphatase concentrations, and an increased incidence of malignancy. Dental sequelae comprised enamel hypoplasia and gingivitis; dermatological manifestations included persistent punctate hypomelanosis and other cutaneous abnormalities enduring decades. This systematic review delineates the multifaceted long-term health consequences of infantile arsenic poisoning from contaminated milk powder, encompassing malignancies, genitourinary, respiratory, cardiovascular, and neurological diseases. These findings establish arsenic exposure during critical developmental windows as a lifelong health determinant that requires specialized, multidisciplinary medical surveillance protocols. Regulatory standards for arsenic in infant nutrition products need to be reevaluated to prevent similar tragedies from occurring.
Chronic Administration of Atomoxetine and Methylphenidate Induces Differential Alterations in the Hippocampus and Striatum of Young Rats.
Bejarano-Coria M, Beciez-Flores D, Corona JC
Neurotox Res · 2026 Feb · PMID 41649674 · Publisher ↗
Atomoxetine (ATX) and methylphenidate (MPH) are routinely prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Although the pathophysiology of ADHD is not fully understood, oxidative stress an...
Atomoxetine (ATX) and methylphenidate (MPH) are routinely prescribed for the treatment of attention-deficit/hyperactivity disorder (ADHD). Although the pathophysiology of ADHD is not fully understood, oxidative stress and neuroinflammation have emerged as contributing factors. ATX has been shown to alter several signal transduction pathways and increase oxidative stress, mitochondrial damage, and cell death in vitro and in vivo. Likewise, MPH has been reported to cause DNA damage, oxidative stress, inflammation, and behavioural alterations in vivo. In this study, we aimed to determine whether chronic treatment with ATX and MPH affects neuronal integrity, reactive oxygen species production, and possible neuroinflammatory processes in the hippocampus and striatum of young rats. Wistar rats (postnatal day 23) received intraperitoneal injections of ATX (3 mg/kg) and MPH (10 mg/kg), once a day for 28 consecutive days. Chronic ATX and MPH treatment decreased the number of neurons (cresyl violet staining) in both the hippocampus and striatum. Furthermore, both treatments increased dihydroethidium fluorescent in the hippocampus, indicating elevated superoxide (reactive oxygen species) production. Additionally, the number of glial fibrillary acidic protein-labelled astrocytes was increased in the hippocampus, reflecting a potential neuroinflammation. Taken together, these findings suggest that chronic ATX and MPH administration in young rats produces differential alterations, characterised by neuronal loss in the hippocampus and striatum, alongside increased reactive oxygen species production and a possible neuroinflammation in the hippocampus.
IGF2BP1 Aggravates NLRP3 Inflammasome Activation and Pro-Inflammatory Phenotype in Microglia-like Cells by Promoting TRIM45 Expression.
Wang P, Huang Y, Ma Q … +4 more , Zhou Y, Wang X, Yang L, Meng T
Neurotox Res · 2026 Feb · PMID 41639535 · Publisher ↗
Cerebral ischemia-reperfusion (I/R) injury is the main cause of early complications and adverse outcomes after treatment such as myocardial infarction and acute ischemic stroke. In this study, we aimed to explore the fun...
Cerebral ischemia-reperfusion (I/R) injury is the main cause of early complications and adverse outcomes after treatment such as myocardial infarction and acute ischemic stroke. In this study, we aimed to explore the functions of insulin like growth factor 2 mRNA binding protein 1 (IGF2BP1) and tripartite motif-containing 45 (TRIM45) in neuron injury after cerebral I/R injury. HMC3 cells were exposed to oxygen-glucose deprivation and reoxygenation (OGD/R) to mimic cerebral I/R injury in vitro. Western blot and qRT-PCR were conducted for gene expression. NLR family pyrin domain containing 3 (NLRP3) inflammasome activity was analyzed by western blot. ELISA kits were utilized to determine the concentrations of inflammatory cytokines. Flow cytometry was used to analyze iNOS cells, CD206 cells and neuron apoptosis. Methylated RNA Immunoprecipitation (meRIP) assay and RIP assay were adopted to analyze the relation between TRIM45 and IGF2BP1. CCK-8 assay and TUNEL assay were adopted for the viability and death of neurons. Mice model of middle cerebral artery occlusion (MCAO) was used to explore the function of IGF2BP2 in cerebral I/R injury. IGF2BP1 level was upregulated in HMC3 cells. IGF2BP1 overexpression promoted NLRP3 inflammasome activation and pro-inflammatory phenotype in OGD/R-stimulated HMC3 cells. Mechanically, IGF2BP1 modulated TRIM45 expression through m6A methylation modification. IGF2BP1 knockdown inhibited NLRP3 inflammasome activation and pro-inflammatory phenotype in OGD/R-stimulated HMC3 cells by m6A methylation modification of TRIM45. Inhibition of IGF2BP1 improved the viability and suppressed the death and apoptosis of neurons in the co-culture system of microglia-like and neurons by regulating TRIM45 expression. Inhibition of IGF2BP1 improved the neurotoxicity of proinflammatory HMC3 cells in co-cultured neurons via reducing the m6A methylation of TRIM45. However, the number of biological replicate samples was relatively small (n = 3) and the results in this study were preliminary study.
Neurotoxicity Mechanisms of Per- and Polyfluoroalkyl Substances: An Integrated Study of Network Toxicology, Molecular Docking, and Mendelian Randomization.
Jiang Z, Wei C, Ma A
Neurotox Res · 2026 Jan · PMID 41617938 · Publisher ↗
BACKGROUND: Observational studies have shown that exposure to per- and polyfluoroalkyl substances can lead to neurotoxicity. We focus on whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) affect b...
BACKGROUND: Observational studies have shown that exposure to per- and polyfluoroalkyl substances can lead to neurotoxicity. We focus on whether perfluorooctanoic acid (PFOA) and perfluorooctane sulfonate (PFOS) affect brain morphology and the potential molecular mechanisms of toxicity. METHODS: Causal relationship between exposure to both PFOA and PFOS and brain morphology was explored based on Mendelian randomization (MR), and the toxic molecular mechanism was investigated using network toxicology. RESULTS: MR analysis indicated PFOA exposure reduced brain volume in left parahippocampal (p = 0.018) and right rostral anterior cingulate (p = 0.007), while PFOS exposure decreased volume in left middle temporal (p = 0.036), paracentral (p = 0.022), postcentral (p = 0.014), posterior cingulate (p = 0.002), rostral middle frontal (p = 0.040), superior frontal (p = 0.027), superior parietal (p = 0.033), and in the right hemisphere: inferior parietal (p = 0.017), superior frontal (p = 0.030), superior parietal (p = 0.025), and caudal middle frontal (p = 0.041). GO/KEGG analyses revealed 161 targets linked to the neurotoxicity of PFOA and PFOS, primarily associated with fatty acid metabolism, GABA signaling, neurotransmitter receptor activity, ferroptosis, and PPAR pathways. Molecular docking verified key targets (PPARG, FASN, SCD, CD36, GOT2) underlying the toxicity mechanism. CONCLUSIONS: Exposure to PFOA and PFOS leads to reduced brain volume - neurotoxicity at the macroscopic level. At the molecular level, we identified PPARG, FASN, SCD, CD36, and GOT2 as key targets implicated in the pathology of brain damage induced by PFOA and PFOS.
Protective Effect of Cordyceps militaris Extract Against Cigarette Smoke Extract Induced Neurodegeneration in Zebrafish Model.
Sharma P, Goyal D, Thakur M … +1 more , Parashar A
Neurotox Res · 2026 Jan · PMID 41591697 · Publisher ↗
BACKGROUND AND OBJECTIVES: Neurodegenerative diseases are characterized by degeneration or progressive loss/death of neurons in specific areas of the brain, often worsened by cigarette smoke through oxidative stress and...
BACKGROUND AND OBJECTIVES: Neurodegenerative diseases are characterized by degeneration or progressive loss/death of neurons in specific areas of the brain, often worsened by cigarette smoke through oxidative stress and inflammation. Cordyceps militaris (C. militaris) exhibits antioxidant and anti-inflammatory properties, suggesting potential neuroprotective effects. This study evaluated the protective role of C. militaris hot water extract (CMWE) against cigarette smoke extract-induced neurodegeneration in zebrafish. METHODS: Neurodegeneration was induced in zebrafish using cigarette smoke extract, and CMWE was administered at 1 mg/L and 4 mg/L. Behavioral performance was assessed using Y-maze, inhibitory avoidance, and novel tank tests. LC-MS was employed to identify CMWE constituents, while antioxidant activity was evaluated by the DPPH assay. Histological analysis of the periventricular grey zone (PGZ) of the optic tectum was performed to assess neuronal integrity. RESULTS: Cigarette smoke exposure led to aimless exploration, impaired memory retention, and increased bottom-dwelling behavior. CMWE improved behavioral outcomes, with 4 mg/L showing greater efficacy than 1 mg/L. LC-MS revealed bioactive compounds including cordycepin, adenosine, ergothioneine, D-mannitol, and vitamins. The DPPH assay confirmed strong antioxidant activity. Histological evaluation showed reduced pyknotic neuronal density in CMWE-treated groups compared with diseased controls, indicating anti-inflammatory effects. CONCLUSIONS: CMWE mitigated cigarette smoke-induced behavioral and histological hallmarks of neurodegeneration in zebrafish, likely via synergistic antioxidant and anti-inflammatory mechanisms. These findings support the potential of C. militaris as a natural product-based therapeutic candidate for neurodegenerative disorders, warranting further studies on its individual constituents and mechanisms of action.
Conopeptides as Modulators of Pain and Inflammation in Chemotherapy-Induced Peripheral Neuropathy by Targeting α7 and α9 Nicotinic Acetylcholine Receptors.
Mosayyebi B, Faradonbeh DR, Hosseindoost S … +4 more , Arsanjani AA, Negahdari B, Majedi H, Malekshahi ZV
Neurotox Res · 2026 Jan · PMID 41499076 · Publisher ↗
Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating complication of cancer treatment, characterized by sensory dysfunction, including allodynia and hyperalgesia. Despite its clinical signifi...
Chemotherapy-induced peripheral neuropathy (CIPN) is a prevalent and debilitating complication of cancer treatment, characterized by sensory dysfunction, including allodynia and hyperalgesia. Despite its clinical significance, there are no FDA-approved preventive options for CIPN, and current symptom management remains limited in effectiveness. Recent insights into CIPN's underlying mechanisms have highlighted the roles of neuroimmune interactions and ion channel dysfunction, particularly involving nicotinic acetylcholine receptors (nAChRs). Notably, the α7 and α9 nAChR subtypes play a critical role in controlling neuronal excitability and inflammatory responses in both peripheral and central sensory pathways. Conopeptides, a group of disulfide-rich peptides from cone snail venom, have attracted attention as highly selective modulators of ion channels involved in pain pathways. This review highlights α-conotoxins targeting nAChRs, specifically RgIA4 and GeXIVA[1,2], which have dual therapeutic effects by blocking pain signals and reducing neuroinflammation. We explore the structural variety and functional specificity of conopeptides, their mechanisms in CIPN animal models, and their potential as disease-modifying agents. The review also covers recent advances in peptide engineering aimed at improving cross-species compatibility, receptor selectivity, and serum stability of conopeptides in targeting nAChR. The article highlights the potential of nAChR-targeting conopeptides as next-generation treatments for CIPN, outlining key challenges and future directions for clinical development.
The Role of Mitochondrial Quality Control in Manganese-induced Neurotoxicity.
Tinkov AA, Kim H, Skalny AV … +8 more , Chang JS, Santamaria A, Lu R, Zhou JC, Bowman AB, Lee ES, Tizabi Y, Aschner M
Neurotox Res · 2025 Dec · PMID 41454179 · Publisher ↗
The objective of the present review is to discuss the involvement of altered mitochondrial quality control in Mn-induced neurotoxicity. Existing data demonstrate that mitochondrial autophagy (mitophagy) and brain mitocho...
The objective of the present review is to discuss the involvement of altered mitochondrial quality control in Mn-induced neurotoxicity. Existing data demonstrate that mitochondrial autophagy (mitophagy) and brain mitochondrial unfolded protein response (mtUPR) are activated in response to Mn exposure to counteract the Mn-induced mitochondrial dysfunction. Both mitophagy and mtUPR have significant overlap and mechanistic intersections with the integrated stress response (ISR). Increased Mn exposures impair mitochondrial dynamics, further aggravating Mn-induced mitochondrial dysfunction. Specifically, Mn suppresses PTEN-induced kinase 1 (PINK1)-Parkin-dependent mitophagy through a variety of mechanisms, including nitric oxide synthase 2 (NOS2)-dependent PINK1 S-nitrosylation, inhibition of transcription factor EB (TFEB) signaling, and mammalian target of rapamycin complex 1 (mTORC1) activation. In addition, Mn promotes mitochondrial fission by up-regulating dynamin-1-like protein (Drp1) expression and phosphorylation via the activation of c-Jun N-terminal kinase (JNK) and inhibition of sirtuin 1 (SIRT1)/peroxisome proliferator-activated receptor gamma coactivator 1-alpha (PGC-1α) pathways. Concomitantly, Mn impairs mitochondrial fusion by inhibiting mitofusin (Mfn) 1/2 and dynamin-like 120 kDa protein (Opa1) expression, leading to a reduction in mitochondrial size and disruption of the mitochondrial network. High-dose Mn exposure results in inhibition of peroxisome proliferator-activated receptor gamma coactivator 1α (PGC-1α)/nuclear factor erythroid 2-related factor 2 (NRF2)-dependent mitochondrial biogenesis. The latter may be mediated by inhibition of SIRT1/SIRT3 activity, as well as modulation of PINK1/ zinc finger protein 746 (ZNF746)/PGC-1α axis. Alterations in the mitochondrial quality control system may contribute to Mn-induced neuronal damage and neuroinflammation, indicating that dysregulation of the brain mitochondrial dynamics is an important mechanism by which Mn induces its neurotoxicity.
Identification of Neurite Outgrowth and Synaptic Plasticity-related Genes Showing Sustained Hypermethylation of Promoter Region in the Hippocampal Dentate Gyrus of Rats Exposed Maternally To Neurotoxicants To Induce Persistent Disruption of Hippocampal Neurogenesis.
Ojiro R, Takahashi Y, Tang Q … +7 more , Sakamaki Y, Shobudani M, Zou X, Kobayashi M, Ebizuka Y, Kigata T, Shibutani M
Neurotox Res · 2025 Dec · PMID 41436698 · Publisher ↗
We previously identified a set of genes with hypermethylated promoter regions that expressed reduced levels of mRNAs by next-generation sequencing in the hippocampal dentate gyrus (DG) of weaned rats [postnatal day (PND)...
We previously identified a set of genes with hypermethylated promoter regions that expressed reduced levels of mRNAs by next-generation sequencing in the hippocampal dentate gyrus (DG) of weaned rats [postnatal day (PND) 21] after maternal exposure to valproic acid, propylthiouracil (PTU), or glycidol, compounds that induce persistent disruption of hippocampal neurogenesis until adulthood at PND 77. The current study was performed to identify immunohistochemically available epigenetic markers of developmental neurotoxicity, focusing on neurite outgrowth and synaptic plasticity-related genes from those identified previously. After maternal PTU exposure, hypermethylation of Jph3, Kcnj6, and Scn1b at weaning and their persistent reduced expression until adulthood were confirmed by methylation-sensitive high-resolution melting and real-time reverse transcription PCR, respectively. Among the translated products of candidate genes, immunohistochemistry revealed decreased numbers of sodium voltage-gated channel β subunit 1 (SCN1B)+ DG granule cells both at weaning and in adulthood after maternal PTU exposure. Maternal or postpubertal exposure to human developmental neurotoxicants (aluminum chloride, ethanol, and lead acetate) revealed that maternal lead acetate exposure also decreased numbers of SCN1B+ cells at weaning. Double immunohistochemistry with granule cell lineage markers revealed that immature and mature granule cells were SCN1B+. In addition, expression of sodium voltage-gated channel α-subunit genes, Scn1a and Scn8a, was reduced at weaning after maternal PTU exposure. These results indicate that SCN1B levels were suppressed in postmitotic granule cells in accordance with promoter-region hypermethylation of Scn1b. The resulting suppressed formation of intact voltage-gated sodium channels might be related to neurotoxicant-impaired neurogenesis and suppressed synaptic plasticity of granule cells.
Taurine Protects Against Melamine-Induced Hippocampal Neurotoxicity in Rats by Attenuating Metabolic Responses, Autophagy and Inflammation.
Atere AD, Msibi MP, Oyovwi MO … +2 more , Ben-Azu B, Seheru M
Neurotox Res · 2025 Dec · PMID 41398135 · Publisher ↗
Melamine, an industrial chemical linked to neurotoxicity, prompted this study investigating taurine's neuroprotective effects in rat brains. The study examined the impact of taurine on brain metabolic enzymes, neurochemi...
Melamine, an industrial chemical linked to neurotoxicity, prompted this study investigating taurine's neuroprotective effects in rat brains. The study examined the impact of taurine on brain metabolic enzymes, neurochemicals, autophagy-related proteins, and oxidative-inflammatory pathways. Twenty-eight rats were divided into four groups (seven rats per group): control (saline), taurine (100 mg/kg), melamine (50 mg/kg/day), and melamine plus taurine. Taurine administration (30 min post-melamine) continued daily for 28 days, starting on day 29 to day 56, which allowed for the assessment of its restorative effect against ongoing melamine-induced neurotoxicity. Non-spatial recognition memory was evaluated using the novel-object recognition memory test (NORT). Following this, brain neurochemical status, metabolic enzymes, autophagic proteins, and oxidative-inflammatory markers were assessed postmortem. Results demonstrated that taurine improved cognitive function in melamine-treated rats, as evidenced by increased exploration of novel objects in the NORT. Taurine protected against melamine-induced oxidative stress. Additionally, taurine reduce tumor necrosis factor-alpha (TNF-α), interleukin (IL)-6, and IL-1β expression, modulated mammalian target of rapamycin (mTOR) and beclin-1, restored brain metabolic enzyme activity, enhanced neurotransmitter levels, and prevented alterations in α-synuclein and paraoxonase 1 (PON1). In conclusion, taurine protects against melamine-induced neurotoxicity in rats by improving autophagic response, downregulating apoptosis and inflammation markers, inhibiting oxidative stress, and potentially restoring brain metabolic enzyme activities and neurotransmitter levels.
Neuroinflammatory Mechanisms and Therapeutic Targets in Oxaliplatin-Induced Peripheral Neuropathy: a Comprehensive Review.
Dehghani S, Khorsandi H, Hosseinzadegan R … +11 more , Rahimi H, Mottaghi M, Fallahpour S, Fazayel SMA, Bayat A, Namini NJ, Karimi A, Morovatshoar R, Mobinikhaledi M, Behfar Q, Ghasemi M
Neurotox Res · 2025 Dec · PMID 41389089 · Publisher ↗
Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting complication that significantly reduces quality of life in cancer patients, with no effective preventive or therapeutic options currently availa...
Oxaliplatin-induced peripheral neuropathy (OIPN) is a severe, dose-limiting complication that significantly reduces quality of life in cancer patients, with no effective preventive or therapeutic options currently available. There is increasing evidence that neuroinflammation plays a central role in OIPN initiation and progression. This review provides a critical and up-to-date analysis of recent studies on the molecular mechanisms of oxaliplatin-induced neuroinflammation, with a particular focus on the integration of mitochondrial dysfunction, immune-mediated inflammation, glial activation, microRNA dysregulation, and gut-nerve axis disruption. Recent findings demonstrate that oxaliplatin disrupts mitochondrial dynamics, increases oxidative stress, and impairs blood-nerve barrier integrity, triggering neuroinflammatory responses. Neuroinflammation in OIPN is mediated through the activation of several key signaling pathways, including MAPK, NF-κB, Wnt/β-catenin, TLR4, and mTOR, which lead to increased production of pro-inflammatory cytokines and activation of glial cells. Furthermore, emerging evidence has identified dysregulation of the gut-nerve axis and alterations in gut microbiota composition as contributing factors that exacerbate oxaliplatin-induced neuroinflammation and neuropathic pain. Various pharmacological and plant-derived compounds, such as naringin, baicalein, and puerarin, as well as selective inhibitors of inflammatory pathways, have shown promising neuroprotective effects in animal models by attenuating inflammatory responses and alleviating neuropathic symptoms. By synthesizing these converging lines of evidence, this review further outlines potential future directions, including the development of combination therapies targeting multiple inflammatory pathways, microbiome-based interventions, and the translation of preclinical findings into well-designed clinical trials.
Investigating the Potential Roles of Environmental Exposures on the Pathology of Amyotrophic Lateral Sclerosis by Overlap Analysis.
Kara NS, Ozisik O, Baudot A … +1 more , Slachtova L
Neurotox Res · 2025 Dec · PMID 41385026 · Publisher ↗
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease causing motor neuron loss. 90-95% of ALS cases are sporadic, and the interplay of genetic predispositions and environmental exposures is esse...
Amyotrophic Lateral Sclerosis (ALS) is a progressive neurodegenerative disease causing motor neuron loss. 90-95% of ALS cases are sporadic, and the interplay of genetic predispositions and environmental exposures is essential in ALS pathology. Several neurotoxic exposures, such as smoking, pesticides, and organic solvents, have been implicated as affecting the risk of ALS. However, it is unclear how these exposures impact specific cellular mechanisms and influence ALS risk. We investigated the potential mechanisms of toxicity of diesel exhaust, toluene, pesticides, and smoking on ALS pathology through a bioinformatics approach. We retrieved the gene sets targeted by these environmental exposures, and the gene sets involved in ALS-associated biological processes. We performed overlap analysis to assess the statistical significance of the overlap between the gene sets associated with environmental exposures and those linked to ALS. Response to oxidative stress, synaptic signaling, lipid metabolic process, cellular oxidant detoxification, and regulation of gliogenesis significantly overlapped with the gene sets targeted by each of the four environmental exposures. Contrarily, chaperone-mediated autophagy, DNA repair, and regulation of action potential, significantly overlapped only with the gene sets targeted by diesel exhaust, pesticides, and toluene, respectively. Finally, transport across the blood-brain barrier, vesicle-mediated transport, actin filament-based transport, autophagy, transport to the Golgi and subsequent modification of proteins, metabolism of lipids, regulation of neurotransmitter receptor levels, and axon guidance significantly overlapped only with the gene set targeted by tobacco smoke pollution. This study aims to investigate the molecular relationships between neurotoxic exposures and ALS by overlap analysis, providing a framework that can be applied to investigate other exposure-disease interactions.
The Small Molecule DDOX Confers Neuroprotection and Alleviates Motor Deficits in a Preclinical Rat Model of Parkinson's Disease.
Borges L, do Nascimento GC, Ferrié L … +4 more , Raisman-Vozari R, Figadère B, Michel PP, Del-Bel E
Neurotox Res · 2025 Nov · PMID 41264055 · Publisher ↗
Tetracycline-derived compounds with anti-inflammatory properties have demonstrated neuroprotective potential in preclinical models of Parkinson's disease. In this study, we investigated the efficacy of DDOX (4-dedimethyl...
Tetracycline-derived compounds with anti-inflammatory properties have demonstrated neuroprotective potential in preclinical models of Parkinson's disease. In this study, we investigated the efficacy of DDOX (4-dedimethylamino 12a-deoxydoxycycline), a novel non-antibiotic tetracycline derivative. We used an intrastriatal unilateral 6-hydroxydopamine (6-OHDA) lesion paradigm in rats, which leads to partial nigrostriatal dopaminergic denervation. Our goal was to assess whether DDOX could preserve nigrostriatal dopaminergic integrity, reduce lesion-associated glial responses in the striatum, and improve motor function. Daily administration of DDOX (20 mg/kg, subcutaneously), beginning five days prior to lesion and continuing for fifteen days post-lesion, significantly attenuated the loss of dopaminergic terminals in the dorsal striatum and that of dopaminergic cell bodies in the ventral substantia nigra, as indicated by tyrosine hydroxylase (TH) immunostaining analysis. DDOX also markedly suppressed lesion-induced glial responses in the striatum. Behavioral assessments revealed that DDOX preserved motor performance, as evidenced by improved forelimb use (stepping test), maintained coordination and balance (rotarod), and maintained spontaneous locomotion (open field - actimeter). Additionally, DDOX significantly diminished amphetamine-induced rotational asymmetry, suggesting preservation of dopaminergic tone. Notably, the extent of functional recovery exceeded the degree of TH-immunoreactive nerve terminal preservation, indicating that DDOX's benefits may extend beyond dopaminergic neuroprotection. Further studies are warranted to elucidate the underlying mechanisms of these effects and confirm DDOX's efficacy in other Parkinson's disease models.
A Balanced Cannabinoids Mixture Protects Neural Stem/progenitor Cells from CoCl2 Induced Injury by Regulating Autophagy and Inflammation: An in Vitro Study.
Azarfarin M, Ghadiri T, Gorji A … +5 more , Ramezani F, Shanehbandi D, Karimipour M, Sadigh-Eteghad S, Farhoudi M
Neurotox Res · 2025 Nov · PMID 41240218 · Publisher ↗
Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under patho...
Although tetrahydrocannabinol (THC) and cannabidiol (CBD) have been individually studied for their neuroprotective roles, few studies have addressed the effects of their balanced 1:1 formulation Satinex (STX) under pathologic conditions like hypoxia. Moreover, the effect of STX on embryonic neural stem/progenitor cells (ENS/PCs) derived from the rat embryonic brain, which are highly vulnerable during early development, remains unexplored. Considering the pivotal role of hypoxia in numerous neuropathological situations, this study examined the impact of STX on rat ENS/PCs exposed to chemically induced hypoxia. ENS/PCs were isolated from rat embryos and subjected to hypoxia using 100 µM cobalt (II) chloride hexahydrate (CoCl₂0.6 H₂O) for 48 h. Cytotoxic activity of STX andCoCl2was assessed using the 3-(4,5-Dimethyl-2-thiazolyl)-2,5-diphenyl-2 H-tetrazolium (MTT) assay, while stem cell identity was confirmed via flow cytometry (Nestin, SOX2). STX (0.1 and 0.5 µM) was applied under both normoxic and hypoxic conditions. Expression levels of hypoxia-inducible factor 1-alpha (Hif1α) mRNA, autophagy markers (Beclin-1, microtubule-associated protein 1 light chain 3-II [LC3-II]), and pro-inflammatory proteins nuclear factor kappa B [NF-κB], Toll-like receptor 2 [TLR2], Toll-like receptor 4 [TLR4]) were assessed using reverse transcription polymerase chain reaction (RT-PCR) and western blot techniques following STX treatment. Based on flow cytometric assays, over 70% of cultivated cells were positive for Nestin and SOX2. Hypoxia significantly reduced cell viability and proliferation, accompanied by increased Hif1α mRNA expression. Treatment with STX (0.1 µM and 0.5 µM) significantly reversed these changes, restoring cell viability and proliferation while reducing Hif1α levels. Hypoxia also elevated autophagy markers (Beclin-1, LC3-II) and pro-inflammatory proteins (NF-κB, TLR2, TLR4), which STX suppressed in a dose-dependent manner. This study provides novel evidence that STX mitigates hypoxia-induced neural damage by downregulating Hif1α and its downstream inflammatory and autophagic signaling pathways. The use of a clinically relevant cannabinoids mixture and a developmentally sensitive cell model underline the translational potential of balanced THC/CBD formulations in the treatment of hypoxia-related neurodegenerative and neurodevelopmental conditions.
Neuroprotective Roles of Metformin in a Streptozotocin-Induced Dementia Model in Rats.
Vizuete AFK, Moreira AP, Zin LEF … +5 more , de Oliveira Marques C, Pacheco RF, Leal MB, Menezes L, Gonçalves CA
Neurotox Res · 2025 Nov · PMID 41212436 · Publisher ↗
Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes m...
Alzheimer's disease (AD) is the leading cause of dementia in humans, with high social and economic costs. AD is predominantly a sporadic disorder, and its risk increases with age and in individuals with type 2 diabetes mellitus (T2DM). Metformin is considered the first line drug for treatment of T2DM and has a plethora of effects in the peripheral and nervous system. However, the neuroprotective mechanism of action of this drug is still under debate. In order to assess the effects of metformin in dementia, we investigated the optimal time to start metformin treatment in animals that were submitted to intracerebroventricular (ICV) administration of streptozotocin (STZ) (3 mg/kg) to induce a sporadic AD-like rodent model of dementia. We used two protocols of metformin administration: early metformin (50 mg/Kg/daily) treatment (2 days after STZ model induction, lasting 28 days) and late metformin (50 mg/Kg/daily) treatment (20 weeks after STZ model induction, lasting 28 days). Both time points improved cognitive behavior in STZ rats, as evaluated by the novel object recognition and Morris's water maze tasks. Moreover, both treatments reduced neuroinflammatory parameters, such as TLR4, RAGE, TNF-α and NF-κB protein expression, induced in STZ animals. Metformin downregulated the methylglyoxal/RAGE/NOX‑2 signaling pathway by restoring glyoxalase 1 activity and GSH levels, which are impaired in the STZ-induced dementia model. Our data contribute to understanding the neuroprotective role of metformin, particularly in conditions involving insulin resistance, such as diabetic encephalopathy and AD.
Novel in silico Evidence of Bisphenol A as a Neuroinflammatory Modulator through the cGAS-STING-NLRP3 Pathway.
V Tom V, Dixit S, Pujar K … +5 more , Sasidharan A, K D, C ZF, Somayaji Y, Fernandes R
Neurotox Res · 2025 Nov · PMID 41212314 · Publisher ↗
Bisphenol A (BPA), a widely prevalent environmental contaminant, has been linked to neuroinflammation; however, the molecular mechanisms underlying this effect remain unclear. In this study, we used molecular docking and...
Bisphenol A (BPA), a widely prevalent environmental contaminant, has been linked to neuroinflammation; however, the molecular mechanisms underlying this effect remain unclear. In this study, we used molecular docking and molecular dynamics simulations to predict the interactions of BPA with key proteins in the cGAS-STING-NLRP3 signaling pathway, an innate immune axis implicated in neuroinflammatory diseases. BPA demonstrated higher predicted binding affinity to these proteins than the reference neurotoxicant rotenone, suggesting a potential to interact with and modulate this pathway. Molecular dynamics simulations indicated stable binding of BPA, with possible structural adaptations observed in cGAS and NLRP3 proteins, which may influence downstream inflammatory signaling. Since this pathway plays a role in neurodegeneration by sensing cytosolic DNA and activating the NLRP3 inflammasome and type I interferon responses, our computational findings raise the possibility of a previously unrecognized route for BPA-mediated neuroimmune modulation, distinct from oxidative stress or NF-κB activation. These predictions underscore the need for further experimental validation and provide a basis for future research into the mechanistic underpinnings and therapeutic targeting of BPA-induced neurotoxicity.
Development of a Novel Aluminium Chloride-Induced Zebrafish Model of Alzheimer's Disease: Involvement of Oxidative Stress, Cholinergic Dysfunction, and Gut Pathophysiology.
Vaja R, Vohra M, Ramachandran AV … +1 more , Baxi D
Neurotox Res · 2025 Nov · PMID 41196470 · Publisher ↗
Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disorder (NDD), and the leading cause of dementia globally, with females being more susceptible than males. Existing animal models for AD are primaril...
Alzheimer's Disease (AD) is a progressive and fatal neurodegenerative disorder (NDD), and the leading cause of dementia globally, with females being more susceptible than males. Existing animal models for AD are primarily pharmacologically induced or transgenic, yet many fail to recapitulate the full spectrum of human AD pathology and thereby elucidating its sex-based differences. This underscores the need for a cost-effective and robust experimental model that reliably mimics the multifactorial nature of AD taking into account the differences that arise due to sex. In recent years, the zebrafish (Danio rerio) has emerged as a promising model organism for studying central nervous system (CNS) disorders, including AD, owing to its high genetic and physiological homology to humans, transparent embryonic development, and amenability to high-throughput screening. This study aims to establish a novel chronic neurotoxicity induced ZF model, using AlCl as an inducing neurotoxic agent. The hypothesis centers on AlCl₃-induced oxidative stress, cholinergic pathway dysfunction, and gut pathophysiological changes as drivers of AD-like pathology. Adult zebrafish, of both sexes were exposed to chronic AlCl₃ treatment over a 28-day period. Post-treatment assessments included histopathological, biochemical, and behavioural analyses to evaluate changes in brain and gut tissues, oxidative stress biomarkers, and cognitive performance. Zebrafish exposed to AlCl₃ exhibited distinct pathological changes in both brain and gut tissues compared to controls. In the brain, hallmarks such as pyknotic neurons, neuronal vacuolisation, and neural tissue necrosis was observed. Gut tissue displayed significant abnormalities, including reduced villi number, epithelial cell loss, and fused or shortened villi. Biochemical analyses revealed elevated oxidative stress, evidenced by altered levels of catalase (CAT), glutathione (GSH), and lipid peroxidation (LPO). Additionally, disruption of the cholinergic system was evident. Behavioural analyses using locomotor tracking revealed marked cognitive deficits, including reduced average speed, decreased distance travelled, and increased immobility. Lastly, our sex specific differences revealed that females were more affected by the biochemical, histological and neurobehavioural parameters as compared to males, thereby indicating that females pose a greater susceptibility towards developing AD. The AlCl₃ -induced zebrafish model successfully replicates key features of human neurotoxicity, which may lead to AD like features including oxidative stress, cholinergic dysfunction, neurodegeneration, and gut-brain axis alterations. This novel and cost-effective model provides a comprehensive platform for exploring sex-mediated neurotoxicity experimental animal model and offers potential utility for screening therapeutic interventions and understanding disease-modifying mechanisms. Keywords: Alzheimer's Disease, Chronic Neurotoxicity, Gut-brain axis, Zebrafish, Sex differences, Alumnium chloride.
A Narrative Review on the Role of Microbiota and Microglia in Premotor Symptoms of Parkinson's Disease.
Tizabi Y, Getachew B, Mendieta L … +6 more , Palafox-Sánchez V, Tsytsarev V, Manaye KF, Tinkov AA, da Silva VDA, Aschner M
Neurotox Res · 2025 Oct · PMID 41171345 · Publisher ↗
With the advent of medical technology and the sustenance of a longer lifespan, an increase in the number of age-related neurodegenerative diseases, including Parkinson's disease (PD), is inevitable. Although current trea...
With the advent of medical technology and the sustenance of a longer lifespan, an increase in the number of age-related neurodegenerative diseases, including Parkinson's disease (PD), is inevitable. Although current treatments for PD provide remarkable symptomatic relief for a few years, their side effects, combined with the progression in neurodegeneration, pose an urgent challenge for development of more effective treatments for this devastating disease. The challenge is further exacerbated by the unknown etiology in most PD cases. Nonetheless, progress in early identification of the premorbid/prodromal symptoms as well as understanding processes leading to their manifestation may help provide novel preventive and/or intervention strategies. The triad of the best-characterized and inter-related symptoms of prodromal PD include hyposmia (decrease sense of smell), constipation, and major depressive disorder (MDD). Recent revelations indicate a crucial role for the gut microbiota (GM) not only in maintaining the integrity of the gastrointestinal system but also that of the central nervous system via its bidirectional relationship with the brain, commonly referred to as the gut-brain-axis (GBA). Moreover, neuroinflammation, underscored by microglial activation, is believed to play a critical role in neurodegenerative as well as neuropsychiatric disorders including MDD. Here, we delve into the primary roles of GM/GBA and microglia, as well as their interactions, with the aim of providing novel diagnostic and/or treatments in PD. Regarding the treatments, we mention potential use of pre- post- or pro-biotics, and nicotinic or toll-like receptor modulators.
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