📋 Browse Articles

Fentanyl is a potent, fast-acting synthetic opioid that has played a major role in the opioid overdose crisis in the United States for over five decades, with opioid-related deaths increasing sharply in recent years. This study investigates the behavioral, histological, and molecular changes in the hippocampus of rats subjected to sub-acute fentanyl exposure. Two groups of rats were studied: one group received multiple fentanyl injections over approximately one week, while the control group received no fentanyl. A battery of behavioral tests related to memory and depression-including the Y-maze, shuttle box, tail suspension test, elevated plus maze, Barnes maze, Morris water maze, and forced swimming test-was administered. Electrophysiological assessments, including field potential recording and electromyography (EMG), were conducted to evaluate neural activity. Western blot analysis was performed to quantify the expression of brain-derived neurotrophic factor (BDNF) and RE1-silencing transcription factor (REST), while immunohistochemical analyses assessed hippocampal cellular alterations. Results showed that sub-acute fentanyl administration impaired behavioral performance in memory assessment tests (Y maze ( Show less

Bupivacaine (BUP), a widely used amide-type local anesthetic, exhibits neurotoxic effects. This study aimed to explore the functions of brain-derived neurotrophic factor (BDNF) and methyltransferase Like 3 (METTL3) in BUP-induced hippocampal neuronal damage. HT22 cells and SH-SY5Y cells were treated with various concentrations of BUP. METTL3 and BDNF were manipulated using either overexpression or knockdown approaches to assess their functional roles. Cell viability, apoptosis, mitochondrial membrane potential and oxidative stress markers (Lactate Dehydrogenase (LDH), Reactive Oxygen Species (ROS), Superoxide Dismutase (SOD), Malondialdehyde (MDA)) were evaluated using Cell Counting Kit-8 (CCK-8), flow cytometry, JC-1 staining and commercial kits. The expression of BDNF, METTL3, Caspase-9, Bax and Bcl-2 was analyzed by quantitative reverse transcription polymerase chain reaction (qRT-PCR) and Western blot. The N6-methyladenosine (m6A) modification of BDNF mRNA was assessed using Methylated RNA Immunoprecipitation (Me-RIP) and commercial kits. BUP treatment dose-dependently reduced viability, while increasing oxidative stress and apoptosis in our cellular model. BDNF expression was down-regulated in BUP-induced cells. Additionally, BUP stimulation suppressed both total m6A levels and METTL3 expression in cell models. Overexpression of BDNF ameliorated BUP-induced cell damage. METTL3 stabilized BDNF through m6A modification, and the depletion BDNF reversed the protective effect of overexpressing METTL3 on BUP-induced neurotoxicity. Together, our results indicated that METTL3 attenuated BUP-induced neurotoxicity by enhancing BDNF expression via m6A modification. Show less

Phthalates are ubiquitous environmental contaminants and endocrine-disrupting chemicals used as plasticizers in consumer products, medical devices, and industrial materials. Evidence from in vitro experiments, animal models, and epidemiological studies suggests that phthalate exposure, particularly to di(2-ethylhexyl) phthalate (DEHP), dibutyl phthalate (DBP), and benzyl butyl phthalate (BBP), may induce neurotoxicity through multiple interconnected mechanisms. The developing brain is especially vulnerable, with prenatal and early-life exposures linked to cognitive deficits, behavioral abnormalities, and neurodevelopmental disorders. Conventional therapeutic options remain limited, highlighting the need for effective neuroprotective strategies. Natural bioactive compounds such as polyphenols, flavonoids, carotenoids, and other phytochemicals have been investigated as potential neuroprotective candidates in preclinical models owing to their multi-target mechanisms (e.g., antioxidant, anti-inflammatory, and neurotrophic actions), potent antioxidant capacity, and regulation of cellular signaling pathways. Preclinical studies demonstrate that lycopene, ferulic acid, coenzyme Q10, omega-3 fatty acids, vanillic acid, and Moringa oleifera extracts attenuate phthalate-induced neurotoxicity by activating the nuclear factor erythroid 2-related factor 2 (Nrf2)/antioxidant response element (ARE) pathway, suppressing nuclear factor-kappa B (NF-κB)-mediated inflammation, modulating MAPK/ERK and PI3K/Akt signaling, and restoring brain-derived neurotrophic factor (BDNF)/TrkB support. Despite these promising findings, challenges persist, including poor bioavailability, lack of standardized dosing, and limited human clinical trials. A structured review of experimental and epidemiological studies was conducted using predefined inclusion criteria. This review integrates evidence across in vitro, in vivo, and human studies to identify key mechanisms of phthalate-induced neurotoxicity, including oxidative stress, neuroinflammation, endocrine disruption, epigenetic dysregulation, and impaired neuroplasticity, and evaluates pathway-specific neuroprotective actions of bioactive compounds while highlighting critical translational gaps. Show less

Glyphosate (GLY) is a widely used herbicide, particularly in agriculture, and its residues in plants and soil can induce toxic effects in various organisms, including humans, with the brain being especially vulnerable. Eugenol (EU), a natural antioxidant found in cloves, has demonstrated protective effects against different toxic substances. This experimental study explored whether eugenol could mitigate neurological damage triggered by glyphosate exposure in rats. A total of forty male Sprague-Dawley rats were allocated into five experimental groups consisting of control, eugenol (100 mg/kg), glyphosate (150 mg/kg), EU50 combined with glyphosate (50 mg/kg + 150 mg/kg), and EU100 combined with glyphosate (100 mg/kg + 150 mg/kg). Animals received the respective treatments by oral gavage for a period of seven days. Motor and anxiety-related behaviors were evaluated using behaviour tests, after which brain tissues were processed for histopathological analysis. Biochemical analyses included ELISA assessment of oxidative stress markers (MDA, SOD1, GSH, and GPx1), RT-PCR analysis of endoplasmic reticulum (ER) stress- and apoptosis-related genes (GRP78, ATF4, CHOP, PI3K/AKT/mTOR, BAX, and Bcl-2), Western blot evaluation of inflammatory and antioxidant signaling pathways (TLR4/NF-κB and Nrf2/HO-1/SIRT1), and immunohistochemical and immunofluorescence analyses of neuroplasticity, circadian rhythm, and autophagy markers (BDNF, BMAL1, CLOCK, Beclin-1, and LC3A/B). GLY exposure significantly increased lipid peroxidation (MDA), ER stress markers (GRP78 and CHOP), pro-inflammatory mediators (TLR4, NF-κB, TNF-α, and IL-1β), apoptotic signaling (BAX and caspase-3), and autophagy-related proteins, while suppressing antioxidant pathway components. Glyphosate exposure induced behavioral impairments accompanied by increased oxidative stress, inflammatory activation, endoplasmic reticulum stress, apoptosis, and dysregulated autophagy in cerebral cortex tissue. EU treatment dose-dependently attenuated these molecular and histopathological alterations, restored antioxidant and cellular stress responses, and significantly improved behavioral performance, indicating a protective role against GLY-induced neurotoxicity. Overall, EU may represent a promising therapeutic candidate for mitigating herbicide-induced brain injury. Show less

2,4-Dichlorophenol (2,4-DCP) is a persistent and toxic metabolite derived from the degradation of the herbicide 2,4-dichlorophenoxyacetic acid (2,4-D) and other chlorinated compounds, representing an emerging environmental concern. Despite evidence of its toxicity, its neurotoxic effects in adult organisms remain poorly understood. This study aimed to evaluate the behavioral, biochemical, and molecular responses of adult zebrafish (Danio rerio) following 14-day exposure to environmentally relevant (30 μg L Show less

Triclocarban (TCC), an antimicrobial agent used in personal care products, has been widely detected in aquatic ecosystems and has raised significant concerns for aquatic organisms and human health. This study aimed to investigate the neurotoxic effects of TCC exposure, a broad-spectrum bactericide, through behavioral, molecular, pathological, and metabolomic analyses. For this purpose, adult zebrafish were exposed to TCC at doses of 3, 10, and 30 μg/L for 96 h, and their brain tissues were removed. Subsequently, behavioral (anxiety and circadian rhythm tests), molecular (qPCR), histopathological, and metabolomic analyses were performed on these fish. The data obtained showed that TCC treatment increased anxiety-like behaviors in zebrafish and caused disruptions in the circadian rhythm. Additionally, it was determined that the expression levels of both core clock genes (Bmal and Gnat2) and genes associated with neuroplasticity, stress response, and neurotransmission (Bdnf, Crhr, 5-ht4, Ache) changed significantly in a dose-dependent manner compared to the control group. Additionally, it was observed that TCC increased degeneration and necrosis in the brain in parallel with the dose increase, while raising 8-OHdG and BDNF protein levels and decreasing NRF2 and SIRT1 protein levels. When metabolomic analysis data were evaluated, it was determined that TCC, especially at the highest dose, significantly altered metabolite levels. These results reveal that TCC, beyond being an environmental pollutant, may cause behavioral disorders and neurotoxic effects. Show less

Although the regenerative capacity of the mammalian brain is quite weak, internal neural stem/progenitor cells (NSPCs) in the brain can provide new neurons into the brain lesions. Leukocytes, particularly T cells, infiltrate injured brain tissue and participate in immune reactions and have a large impact on the progress of the lesion. However, the effect of T cells on the regeneration of brain tissue remains unclear. Trimethyltin (TMT) is an organotin that has selective neurotoxicity on granule neurons in the hippocampal dentate gyrus. TMT-induced hippocampal lesion is mostly regenerated because adjacent NSPCs can provide new granule neurons. In this study, using TMT-injected mice as a model of brain tissue regeneration, the influence of T cells on hippocampal tissue regeneration was investigated. When TMT was injected into nude mice lacking T cells, they exhibited shortened immobility time in the tail suspension test, indicating improved functional outcomes. Immunohistochemical analysis revealed improved granule neuron replenishment and enhanced survival and differentiation of new neurons in nude mice. Microglial reaction characterized by phagocytosis and astrocytic reaction with brain-derived neurotrophic factor (BDNF) expression were enhanced in nude mice. Hippocampal tissue regeneration was impaired when nude mice were repopulated with total lymphocytes or with CD4- or CD8-positive cells. Repopulations of T cells altered microglial reactions; however, changes in astrocytes were not reproduced. These results suggest that both helper and cytotoxic T cells inhibit hippocampal tissue regeneration by preventing neuronal replenishment. T cells also affect lesion clearance by microglia and astrocytic BDNF expression; however, their effect is stronger on microglia. These findings provide novel insights into the immune regulation of brain tissue regeneration. Show less

(ACR)-induced neurotoxicity, focusing on oxidative stress, endoplasmic reticulum (ER) stress, neuroinflammation, and apoptosis mechanisms. Fifty male Sprague-Dawley rats were divided into five groups: Control, ACR, GA50 +ACR, GA100 +ACR, and GA100. GA (50 and µmg/kg) and ACR (50 mg/kg) were administered intraperitoneally for 14 days. ACR exposure significantly decreased antioxidant enzyme activities (SOD, GSH, GPx, CAT) and increased malondialdehyde (MDA) levels, pro-inflammatory cytokines (TNF-α, IL-1β, IL-6), neuronal nitric oxide synthase (nNOS), and apoptosis-related gene expression (Bax and caspase-3). Histopathological analysis revealed neuronal degeneration and vascular hyperemia, while BDNF, Nrf2, and HO-1 immunoreactivity decreased in the ACR group. GA treatment, particularly at 100 mg/kg, markedly ameliorated these biochemical, molecular, and histopathological alterations. These findings indicate that GA exerts significant neuroprotective effects against ACR-induced brain injury by modulating oxidative stress, ER stress, inflammatory, and apoptotic pathways. Show less

This study aimed to investigate the effects of L-borneol on the molecular, biochemical, and histological damage caused by acrylamide (ACR) in the hippocampus of adult male Wistar rats. It also examined the impact of L-borneol on spatial memory and anxiety-like behaviors in these animals. Animals were divided into four groups: control, L-borneol, ACR, and ACR + L-borneol. ACR (25 mg/kg) and L-borneol (50 mg/kg) were administered orally for 21 consecutive days. L-borneol reduced levels of malondialdehyde and nitric oxide, increased glutathione content, and enhanced superoxide dismutase activity in the hippocampus of rats treated with ACR. In addition, L-borneol lowered the expression of pro-inflammatory markers, nuclear factor-κB, and inducible nitric oxide synthase in the hippocampus. It effectively prevented changes in the expression of apoptosis-related genes, which are associated with decreased neuronal death in the cornus ammonis 1 and dentate gyrus regions. Moreover, L-borneol increased the expression of sirtuin 1 (SIRT1), nuclear factor erythroid 2-related factor 2 (Nrf2), heme oxygenase 1 (HO-1), brain-derived neurotrophic factor, and alpha 7-nicotinic acetylcholine receptors, while reducing the expression and activity of acetylcholinesterase. Finally, L-borneol improved spatial memory and reduced anxiety-like behaviors. In conclusion, L-borneol enhances behavioral performance in ACR-exposed animals by decreasing oxidative and nitrosative stress, as well as inhibiting inflammation and apoptosis. It appears that the upregulation of the SIRT1/Nrf2/HO-1 signaling pathway and the stimulation of acetylcholine signaling are crucial for mitigating ACR-induced neurotoxicity. Show less

Phthalates are well-known emerging contaminants in the environment and food packaging, posing serious risks to human health as endocrine disruptors with significant neurotoxic potential. Epidemiological and experimental evidence have linked early-life phthalate exposure to neurodevelopmental disorders, including attention deficit hyperactivity disorder (ADHD) and autism spectrum disorder (ASD). However, the precise molecular mechanisms responsible for these associations remain poorly understood. This study aimed to comprehensively investigate the putative toxic targets and molecular pathways underlying phthalate-induced ADHD and ASD through integrated network toxicology and molecular docking approaches. Targets related to phthalates, ADHD, and ASD were extracted from various databases, yielding 21 potential targets associated with ADHD and ASD, which are common to the studied phthalates. Network analysis highlighted BDNF and ESR1 as the top two core targets. Functional enrichment analyses demonstrated that the core targets are involved in multiple pathways. Furthermore, the GEO database was queried to identify differentially expressed genes (DEGs) and gene modules through Weighted Gene Co-expression Network Analysis (WGCNA) using the R package. Moreover, molecular docking demonstrated high binding affinity between phthalates and core targets, with di(2-ethylhexyl) phthalate with BDNF and diisononyl phthalate with ESR1, emphasizing the potential role of phthalate exposure in neurodevelopmental disorders. The stability of these complexes was demonstrated through molecular dynamics simulations, which confirmed their binding interactions remained constant throughout the simulation. Our findings contribute to a deeper understanding of the intricate molecular mechanisms of phthalate-induced neurotoxicity, offering a valuable foundation for the development of future therapeutic strategies to mitigate their adverse effects on neurodevelopment. Show less

Aconiti Lateralis Radix Praeparata (Fuzi in Chinese) is an herbal medicine for restoring yang from collapse. However, the multiregional neurotoxicity of Fuzi was unclear. This work was designed to discover the multiregional neurotoxicity-associated metabolic alterations induced by Fuzi in brain of rat. Fuzi-distributed components in cerebrospinal fluid and multiple brain regions were analyzed by using ultra-high performance liquid chromatography coupled with quadrupole-time-of-flight mass spectrometry (UHPLC-QTOF-MS). The multiregional neurotoxicity including hippocampus, striatum and cerebellum was evaluated by behavioral tests, biochemical examinations, Hematoxylin/eosin (H&E), Nissl staining, TUNEL staining, reactive oxygen species and metabolomic analyses. Both cerebrospinal fluid metabolomics and the multiregional target tissue (hippocampus, striatum and cerebellum) metabolomics of the brain, based on UHPLC-QTOF-MS, were conducted to reveal the metabolic changes associated with Fuzi neurotoxicity. 13, 11, 11 and 8 ingredients of Fuzi were distributed into the cerebrospinal fluid, hippocampus, striatum, and cerebellum, respectively. Fuzi exposure could cause motor dysfunction and anxiety-like behaviors and decrease the level of brain derived neurotrophic factor (BDNF) and increase the level of neuron specific enolase (NSE). Fuzi exposure produced oxidative stress, neuronal lesions, neuronal apoptosis and metabolic alterations, which produced the multiregional neurotoxicity in the brain. The differentially expressed metabolites associated with Fuzi exposure in the cerebrospinal fluid, hippocampus, striatum and cerebellum predominantly involved glycerophospholipid metabolism, sphingomyelin metabolism, arachidonic acid metabolism, purine metabolism, amino acid metabolism, TCA cycle and fatty acid β-oxidation. Fuzi exposure produced the multiregional neurotoxicity in the hippocampus, striatum and cerebellum of the brain. Show less

Microplastic (MPs) pollution is widespread in the environment and poses growing risks to food safety and human health. In a 60-day oral exposure study, male Swiss mice received MPs (10 mg/kg b.wt), and the neuroprotective potential of taurine (Tau, 200 mg/kg b.wt) was evaluated. MPs exposure induced pronounced anxiety-like behavior, evidenced by increased peripheral zone activity in the open field test (+ 81.1%) and elevated anxiety index in the elevated plus maze (+ 75.9%), along with significant memory and spatial learning impairments in the Y-maze (increased trials + 31.6% and latency + 75.2%). Neurochemically, MPs increased acetylcholinesterase (AChE) activity (+ 89.4%) while reducing dopamine (-29.4%) and γ-aminobutyric acid (GABA) (-17.9%) levels. MPs also triggered marked oxidative stress, as shown by elevated reactive oxygen species (+ 107.6%) and malondialdehyde (+ 249.0%), accompanied by reduced total antioxidant capacity (-26.2%). At the molecular level, MPs downregulated CREB1 (-82.2%) and BDNF (-80.2%) while markedly upregulating AKT1 (~ fivefold) and pro-inflammatory cytokines (TNF-α, IL-6, CXCL-10, and IL-1β; 5.2-7.2-fold). Histopathological analysis revealed severe neurodegenerative alterations across the cerebrum, hippocampus, and cerebellum. Tau co-treatment significantly ameliorated MPs' induced neurotoxicity by reducing anxiety and memory deficits, lowering AChE activity (- 17.3%), restoring dopamine (+ 28.8%) and GABA (+ 14.2%) levels, attenuating oxidative stress (ROS -45.4% and MDA -44.7%), suppressing inflammatory gene expression (-51.0 to -68.1%), and partially normalizing CREB1 and BDNF expression (+239% and +240%, respectively). Collectively, these findings identify Tau as a promising natural neuroprotective agent against MPs' induced neurotoxicity. Show less

Depression is a prevalent mental disorder in modern society, with a complex and incompletely understood etiology. Accumulating evidence indicates that pesticide exposure is a potential risk factor for mental health disorders. Atrazine (ATR), a widely used herbicide with the highest global application rates and frequently detected in environmental media, has been confirmed to possess neurotoxicity. However, there are currently no reports examining its effects on depression. Therefore, this study aimed to investigate the effects of subchronic ATR exposure on depression-like phenotypes in mice through behavioral tests, pathological examinations, and molecular analyses. The results demonstrated that ATR exposure induced significant depressive-like behaviors and led to neuronal reductions in key brain regions associated with depression, such as the hippocampus and prefrontal cortex. These effects were mechanistically linked to oxidative damage and decreased expression levels of 5-hydroxytryptamine (5-HT) and brain-derived neurotrophic factor (BDNF). Collectively, this study not only reveals the potential role and mechanism of ATR as an environmental risk factor for depression, but also provides a theoretical basis for the prevention and treatment of its new neurotoxicological effects and future related research. Show less

Pendimethalin (PMN) is a potent agrochemical that has shown severe neural alterations. Sanguinarine (SAN) is a naturally derived alkaloid that exhibits a wide range of biological properties. The current research was conducted to explore the palliative potential of SAN against PMN-induced neurotoxicity. Thirty-two Sprague Dawley rats were divided into the control, PMN (125 mg/kg), PMN (125 mg/kg) + SAN (15 mg/kg), and SAN (15 mg/kg) alone treated group. PMN intoxication upregulated the mRNA expressions of Aif1 (iba1), cd68, TNF-α, IL-10, IL-6, IL-1β, Nos2, Arg1, and Trem2 while inhibiting the mRNA expression of Tmem119. Neural tissues showed altered redox state after PMN exposure as evidenced by escalated levels of ROS and MDA coupled with marked declined in the activities of HO-1, GPx, CAT, GSR, SOD, and GST. Additionally, PMN administration provoked a sharp decline in the levels of NGF, BDNF, GDNF, Synaptophysin, and PSD-95. Moreover, exposure of PMN elevated the levels of Caspase-9, Bax, and Caspase-3 coupled with a significant reduction in the levels of Bcl-2. Neural tissues showed severe morphological alterations including vacuolar degeneration, neuronal loss, microglial activation, apoptotic bodies, capillary congestion, perineuronal vacuolation, and neural edema after PMN intoxication. Importantly, SAN supplementation notably alleviated neural damage via suppressing the activation of microglial and inflammatory pathways along with regulating redox profile, apoptotic indices, and histopathological alterations. Our in-silico assessment showed excellent binding affinity of SAN with key regulatory proteins thereby suggesting its critical role in suppressing the activation of microglial cells. Show less

The purpose of our study was to investigate the neuroprotective effects of Nigella sativa (NSt) ethanolic extract (200 mg/kg) and/or Telmisartan(Tel) (10 mg/kg) against fipronil (Fip) (9.7 mg/kg)-induced neurobehavioral toxicity in rats, besides exploring the underlying mechanistic signaling pathways. Our results showed that the phytochemical analysis of NSt ethanolic extract by ultra-performance liquid chromatography-electrospray ionization-tandem mass spectrometry (UPLC-ESI-MS) revealed 43 compounds, mainly alkaloids, phenolics, terpenoids, fatty acids and flavonoids. While in our in vivo model of neurotoxicity, the combination of NSt and Tel effectively restored neurobehavioral alterations in rotarod, open field and T-maze tests. Additionally, the cotreatments of NSt and Tel significantly decreased acetylcholine, tumor necrosis factors-α, interleukin (IL)-6, IL-1β, MDA, BAX, P62, LC3B and IBA-1. Conversely, they significantly upregulated GABA, brain-derived neurotrophic factor, superoxide dismutase, catalase, glutathione peroxidase and antiapoptotic BCl2, P70S6K and miRNA137-5P without significant change in mTOR expression in hippocampus. Also, they ameliorated pathological alterations as detected by H&E staining, reduced glial fibrillary acidic protein and caspase-3 immunoreactivity. Electron microscopic examination of the combination group revealed the restoration of nuclear and mitochondrial structures with less glial activation and multivesicular bodies. In conclusion, the combination of NSt and Tel are notable agents in mitigating hippocampal neuronal necrosis and astrogliosis and reduced Fip-induced neurotoxicity. Show less

Lead (Pb) accumulation in the hippocampus and the resulting oxidative stress contribute to memory impairments, highlighting the hippocampus as a primary target for Pb neurotoxicity. Selenium-containing peptides TSeMMM and SeMDPGQQ are able to alleviate Pb-induced oxidative neurological damage and the specific microRNAs involved in the memory protection by the two peptides need to be explored. In this study, mouse memory impairment models were constructed through the administration of 20 mg kg Show less

Radiation-induced brain injury causes significant neurotoxicity and cognitive dysfunction in patients undergoing radiotherapy for brain tumors. This study aimed to evaluate the neuroprotective effects of intranasal ketamine on radiation-induced brain injury, specifically focusing on its modulation of perineuronal networks (PNNs), extracellular matrix components, and neuroinflammation. Eighteen male New Zealand White Rabbits were divided into three groups: normal controls, irradiation (IR) with saline (IR + saline), and IR with ketamine (IR + ketamine). Whole-brain IR (20 Gy) was applied to the IR groups, and ketamine (2 mg/kg/day) was administered intranasally for 15 days. Biochemical markers, including malondialdehyde (MDA), tumor necrosis factor-alpha (TNF-α), brain-derived neurotrophic factor (BDNF), ADAMTS4, and syndecan-1 levels, were measured. Histopathological analysis of hippocampal and cerebellar regions assessed neuronal survival and astrogliosis. Magnetic resonance spectroscopy (MRS) evaluated lactate and Ketamine administration significantly reduced oxidative stress (MDA) and inflammatory markers (TNF-α) while restoring BDNF levels compared to the IR + saline group. ADAMTS4 and syndecan-1 levels were reduced, changes consistent with PNN-associated extracellular matrix dynamics, but without direct confirmation by core PNN markers such as aggrecan or WFA staining. Histopathology showed increased neuronal survival and decreased reactive astrogliosis in ketamine-treated groups. Intranasal ketamine demonstrates significant neuroprotective effects in a radiation-induced brain injury model by reducing oxidative stress and inflammation, modulating extracellular matrix components, and preserving neuronal integrity. These findings highlight ketamine's potential as a therapeutic agent, although direct PNN markers and broader cytokine panels were not assessed. Overall, ketamine showed neuroprotective effects across biochemical, histological, and MRS-supported metabolic readouts. Show less

Sensory neurotoxicity involves damage to the sensory nerves, often resulting from exposure to chemicals, medications, toxins, infections, or neurological disorders. Benzalkonium chloride (BKC) is a widely used quaternary ammonium compound with antiseptic properties, commonly present in pharmaceuticals, household products, and cosmetics. While the potential neurotoxicity of BKC has been previously explored in ocular and nasal epithelia, its impact on other sensory systems and the underlying mechanisms remain largely unclear. In this study, we used zebrafish (Danio rerio) embryos to assess the developmental neurotoxicity of BKC. Embryonic exposure to 0.72, 1.28, and 2.24 mg/L BKC led to dose-dependent impairments in mechanosensory hair cells, reduced startle responses, and heightened nociceptive sensitivity upon noxious stimulation. BKC exposure induced pronounced oxidative stress, evidenced by increased reactive oxygen species levels, reduced antioxidant enzyme activity, and altered expression of redox-regulating genes. Moreover, BKC significantly upregulated inflammatory and pain-associated genes, including tnfa, il1b, cox2, bdnf, and trpa1b. Expression profiling of hair cell differentiation markers revealed increased pou4f3 and decreased tmc2a/tmc2b, suggesting that BKC disrupts both terminal differentiation and mechanotransduction processes in sensory hair cells. Collectively, these findings uncover a novel mechanistic link between oxidative stress, impaired hair-cell maturation, and sensory dysfunction, offering new insights into the mechanisms underlying BKC-induced sensory neurotoxicity. This study emphasizes the ecological and toxicological relevance of quaternary ammonium compounds in aquatic environments. Show less