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PubMed1992

Embryotoxicity and neurotoxicity in rats associated with prenatal exposure to DURSBAN.

DURSBAN (DB; active ingredient chlorpyrifos) is a widely-used organophosphate insecticide. The teratogenic and neurotoxic potential of DB was evaluated in rats in utero by exposing embryos on days 0-7 or days 7-21 of development. These prenatal exposures to DB (0.03, 0.1 or 0.3 mg chlorpyrifos/kg, ip) induced physical abnormalities and embryotoxicity. Rat pups which had been exposed to 0.3 mg chlorpyrifos/kg prenatally demonstrated significant behavioral neurotoxicity on postnatal day 16 in the rotorod test compared to time-matched saline-infused litters. Exposure to DB on postnatal day 3, 10 or 12 also caused neurotoxicity as evaluated by the rotorod test. Our studies suggest prenatal exposure to relatively low concentrations of DB may be associated with embryotoxicity, fetal lethality and behavioral neurotoxicity.

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↗

PubMed1979

Effects of cortical ablation on the neurotoxicity and receptor binding of kainic acid in striatum.

Lesions of the cerebral cortex alter striatal neuronal vulnerability to locally injected kainic acid. Whereas extensive lesions involving the frontal-parietal-occipital cortex are most effective, lesions limited to the frontal or to the dorsal-lateral parietal cortex offer partial protection. The extensive cortical lesions are associated with selective, marked reductions in the presynaptic markers for glutamatergic afferents in striatum. The protective effects of decortication appear between 6 and 24 hours after the lesion and are maintained up to 30 days after decortication. Whereas decortication results in only a transient reduction of specific receptor binding of [3H]kainic acid to striatal membranes, lesion of striatal intrinsic neurons with kainic acid causes a delayed but marked reduction in specific binding of the ligand. Coadministration of L-glutamic acid (1 mumole) with kainic acid (9 nmoles) partially restores the neurotoxic action of kainic acid in the decorticate striatum; GABA, alanine, and proline (1 mumole) are ineffective with regard to restoring kainate's toxicity for striatal GABAergic neurons. These results suggest that afferent input exerts a permissive effect on the neurotoxic action of kainic acid and that neurotoxicity may involve a cooperative interaction between kainic acid at specific receptors on vulnerable neurons and synaptically released endogenous neurotransmitters, in particular L-glutamic acid.

Animals↗

PubMed1977

Tri-O-tolyl phosphate neurotoxicity: lack of evidence for autoimmunologic involvement.

Studies on the involvement of autoimmunity in the pathogenesis of tri-O-tolyl phosphate (TOTP) induced neurotoxicity in chickens were conducted. Immunosuppressive therapy including gamma-radiation and drug treatments was utilized to determine its effects on the neurotoxic syndrome. Whole-body gamma-irradiation up to 1020 roentgens failed to show any consistent protection from the TOTP induced paralysis. Therapy involving prednisone alone or in combination with 6-mercaptopurine and antilymphocyte serum likewise indicated no protection. Stimulation of humoral and cellular immunity by TOTP was investigated. Complement fixation, precipitation tests, splenic migration inhibition, and skin tests did not indicate stimulation of autoimmunity toward nervous tissue or liver. The present investigation was unable to demonstrate primary involvement of an autoimmune nature in the neurotoxicity produced by TOTP in the chicken.

Animals↗

PubMed1992

Intrathecal oxymetazoline does not produce neurotoxicity in the spinal cord of the rat.

To determine if intrathecal (i.t.) oxymetazoline (OXY) induces histological evidence of spinal neurotoxicity, male, Sprague-Dawley rats (300-450 g; implanted with an i.t. catheter) were treated with i.t. saline or 100 nmol OXY twice daily for 3 days, or 200 or 300 nmol OXY once daily for 3 days. Spantide (D-Arg1, D-Try7,9, Leu11-substance P; 0.067 nmol = 0.1 microgram, 0.167 nmol = 0.25 microgram or 0.334 nmol = 0.5 microgram) or capsaicin (0.164 mumol = 50 micrograms), given as a single i.t. injection, were used as positive controls. Animals were killed 12 h after the last injection of saline or OXY, and 72 h after spantide or capsaicin. Spinal cord sections (L1 and adjacent segments) were examined by light microscopy for changes in gross morphology, substance P-like immunoreactivity (SP-IR) and calcitonin gene related peptide-like immunoreactivity (CGRP-IR). All doses of i.t. OXY produced antinociception (tail-flick ED50 = 53.7 nmol, paw pressure withdrawal ED50 = 93.3 nmol). Rectal temperature decreased by 1.5-2.4 degrees C up to 12 h after 100 nmol of i.t. OXY. There were no signs of inflammation or necrosis, and no detectable loss or damage to either spinal afferents or motor neurons as judged by SP-IR and CGRP-IR structures in spinal cords of OXY-treated animals (all doses) as compared to i.t. saline controls. Spantide (0.1 microgram) had no antinociceptive or neurotoxic effect; 0.25 microgram induced irreversible loss of the TF reflex and transient hind limb paralysis; 0.5 microgram induced irreversible loss of TF and PP responses, permanent hind limb paralysis, bladder and bowel dysfunction. The spinal cords from these animals showed signs of extensive necrosis, cavitation, and haemorrhage in the ventral horn accompanied by a loss of CGRP-IR motor neurons. Capsaicin-treated rats exhibited a permanent loss of the TF but not the PP response and a marked reduction of SP-IR spinal afferents in the dorsal horn. It is concluded that i.t. OXY produces antinociception in the rat with no detectable spinal neurotoxicity as assessed by parameters which are sensitive to the neurotoxins, spantide and capsaicin.

Analgesics↗

PubMed1979

Delayed neurotoxic, late acute and cholinergic effects of S,S,S-tributyl phosphorotrithioate (DEF): subchronic (90 days) administration in hens.

Subchdronic administration of S,S,S-tributyl phosphorotrithioate (DEF) caused 3 toxicologic effects in hens, depending upon route of administration. Small delay oral doses (0.5--20 mg/kg) of DEF produced ataxia, which progressed to paralysis and death in some birds. Large daily oral doses (40 and 80 mg/kg) caused a 'late acute' effect 4 days after administration. The clinical signs of the late acute effect were identical to those produced by n-butyl mercaptan (nBM), a hydrolytic product of DEF, and were not relieved by atropine sulfate. The late acute effect of DEF overlapped with the clinical signs of delayed neurotoxicity. These hens died early, and while one hen showed histopathological lesions in peripheral nerves, another showed unequivocal lesions in the central nervous system. Topical application of daily doses of DEF consistently produced delayed neurotoxicity in the absence of late acute poisonining and was characterized by degeneration of the central and peripheral nerve tissues. Orally administered DEF was rapidly metabolized in the gastrointestinal tract to nBM, which apparently caused the late acute toxic effect. Topically administered DEF, which was not subjected to gastrointestinal tract hydrolysis, caused delayed neurotoxicity but did not produce a late acute effect.

Animals↗

PubMed1992

Blockade of nitric oxide formation does not prevent glutamate-induced neurotoxicity in neuronal cultures from rat hippocampus.

This study examined the role of nitric oxide (NO) in glutamate-induced, N-methyl-D-aspartate (NMDA) receptor-mediated neurotoxicity in rat hippocampal neuronal cultures grown under serum-free conditions. Formation of cGMP was used as an indirect measure of NO formation. Neuronal cell degeneration was monitored by measuring the release of lactate dehydrogenase (LDH). Neuronal cells showed a 4-fold increase in cGMP formation and release of LDH upon exposure to 30 microM glutamate. cGMP formation was fully inhibited by 1 microM nitro-arginine (N-Arg), 100 microM hemoglobin or 1 microM MK-801. In the presence of 1 microM MK-801, glutamate induced neither cGMP formation nor neuronal cell degeneration. However, when NO formation was inhibited by means of 100 microM N-Arg, glutamate still induced neurotoxicity. Therefore, in serum-free hippocampal cultures glutamate neurotoxicity occurs notwithstanding complete inhibition of the NO-synthase enzyme by N-Arg. Our data provide evidence that NO, synthesized upon glutamate exposure, has not a primary toxic action in pure hippocampal neuronal cultures.

Amino Acid Oxidoreductases↗

PubMed1978

Search for relationships among the hemolytic, phospholipolytic, and neurotoxic activities of snake venoms.

Several snake venom neurotoxins are larger and more complex than the well-studied group of postsynaptic toxins exemplified by alpha-bungarotoxin. Several of these, exemplified by beta-bungarotoxin, show phospholipase A2 activity (phosphatide 2-acylhydrolase, EC 3.1.1.4) when tested in the presence of detergents. The high hemolytic activity of crotoxin, the neurotoxin of Crotalus durissus terrificus, in the presence of lecithin has been attributed to this activity. The phospholipase A2 activity of several snake venom proteins has now been compared under the physiological conditions of the hemolysis tests. It appears that only the basic component of crotoxin, B, is enzymatically active, and that its activity is not inhibited by component A under these conditions, or in the presence of deoxycholate. Phosphatidylserine is found to be digested more readily than egg white phosphatidylcholine; and also causes hemolysis in conjunction with much lower levels of crotoxin. In neither case is calcium required or stimulating. Phospholipase from Crotalus adamanteus, which is not neurotoxic, digests phosphatidylcholine more rapidly than does crotoxin, but phosphatidylserine more slowly; yet it is slightly less active than crotoxin in the hemolysis test with phosphatidylcholine, and much less with phosphatidylserine. The digestion of several phospholipids by either enzyme fails to release the expected protons in the absence of detergents at 37 degrees .beta-Bungarotoxin, highly neurotoxic, has negligible phospholipase A2 activity in the absence of detergents, and is almost nonhemolytic in conjunction with all phospholipids tested.Binding studies with (125)I-labeled compounds show that rabbit erythrocytes and ghosts have much greater affinity for crotoxin than for beta-bungarotoxin and do not bind Crotalus adamanteus phospholipase. The crotoxin complex is split in the course of binding, with only component B, the hemolytic component, becoming bound. It appears that the role of component A may be to diminish the nonspecific binding tendency of component B. Our data appear to be consistent with the concepts that affinity to membranes, particularly to specific sites on synaptic membranes, is the critical requirement for beta type neurotoxicity, and that this property, at least in some instances, has evolved from phospholipase A2 enzymes, but does not necessarily require retention and expression of enzymatic activity.

Animals↗

PubMed1978

An electrodiagnostic study of the neurotoxicity of methyl n-amyl ketone.

The neurotoxicity of methyl n-amyl ketone was investigated in a chronic inhalation study lasting 9 months. Rats and monkeys were exposed 6 hrs/day, 5 days/week, to mean MAK levels of 0, 131, and 1025 ppm. Electrodiagnostic measures of nervous system function revealed no neurotoxic impairment at either MAK exposure. Body weights were similarly unaffected. Gross and histopathology also indicated no adverse effects of MAK. It was concluded that MAK does not possess neurotoxic properties similar to those possessed by methyl n-butyl ketone.

Action Potentials↗

PubMed1975

P-Chloramphetamine: Selective neurotoxic action in brain.

Injection of 2.5,5, 10, or 20 milligrams of p-chloroamphetamine per kilogram of body weight into rats produced evidence of cytopathological changes in sections of brain stained by a Nissl or silver method. As early as 1 day after drug injection cells demonstrated an intense Nissl staining, intense argyrophilia, cellular shrinkage, and perineuronal spaces. At 30 days after injection both stains revealed cellular debris and glial reactions characteristic of cellular dissolution. The neurotoxic effects of 2.5, 5, or 10 milligrams of p-chloroamphetamine per kilogram were primarily restricted to an area of the ventral midbrain tegmentum corresponding to the distribution of the B-9 serotonergic cell group. After 20 milligrams of p-chloroamphetamine per kilogram there was also evidence of neurotoxic effects on cells within the substantia nigra. These results confirm previous suggestions that the long-term reduction in serotonin content of brain, tryptophan-5-hydroxylase activity, and uptake of serotonin after injection of p-chloroamphetamine is due to a neurotoxic effect of the drug or some metabolite on serotonergic cell bodies.

Amphetamine↗

PubMed2026

Exogenous lactate ameliorates Aβ-induced energy deficit and neurotoxicity with increased mitochondrial TCA cycle carbon flux in SH-SY5Y cells.

A growing body of evidence has demonstrated the existence of metabolic dysfunction in neurodegenerative diseases, including Alzheimer's disease (AD), suggesting that deprivation of energy substrates impairs cellular dynamics. As glucose utilization declines in patients with AD, the need for alternative energy sources becomes crucial to sustain neuronal activities and prevent cell death induced by neurotoxic proteins, such as amyloid beta (Aβ) aggregates. In this context, lactate has been investigated as a potential alternative brain energy substrate in several studies, yet its impact on neuronal cells under Aβ-induced toxicity remains unclear. We confirmed significant suppression of energy production-related biological pathways by analyzing brain transcriptomic data of patients with AD. In subsequent in vitro studies, exogenous lactate treatment ameliorated neuron-like cell death caused by Aβ aggregates. Using a 13C stable isotope tracer, we verified cellular lactate uptake and its incorporation into tricarboxylic acid (TCA) cycle in neurons under the neurotoxic condition. 13C metabolic flux analysis further supported these findings by revealing that lactate treatment restored Aβ-suppressed mitochondrial TCA cycle fluxes. These metabolic improvements were accompanied by increased expression of mitochondrial proteins. These findings support lactate shuttling as a mechanism for supplying lactate-derived carbon to mitochondrial energy metabolism, which may improve neuronal resilience under Aβ-induced metabolic stress.NEW & NOTEWORTHY This study shows that lactate treatment attenuates Aβ-induced cell death in neuron-like cells and supports mitochondrial carbon metabolism. Glycolytic hypometabolism was observed in human AD brain transcriptome and Aβ-treated neuron-like cells. We confirmed that lactate replenished mitochondrial energetics, making neurons more resilient to neurotoxicity. Using 13C tracing and metabolic flux analysis, we found that lactate-derived carbon was incorporated into the TCA cycle and that lactate treatment was associated with restoration of Aβ-suppressed mitochondrial fluxes.

Humans↗

PubMed1975

Fenfluramine: evidence for a neurotoxic action on midbrain and a long-term depletion of serotonin.

A single injection of fenfluramine (100 mumol/kg) produced evidence of neurotoxicity in cresyl violet or silver stained sections of rat brain which was restricted to the serotonergic (B-9) cell group located in the ventromedial midbrain tegmentum. Reacting cells throughout this region exhibited an irregular shape and an intense staining of the cytoplasm, while in the caudal 1/4 of this region the reacting cells also exhibited a perineuronal space. These effects were greatly reduced in the rostral 3/4 of B-9 at 14 and 30 days after fenfluramine. In the caudal 1/4 of B-9 the neurotoxic actions remained prominent and included signs of cellular dissolution. These signs of an irreversible degenerative effect of fenfluramine on cells in the caudal 1/4 of the B-9 region were identical to those seen after p-CA, while the effects in the rostral 3/4 of B-9 were not as prominent. The differential neurotoxic effects of fenfluramine and p-CA on cells in the rostral 3/4 of B-9 were associated with a differential effect on serotonin content of hippocampus and amygdala.

Animals↗

PubMed1992

Neurotoxic effect of vincristine on ultrastructure of hypothalamus in rabbits.

The neurotoxic side-effects are a striking accompaniment of the therapy with vincristine (VCR). Data concerning the influence of VCR on the central nervous system are controversial. In the present study a schedule of VCR treatment was employed to develop the neurotoxic side effects in New Zealand rabbits. In all treated animals neurons were primarily and most severely affected cells. Most of them underwent degeneration. The consecutive stages of the increasing condensation of chromatin and cytoplasm of these cells were observed. Degeneration of the synaptic connections and secondary changes in myelin sheaths of degenerating axons were found. Debris of some death cells were localized intracellularly or as typical apoptotic bodies ingested by some glial cells. Astroglia underwent swelling and their processes separated dying neurons from the surroundings. All the results lead to conclusion that the VCR treatment concomitant with neurotoxic symptoms may affects regions of CNS lacking of blood-brain barrier. Neurons are most vulnerable cells of the brain parenchyma. The changes induced in neurons by the drug are characteristic in many aspects to those described in many cells undergoing apoptosis.

Animals↗

PubMed1979

Cellular responses to neurotoxic compounds of environmental significance.

Many neurotoxic chemicals of environmental significance can be conveniently classified according to their cellular site of action in the nervous system. This paper considers neurotoxins which damage the nerve cell body (neuronopathy), its axonal process (axonopathy), or the myelin sheath which segmentally enwraps the myelinated axon (myelinopathy). Each of these three conditions can be reproduced in experimental animals for study of the mechanisms and consequences of neurotoxic damage. Detailed morphological examination of toxic distal axonopathies have stimulated biochemical studies which promise to yield a precise explanation of the molecular basis for this common type of neurotoxic disease. It seems possible that a precise description of the molecular basis for toxic distal axonal degeneration is within sight.

Animals↗

PubMed1976

The comparison of fluoxetine and nisoxetine with tricyclic antidepressants in blocking the neurotoxicity of p-chloroamphetamine and 6-hydroxydopamine in the rat brain.

Fluoxetine prevents the loss of 5-hydroxytryptamine (5HT) uptake in synaptosomes of cerebral cortex after intraperitoneally administered p-chloroamphetamine (p-CA) with an ED50 of 3.8 mg/kg i.p. in rats. However, at 50 mg/kg, it does not prevent the loss of norepinephrine (NE) uptake in synaptosomes of hypothalamus after intraventricularly administered 6-hydroxydopamine (6-OHDA). Nisoxetine, on the other hand, centrally protects NE uptake from the neurotoxic effect of 6-OHDA with an ED50 value of 5 mg/kg i.p. At 50 mg/kg, it gives only 35% protection of 5HT uptake from the neurotoxic effect of p-CA. In comparison with the ED50 values of tricyclic antidepressants, both fluoxetine and nisoxetine are more potent and selective blockers of neurotoxicity resulting from the central actions of p-CA and 6-OHDA, respectively, in vivo.

Amphetamines↗