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PubMed1979

Paradoxical lithium neurotoxicity: a report of five cases and a hypothesis about risk for neurotoxicity.

There have been many reports of probable lithium-induced organic brain syndromes occurring when serum lithium levels are within or close to the therapeutic range. The authors report on five patients who developed clinical syndromes suggestive of severe neurotoxicity during lithium treatment. In all cases lithium levels were between .75 and 1.7 mEq/liter. The patients who developed neurotoxicity had markedly higher global ratings of psychotic symptomatology and anxiety in the pretoxic period than did patients who never deveoped neurotoxicity. When the acute manic state is characterized by marked psychotic symptoms and intense anxiety, it may be associated with increased vulnerability to the development of severe lithium neurotoxicity.

Adolescent↗

PubMed1977

Improved assay of neurotoxic esterase for screening organophosphates for delayed neurotoxicity potential.

The assay of neurotoxic esterase (NTE) in brains taken from dosed hens enables potential neurotoxicity of organophosphate pesticides, plasticers, etc. to be assessed. The original assay [Johnson, M.K. Biochem. J. 114, 711-717 (1969)] has been simplified to eliminate centrifugation and transfer steps and both the selectivity and the sensitivity have been increased. The procedures necessary to obtain stable reagent stocks are described.

Animals↗

PubMed1977

Neurotoxicity of organophosphorus insecticides Leptophos and EPN.

Phosfolan, chlorpyrifos, and stirophos when applied to white mice at sublethal doses did not induce any delayed neurotoxic effect. On the other hand, Leptophos and EPN when administered orally at sublethal or lethal levels clearly produced a delayed neurotoxic ataxia in treated mice. The five tested organophosphorus insecticides were compared for their ability to inhibit cholinesterase, neurotoxic esterases and monoamine oxidase. I50 values were estimated for each case. The results revealed that all five compounds were inhibitors of cholinesterase, but only Leptophos and EPN were shown to be potent inhibitors for both neurotoxic esterase and monoamine oxidase in the mouse brain. Additional particular properties of both Leptophos and EPN were found in their ability to cause delayed neurotoxic ataxia in chickens and sheep fed once on sublethal doses of these compounds. It is believed that the phosphonate ester configuration of EPN and Leptophos has a specific mode of toxic action which is mainly located at the central nervous system. It is also postulated that these delayed neurotoxic agents might inhibit postganglionic sympathetic neurons, thus resulting in chronic paralytic effects.

Administration, Oral↗

PubMed2026

Zebrafish as a Model Organism to Study Neurotoxicity: A Potential Tool for Neuroprotective Drug Discovery.

INTRODUCTION: Danio rerio, the zebrafish, serves as an excellent model in neuroprotective drug discovery due to its conserved nervous system organization, neurotransmitter pathways, antioxidant defenses, and genomic similarity to mammals. METHODS: A systematic literature search following PRISMA 2020 guidelines was conducted across Pub- Med, Scopus, Web of Science, and Google Scholar. Studies published between 2020 and 2025 were prioritized, with earlier key papers included for context. The data on larval, adult, and genetically modified zebrafish models were analyzed for neurotoxic effects, focusing on study design, toxicants, and neurobehavioral or molecular outcomes. RESULTS: Neurotoxicants such as chlorpyrifos, bisphenol, triphenyl phosphate, aluminum, ammonium acetate, arsenic, zinc, acrylamide, methylmercury, and tris (1,3-dichloro-2-propyl) phosphate were shown to cross the zebrafish blood-brain barrier. These exposures caused significant behavioral alterations, neurotransmitter imbalances, oxidative stress, and gene or protein expression changes related to brain function. Analysis of the transgenic zebrafish revealed notable alterations in neuronal development and axonal morphology upon exposure to various neurotoxic chemicals. DISCUSSION: Zebrafish display neurotoxic responses with a close resemblance to mammals, supporting their translational value in neurotoxicity and drug discovery studies. However, limitations such as a less complex brain compared to mammals, quick neuronal regeneration, limited tissue access, and difficulties in drug absorption quantification warrant refinements in zebrafish models. CONCLUSION: Zebrafish offer a versatile, cost-effective, and genetically tractable system for neurotoxicity and neuroprotection research. This systematic review highlights their crucial role in neuroprotective drug discovery while emphasizing the need for improved methodological approaches to enhance translational reliability.

Animals↗

PubMed1979

Biochemical and pharmacological properties of a neurotoxic protein isolated from the blood serum of heavily burned patients.

Blood serum of heavily burned patients contains neurotoxic substances which are not present in normal control sera. In the present paper, we describe the purification by gel filtration and ultracentrifugation of such a neurotoxic factor. The purified factor appeared to be a high molecular weight (2 to 3.10(6) daltons) lipoprotein. This factor was present in all the sera of patients with more than 35 per cent of the body surface burned. When injected into rabbits the lipoprotein caused a flattening of the EEG tracing, then trembling and convulsions with bursts of spikes on the EEG. The activity of this neurotoxic substance was enhanced when the permeability of the blood-brain barrier was increased by previous intraventricular injection of collagenase. The presence of such a neurotoxic factor in the blood serum of burned patients, together with the increased serum collagenase activity they exhibit may explain the neurotoxic symptoms observed in them.

Animals↗

PubMed1979

Neurotoxicity of human eosinophils.

Eosinophils contain a substance that is neurotoxic when injected intracerebrally or intrathecally into laboratory animals-an effect known as the "Gordon phenomenon." We found neurotoxic activity in eosinophils from three patients with eosinophilic syndromes by injecting cell preparations into rabbits and guinea pigs. These animals developed a syndrome of muscular rigidity and ataxia, progressing to severe paralysis. No neurotoxic activity was found in preparations of polymorphonuclear or mononuclear leukocytes from normal donors. Examination of the brains of affected animals confirmed widespread loss of Purkinje cells, as described by earlier investigators. A new finding was severe spongy change occurring in the white matter of the cerebellum, brainstem, and spinal cord. Electron microscopic examination showed that vacuoles formed within the myelin sheaths of axons by separation of lamellae. Associated axonal degeneration was common and was also seen occasionally in peripheral nerves. Gray matter in the cerebral hemispheres and spinal cord was normal. This eosinophil-derived neurotoxin was partially purified by ultracentrifugation of sonicated eosinophils and fractionation of the supernate by gel filtration. Fractions with neurotoxic activity eluted at a position consistent with a molecular weight of approximately 15,000. The neurotoxic activity of this material withstood lyophilization and dialysis but was destroyed by heating to 90 degrees C. Injection of eosinophil-derived neurotoxin into laboratory animals may provide a useful short-term experimental model for study of mechanisms of damage to myelinated nerve fibers. The clinical significance of the Gordon phenomenon has yet to be established.

Animals↗

PubMed1979

Relationships between plasma concentrations of diphenylhydantoin, phenobarbital, carbamazepine, and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant or neurotoxic effects in experimental animals.

The relationships between plasma concentrations of diphenylhydantoin (DPH), phenobarbital (PB), carbamazepine (CBZ), and 3-sulfamoylmethyl-1,2-benzisoxazole (AD-810), a new anticonvulsant agent, and their anticonvulsant and neurotoxic effects were studied in various species of animals. Anticonvulsant activities of test drugs were examined by the maximal electroshock seizure (MES) test. Neurotoxicities were determined by the rotorod performance test in mice and rats and by behavioral observations in rabbits, dogs, and monkeys. It was demonstrated that both the anticonvulsant effects and the neurotoxic effects of the drugs tested were more closely correlated with their plasma concentrations than with the dosages administered. There was a critical plasma concentration for each drug to show an anticonvulsant effect or to cause a neurotoxic effect in an individual animal. The critical plasma concentrations for anticonvulsant and neurotoxic effects of each drug were relatively constant among different species, with the exception of DPH in rabbits, which had twice the value in other species. The therapeutic ranges of plasma concentrations of DPH, PB, and CBZ determined in various species of animals coincided well with those recommended clinically. AD-810 was found to be effective against MES without signs of neurological toxicity in the ranges of plasma concentrations of 9.8 to 74.0, 10.8 to 95.0, 9.6 to 117.0, and 12.6 to 96.2 microgram/ml in mice, rats, rabbits, and dogs, respectively. These results seem to suggest that AD-810 may be effective clinically at plasma concentrations above 10 microgram/ml, with a therapeutic range up to 70 microgram/ml, which is much wider than the therapeutic ranges of DPH (10--20 microgram/ml), PB (10--30 microgram/ml), and CBZ (4--10 microgram/ml).

Animals↗

PubMed1978

Vascular permeability and neurotoxicity.

Neurotoxic substances affect the nervous system in a selective manner. One possible basis for this selectivity is blood vessel permeability. In general, the central nervous system and the peripheral nerve trunks have impermeable blood vessels, but in certain parts the capillaries are "leaky," allowing the passage of a plasma filtrate. Intravenously injected protein tracers rapidly reach nerve cells in these regions, with the implication that these nerve cells are also readily accessible to circulating neurotoxic substances. Some examples of neurotoxicity in the central nervous system show a selectivity that could be due to capillary permeability. In experimental methylmercury poisoning, cranial nerve V and sensory dorsal root ganglia, which lie in regions of vascular permeability, are particularly susceptible. A number of drug and chemically induced neuropathies are predominantly sensory, and may be due, directly or indirectly, to the accessibility of neurotoxic substances to sensory neurons. Examination of areas of potential vulnerability to circulating toxic substances may be of value in the experimental testing of substances for neurotoxicity, where pharmacological tests may be negative and clinical symptoms difficult to assess.

Animals↗

PubMed1979

Animal models for the comparative assessment of neurotoxicity following repeated administration of vinca alkaloids.

Neurotoxicity is the major side effect occurring during the clinical use of vincristine (VCR). Animal models predictive of potential neurotoxicity would be very useful in the preclinical development of new vinca compounds. To simulate conditions in which neurotoxicity is produced during the clinical use of VCR, experimental animals (except the guinea pig) were given the test compounds by the iv route over a prolonged time period. Doses were selected based on the production of leukopenia. Vindesine (VDS), a chemically modified vinblastine (VBL) product, was compared with VCR and VBL in animal studies. Definite neurotoxic manifestations developed when VCR was given to chickens, cats, and monkeys. The administration of VDS or VBL did not produce neurotoxic signs in these species. The mouse, rat, dog, and guinea pig were not found to be useful models. Thus, it would appear the chicken, cat, and monkey would be appropriate animal models for the preclinical testing of new vinca compounds.

Animals↗

PubMed2024

Integrated multi-omics approaches reveal the neurotoxicity of triclocarban in mouse brain.

Triclocarban (TCC) is an antimicrobial ingredient that commonly incorporated in many household and personal care products, raising public concerns about its potential health risks. Previous research has showed that TCC could cross the blood-brain barrier, but to date our understanding of its potential neurotoxicity at human-relevant concentrations remains lacking. In this study, we observed anxiety-like behaviors in mice with continuous percutaneous exposure to TCC. Subsequently, we combined lipidomic, proteomic, and metabolic landscapes to investigate the underlying mechanisms of TCC-related neurotoxicity. The results showed that TCC exposure dysregulated the proteins involved in endocytosis and neurodegenerative disorders in mouse cerebrum. Brain energy homeostasis was also altered, as evidenced by the perturbation of pyruvate metabolism, TCA cycle, and oxidative phosphorylation, which in turn caused mitochondrial dysfunction. Meanwhile, the changing trends of sphingolipid signaling pathway and overproduction of mitochondrial reactive oxygen species (mROS) could enhance the neural apoptosis. The in vitro approach further demonstrated that TCC exposure promoted apoptosis, accompanied by the overproduction of mROS and alteration in the mitochondrial membrane potential in N2A cells. Together, dysregulated endocytosis, mROS-related mitochondrial dysfunction and neural cell apoptosis are considered to be crucial factors for TCC-induced neurotoxicity, which may contribute to the occurrence and development of neurodegenerative disorders. Our findings provide novel perspectives for the mechanisms of TCC-triggered neurotoxicity.

Animals↗

PubMed2026

Polystyrene microplastics induce auditory neurotoxicity in mammals: Integrated multi-omics profiling reveals oxidative damage and synaptic molecular dysregulation.

Microplastics (MPs) are ubiquitous environmental pollutants, yet their neurotoxic effects on the auditory system remain poorly understood. This study develops an integrated multi-level analytical framework combining auditory neurophysiology, behavioral assessment, tissue biochemistry, transcriptomics, and proteomics to investigate polystyrene (PS)-MPs-induced auditory neurotoxicity in rats. PS-MPs infiltrate the auditory system and significantly impair auditory processing, with central dysfunction emerging earlier and more prominently than peripheral alterations. Multi-omics analyses reveal coordinated suppression of glutamatergic synapse and Wnt signaling pathways in the cochlear nucleus. Mechanistically, PS-MPs perturb the crosstalk between glutamatergic synaptic and Wnt signaling, promoting AMPA receptor (AMPAR) internalization and potentially affecting synaptic plasticity-related processes and neuronal responsiveness. In parallel, PS-MPs trigger oxidative stress, apoptosis, and glial activation, reflecting pronounced neuroinflammatory and redox imbalance. In primary cochlear nucleus neurons (PCNNs), these mechanisms were further validated in vitro, where activation of Wnt signaling by Wnt3a significantly alleviated oxidative injury and reduced AMPAR internalization. Collectively, these findings provide comprehensive preclinical evidence for the neurotoxic potential of MPs and reveal a previously unrecognized PS-MPs-induced auditory neurotoxicity, although further studies are needed for human relevance. Results from the rat model further implicate Wnt-mediated signaling as a potential modulatory pathway underlying MPs-induced synaptic molecular alterations and redox dysfunction.

Animals↗

PubMed1979

The role of crotoxin subunits in tropical rattlesnake neurotoxic action.

The major toxin (crotoxin) of Crotalus durissus terrificus (neotropical rattlesnake) is known to be a reversible non-covalently associated complex consisting of an acidic and basic subunit. On separation biological activity is found only with the basic subunit, yet, although void of detectable biological activity, the acidic subunit is essential for the full neurotoxic activity of the complex. Recent evidence suggests that crotoxin A serves as a 'chaperone' to enhance the specificity of crotoxin B and, upon binding, crotoxin A is released to the medium. This study was designed to test this hypothesis. Dimethyl suberimidate, a bifunctional cross-linking agent, was used to irreversibly bind the two subunits. Disc electrophoresis, ion-exchange chromatography, molecular sieve chromatography, capillary isotachophoresis and isoelectric precipitation confirm the existence of an inter-subunit covalently cross-linked complex. The conversion of a dissociable complex to a non-dissociable complex abolished neurotoxicity. Although neurotoxicity was lost, phospholipase A2 (phosphatide 2-acyl-hydrolase, EC 3.1.1.4), which is found associated with many presynaptic neurotoxins, was unaffected. The data in this paper add credence to the 'chaperone' concept of crotoxin A and the importance of the reversible nature of the complex for full expression of neurotoxicity.

Crotalid Venoms↗

PubMed1979

Delayed neurotoxicity of subchronic oral administration of leptophos to hens: recovery during four months after exposure.

Daily oral administration of small doses of technical grade O-methyl O-4-bromo-2,5-dichlorophenyl phenylphosphonothioate (leptophos, 0.5-20.0 mg/kg) caused delayed neurotoxicity in hens. Severity of clinical condition and progression or improvement of signs of delayed neurotoxicity depended on the dose and duration of administration. Hens given 20.0 mg/kg suffered ataxia, paralysis, and death. Intermediate doses (5 and 10 mg/kg) caused ataxia, with most treated hens showing no change in clinical condition during the 4-mo observation period. Hens given small doses (2.5 and 1.0 mg/kg) demonstrated regression of neurological deficits after administration of leptophos was stopped. Hens given the smallest tested dose (,.5 mg/kg) developed mild ataxia and showed total recovery during the observation period. Days of administration and total administered dose before onset of ataxia depended on the daily dose. Degeneration of axons and myelin i, the spinal cord was the most consistent histopathologic change and was identical to that observed in tri-o-cresyl phosphate (TOCP) control hens. Only one hen, which died early in the treatment period, showed peripheral nerve degeneration. Controls consisted of 3 groups of hens given a daily oral dose of 10.0 mg/kg TOCP, 1.0 mg/kg O,O-diethyl O-4-nitrophenyl phosphorothioate (parathion), or an empty gelatin capsule. TOCP-treated hens developed delayed neurotoxicity, whereas those given parathion showed initial leg weakness but subsequently recovery without developing delayed neurotoxicity. Controls given gelatin capsules remained normal.

Animals↗

PubMed1977

Mechanism of neurotoxicity of cardiotonic glycosides.

1 In cats intracerebroventricular administration of 5, 10, 20 mug of peruvoside, a cardiac glycoside obtained from the plant, Thevetia neriifolia, and 10 and 20 mug of ouabain, produced marked neurotoxicity. This was dose-related. 2 Prior administration reserpine (2 mg/kg i.m., 500 mug i.c.v.) or tetrabenazine (25 mg/kg i.v., 50 mg/kg i.v. and 2 mg/,g i.c.v.) suppressed the neurotoxicity, but lithium carbonate (100 mg/,g i.p., 2 mg 2.c.v.) and haloperidol (200 mug i.c.v.) were ineffective. 3 Prior administration of 2-bromolysergic acid diethylamide (BOL-148, 200 mug i.c.v.) or p-chlorophenylalanine (PCPA) (400 mg/kg i.p.) suppressed the neurotoxicity induced by peruvoside and ouabain. 4 Perfusion of the lateral ventricles of cats with 10, 20 and 30 mug of peruvoside or ouqbain produced a massive release of 5-hydroxytryptamine (5-HT). This was dose-related. Prior administration PCPA suppressed the release of 5-HT. 5 The results of the findings indicate the involvement of 5-HT in the genesis of neurotoxicity induced by peruvoside or ouabain.

Animals↗

PubMed1979

Neurotoxicities of current leukemia therapy.

While major advances have been made in the treatment of acute leukemia, complications of therapy are significant. One of the most worisome complications is the neurotoxicity which is related to both central nervous system prophylaxis (cranial irradiatif neurotoxicity may be acute or delayed, and may range in severity from mild headaches ann of treatment-related neurotoxicity is important since this may permit amelioration of otherwise irreversible neurological sequelae in some patients. We review the clinical, phyh irradiation and chemotherapy, and offer recommendations for monitoring, evaluating and treating patients with potential or proven neurotoxicity.

Antineoplastic Agents↗

PubMed2026

Micro- and nanoplastics-induced neurotoxicity: a CNS-centered, evidence-graded adverse outcome pathway framework based on systematic weight-of-evidence assessment.

Micro- and nanoplastics (MPs/NPs) are ubiquitous anthropogenic particulate pollutants posing emerging threats to human neurological health. Severe heterogeneity in particle physicochemical properties, environmental aging status, exposure paradigms and experimental platforms has created persistent mechanistic uncertainties in MP/NP neurotoxicology, hindering reliable hazard characterization and risk translation. Here, we systematically consolidate empirical toxicological evidence and construct a dedicated central nervous system (CNS)-targeted adverse outcome pathway (AOP) network integrated with rigorous weight-of-evidence (WoE) grading to elucidate the hierarchical, particle-specific toxic cascades underlying MP/NP-induced neural injury. Our synthesis overturns the conventional linear toxicity paradigm, demonstrating that MPs/NPs trigger neurotoxicity via a complex multi-input mechanistic network. We definitively establish oxidative stress as a robust early convergent key event-rather than a universal molecular initiating event-orchestrating ROS overproduction, lipid peroxidation, mitochondrial dysfunction, and neuroinflammation to propagate neuronal damage. This core module is driven by five distinct particulate upstream triggers: particle-biomolecule interfacial perturbation, corona-facilitated cellular internalization, plastic-associated chemical leaching, aging-derived free radical reactivity, and gut-borne systemic neurotoxic signaling. Downstream pathogenic outcomes encompass glial overactivation, neurotransmitter dyshomeostasis, autophagy-lysosome dysfunction, metabolic reprogramming, regulated neuronal cell death, and behavioral impairments. Tiered WoE analysis confirms strong validation for early oxidative/inflammatory cascades, moderate support for gut-brain axis crosstalk and intracellular trafficking disruption, and nascent evidence for synaptic dysfunction and neurodegeneration-linked proteostatic defects. Extrapolation to human health risk remains constrained by the frequent use of high-dose exposure paradigms, limited validated data on internal dosimetry in the human brain, discrepancies between effective concentrations in experimental models and environmentally relevant human tissue burdens, and insufficient causal validation of distal adverse outcomes. We highlight key research priorities including aged mixed-particle exposure systems, leachate-controlled assays, quantitative internal dose evaluation, and mechanistic intervention verification. This evidence-stratified AOP framework resolves longstanding mechanistic ambiguities in particulate neurotoxicity, providing a standardized, causality-based foundation for future mechanistic exploration and health risk assessment of global plastic pollution.

Adverse outcome pathway↗

PubMed2026

Multi-omics analysis reveals coordinated epigenetic dysregulation in atrazine-induced dopaminergic neurotoxicity.

Atrazine (ATR), a widely used triazine herbicide, has been linked to neurotoxicity, yet the epigenetic mechanisms underlying its dopaminergic effects remain unclear. This study investigated whether coordinated miRNA dysregulation and DNA methylation alterations contribute to ATR-induced Parkinson's disease (PD)-like neurotoxicity. Male Sprague-Dawley rats were administered ATR (50 mg/kg/day) for 90 days, resulting in motor and cognitive deficits with dopaminergic dysfunction, including increased α-synuclein and reduced tyrosine hydroxylase expression. Small RNA sequencing identified 72 differentially expressed miRNAs in the substantia nigra, enriched in PI3K-Akt, MAPK, and Ras signaling pathways. In a cohort of six PD patients and six matched controls, genome-wide DNA methylation profiling revealed 4694 differentially methylated positions, predominantly hypomethylated, with overlapping enrichment in neuronal signaling pathways. Weighted gene co-expression network analysis identified a PD-associated module strongly correlated with disease status (r = -0.95, P < 0.001). Multi-omics integration identified CASP3 as a central hub gene. External validation supported CASP3 relevance in PD (AUC = 0.833), and molecular docking suggested potential ATR-CASP3 interaction. Further analysis predicted upregulated miR-3552 as a potential upstream regulator of CASP3. These findings indicate that ATR-induced neurotoxicity may be mediated through the miR-3552/CASP3 signaling axis, ultimately regulating apoptosis and contributing to neurodegeneration.

Animals↗

PubMed1978

Intrathecal methotrexate overdose without neurotoxicity: case report and literature review.

A 24-month-old female developed a central nervous system relapse, while in bone marrow remission, eight months after the diagnosis of acute lymphocytic leukemia was made. Inadvertently, she received 14 times the standard dose of intrathecal methotrexate (170 mg/m2 vs. 12 mg/m2). Treatment with intravenous leucovorin and oral dexamethasone was given. Her only symptomatology was mild headaches. No neurological abnormalities developed. Her cerebrospinal fluid methotrexate levels (5.2 X 10(-6)M at 23 hours and 5.9 X 10(-7)M at 47 hours) and half-life (t 1/2 = 8 hours) were within the range previously reported in patients following standard doses of intrathecal methotrexate who did not develop neurotoxicity. The various manifestations of neurotoxicity associated with the use of intrathecal methotrexate as well as those factors considered to play a part in the development of neurotoxicity are reviewed.

Adolescent↗