The ototoxic effects induced in rats by treatment for 12 weeks with 2-butenenitrile, 3-butenenitrile and cis-2-pentenenitrile

Brainstem auditory and visual evoked-potentials were studied in male Sprague-Dawley rats during subchronic oral treatment with three unsaturated aliphatic nitriles. The rats were given, by gastric intubation, doses of 10, 20 and 40 mg x kg(-1) 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg x kg(-1) of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Rats in the high dosage groups exhibited a complete disappearance of the five waves of the auditory evoked-potentials. There was a decrease in the amplitudes of the 2nd component of the auditory evoked-potentials. Those changes were not reversible at the 8th week of the recovery period. A dose-dependent effect on inner and outer hair cells was observed in the organ of Corti. The basal part of the cochlea was the most affected. Though no measurements were made of systemic exposure, a tentative ranking of decreasing ototoxicity of these three unsaturated nitriles might be proposed based on the electrophysiological deficiencies and histological losses observed: 3-butenenitrile >cis-2-pentenenitrile >cis/trans-2-butenenitrile. Moreover, rats treated with those nitriles showed a corneal opacity as well as a decrease in the amplitude and lengthening of the peak latencies of the visual evoked-potentials. These latter changes were reversible by the end of the 8th week of the recovery period and appeared to be related to the opacity of the cornea.     

Alterations in the metabolism of serotonin and dopamine in the central nervous system of mice displaying a persistent dyskinesia due to crotononitrile or 2-pentenenitrile

The effect of crotononitrile (4.22 mmol/kg, CRN) or 2-pentenenitrile (2.00 mmol/kg, 2-PN), which exhibit long-term dyskinesia, was examined on the metabolism of serotonin (5-HT) and dopamine (DA) in five brain regions of mice 1, 5, 12 and 35 days after dosing with CRN or 2-PN or vehicle (0.1 ml/25 g). One day after injection, CRN increased the level of the following substances and the ratio of 5-hydroxyindoleacetic acid (5-HIAA)/5-HT: 5-HT in medulla oblongata plus pons (144% of control); 5-HIAA in cortex (162%), striatum (166%), medulla oblongata plus pons (212%), hypothalamus (146%) and midbrain (167%); 5-HIAA/5-HT in medulla oblongata plus pons (148%) and midbrain (133%). The changes caused by 2-PN were as follows: DA levels in cortex (176% of control, 35 days after dosing); HVA levels in striatum (136%, 1 day); 5-HT levels in hypothalamus (141%, 35 days); 5-HIAA levels in striatum (150%, 1 day), medulla oblongata plus pons (159%, 1 day) and midbrain (146%, 1 day); 5-HIAA/5-HT in striatum (153%, 1 day) and midbrain (134%, 1 day). The results suggest that changes in the 5-HT system are involved in the appearance of the dyskinetic syndrome which was seen in mice 1–2 days after dosing with CRN or 2-PN.     

Electrophysiological deficiency in peripheral nerve induced by treatment for 12 weeks with 2-butenenitrile, 3-butenenitrile, cis-2-pentenenitrile and 3,3-iminodipropionitrile in rats.

Motor and sensory conduction velocities and amplitudes of the sensory and motor action potentials of the tail nerve were studied in male Sprague-Dawley rats during subchronic oral treatment with three unsaturated aliphatic nitriles. The rats were given, by gastric intubation, doses of 10, 20 and 40 mg x kg(-1) 3-butenenitrile (allyl cyanide) and 25, 50 and 100 mg x kg(-1) of either cis/trans-2-butenenitrile (crotononitrile) or cis-2-pentenenitrile once a day, 5 days per week for 12 weeks. Moreover, 3,3'-iminodipropionitrile was administered likewise at doses of 25, 50 and 100 mg x kg(-1) as reference neurotoxicant. Oral administration of the three unsaturated nitriles produced deafness and absence of reaction when the animals were subject to droptest. Moreover, rats exhibited both time- and concentration-dependent decreases in motor and sensory conduction velocities and amplitudes of the sensory action potentials. Nerve conduction velocities were partially reversible after 8 weeks of recovery. Rats receiving 3,3'-iminodipropionitrile developed deafness, head weaving and significant irreversive deficiencies in all the electrophysiological parameters studied. Further toxicological studies with related unsaturated nitriles should be carried out to determine the potential importance of the cis/trans isomerism in the observed neurotoxicity.     

Oral toxicity study of 2-pentenenitrile in rats with reproductive toxicity screening test

A combined repeated-dose toxicity study with reproduction was conducted with 2-pentenenitrile (2-PN). Rats (10/sex per dose level) were dosed with 2-PN once daily by gavage at dose levels of either 0, 1, 3, or 10 mg kg(-1) day(-1) for 28 days, prior to and during cohabitation, and through day 3 of lactation. General clinical observations were recorded daily; body weights were recorded weekly. A neurobehavioral evaluation consisting of a functional observational battery and motor activity was conducted in all parental rats (10/sex per group). Clinical pathology parameters (hematology, clinical chemistry, coagulation) were measured in parental rats. Pup weights and clinical signs were recorded at birth and on lactation day 4. Parental rats were given a gross pathological examination, organ weights were obtained, and histological examination was conducted for the control and 10 mg kg(-1) day(-1) groups. No effects were seen with regard to mortality, clinical signs, functional observational battery and motor activity, hematology, or organ weights. Females receiving 10 mg/kg and males from all dose groups showed lower body weight gains and feed efficiency. Increased albumin concentrations were seen in both sexes given 10 mg/kg. Females in the 10 mg/kg group showed degeneration of the olfactory mucosa. No effects on the numbers of pups born, number surviving to lactation day 4, pup weight, and no gross anatomical development changes were observed. Under the conditions of this study, the no-observed-effect level (NOEL) for systemic toxicity in rats was 3 mg kg(-1) day(-1), based on degeneration of olfactory mucosa in females at 10 mg kg(-1) day(-1). The NOEL for reproductive and neurobehavioral toxicity in rats and for toxicity to offspring was 10 mg kg(-1) day(-1), the highest dose level tested.     

Behavioral suppression induced by oral administration of monosodium L-glutamate in rats

Adult male rats, trained under a fixed ratio 30 schedule of food reinforcement, were observed for behavioral changes after oral administration of monosodium L-glutamate (MSG). Following the administration of more than 0.5 g/kg of MSG, transient suppression was observed as a function of dose level. Thus, responses were inhibited immediately after MSG, attained the minimum at 20–25 min, and then abruptly returned to the initial level. When oral MSG 2.0 g/kg was concurrently accompanied by subcutaneous diazepam 0.25–1.0 mg/kg or oral caffeine 5–20 mg/kg, the MSG-induced suppression was markedly modified. Thus, the several minutes suppression observed immediately after MSG was significantly antagonized by these drugs. However, the suppression observed at 15–30 min was significantly enhanced by diazepam in proportion with the dose, and markedly antagonized by caffeine. There were indications that MSG's central action might be involved in the development of behavioral suppression induced by it. The exact nature of the toxic hazards of MSG remain obscure, but nevertheless present indications are that one should refrain from adding a large dose of MSG to food.     

Behavioral sensitization is induced by intravenous self-administration of cocaine by rats

Rats were prepared with jugular catheters and assigned randomly to one of three groups: intravenous (IV) self-administration of cocaine, yoked administration of cocaine or vehicle. Rats experienced intermittent administration of cocaine (0.75 mg/kg per injection) or vehicle (0.1 ml/injection) for six test sessions, in accordance with the pattern of injections made by the self-administration group. Sensitization of motor activity between pre-and post-treatment challenges of cocaine (3 mg/kg, IV) was observed after both self- and yoked administration of cocaine but not in the yoked-vehicle group. These data indicate that sensitization as a consequence of drug self-administration may be an important factor in the etiology of addiction.     

Muscle necrosis in rats induced by 2-methoxy-p-phenylenediamine.

p-Phenylenediamine, together with several of its amino and alkyl derivatives, are known to be myotoxic in animals and man. In the present study, it was found that 2-methoxy-p-phenylenediamine, a component of oxidative hair dyes, similarly causes necrosis of skeletal muscle (gastrocnemius, diaphragm and tongue) in rats. The myotoxicity of 2-methoxy-p-phenylenediamine was much greater than that of p-phenylenediamine itself. This observation is consistent with the relative efficacy of these substances in disrupting mitochondrial metabolism, an effect which is believed to be responsible for the selective toxicity of p-phenylenediamine derivatives to muscle.     

Antinociception induced by intracerebroventricular or intrathecal administration of gentamicin in rats.

1. The intrathecal (i.t.) administration of gentamicin (AD50 = 3.98 micrograms) produced marked and dose-dependent antinociception in rats, as assessed by the tail-flick test. A weaker effect was obtained following intracerebroventricular drug administration (AD50 = 50.12 micrograms). 2. A transitory but dose-dependent antagonism of the effect of i.t. gentamicin was obtained following i.t. administration of calcium chloride (4 and 8 micrograms). 3. The magnitude and duration of morphine antinociception (5 micrograms, i.t.) were enhanced by the previous (intraperitoneal) i.p. or i.t. administration of gentamicin. 4. These results indicate that gentamicin-induced antinociception may depend on its calcium-antagonist property and involves drug diffusion to a spinal site of action.     

Behavioral and biochemical changes induced by lithium and l-tryptophan in muricidal rats

Lithium (0.5–12 meq/kg) and l-tryptophan (100–800 mg/kg) inhibited the muricidal (mouse killing) response in isolated, male, Long Evans rats and did so both in an acute (single dose) and on a longer-term intraperitoneal treatment basis. The response was dose-dependent. There was no concomitant motor impairment at doses effective in inhibiting the muricidal response. Plasma lithium levels were positively correlated with the percentage inhibition of muricidal behavior. When lithium and l-tryptophan were administered in combination in their smallest effective doses, the behavioral interaction was synergistic in the acute and additive in the longer-term treatment. The effects of pharmacological treatment on the inhibition of muricidal behavior were: lithium and l-tryptophan < l-tryptophan <-lithium.The results of biochemical assays showed that these compounds increased fore- and hindbrain serotonin turnover. The biochemical action of lithium and l-tryptophan in combination on brain serotonergic pathways was again clearly more potent than that which occurred after treatment with either lithium or l-tryptophan alone. The magnitude of the biochemical changes paralleled those of the psychophar-macological changes.These data show an interaction between lithium and l-tryptophan both in the repression of aggressive behavior in rats and in the alteration of centrally acting serotonergic function. These data further elucidate a mechanism of action through central serotonergic function for a psychotherapeutic agent, lithium, and for aggressive behavior, muricide.     

Behavioral and endocrine changes induced by perinatal fenvalerate exposure in female rats

Pyrethroid insecticides have recently been linked to endocrine disruption. Endocrine disrupting chemicals have been defined as exogenous agents that interfere with the synthesis, secretion, binding, action, or elimination of natural hormones in the body. Previous research conducted in our laboratory suggests that perinatal exposure to fenvalerate, a type-II pyrethroid, interferes with brain sexual organization in male pups, probably acting on a critical perinatal hormone-related period. In the present study we investigate the effects of maternal exposure to fenvalerate (FV) during the prenatal and postnatal periods of sexual brain organization of female offspring. Behavioral (open-field, stereotyped and sexual behaviors), physical (sexual maturation, body and uterine weights), and neuroendocrine (estrous cycle and gonadal hormone levels ) parameters were assessed. Results show that 1) sexual maturation was delayed, albeit body weight was unchanged until adulthood; 2) there was a reduction in sexual behavior; 3) the estrous cycle was abnormal, and the uterine weight at different phases of the estrous cycle was modified; 4) gonadal hormone levels in the plasma were not affected, neither was stereotypy nor open-field behaviors. These results were attributed to an anti-estrogenic effect of perinatal exposure to FV during the critical periods of female brain sexual organization.     

Behavioral alterations induced in rats by a pre- and postnatal exposure to 2,4-dichlorophenoxyacetic acid.

The purpose of this study was to determine whether the behavioral development pattern was altered by a pre- and postnatal exposure to 2,4-Dichlorophenoxyacetic acid (2,4-D). Pregnant rats were daily orally exposed to 70 mg/kg/day of 2,4-D from gestation day (GD) 16 to postnatal day (PND) 23. After weaning, the pups were assigned to one of the two subgroups: T1 (fed with untreated diet until PND 90) and T2 (maintained with 2,4-D diet until PND 90). Effects on offsprings were evaluated with a neurotoxicological test battery. Neuromotor reflexes, spontaneous motor activity, serotonin syndrome, circling, and catalepsy were analyzed during various postnatal ages. 2,4-D neonatal exposure induced delay of the ontogeny of righting reflex and negative geotaxis accompanied by motor abnormalities, stereotypic behaviors (excessive grooming and vertical head movements), and hyperactivity in the open field. Adult rats of both sexes (T2 group) showed a diminution of ambulation and rearing, while excessive grooming responses were only observed in T2 males. Besides, these animals manifested serotonin syndrome behaviors, catalepsy, and right-turning preference. Some behaviors were reversible, but others were permanent, and some were only expressed after pharmacological challenges.     

Behavioral abnormalities and apoptotic changes in neurons in mice brain following a single administration of allylnitrile

A single dose of allylnitrile in mice might induce persistent behavioral abnormalities, of which the mechanism is not yet known. The present study was undertaken to explore the relationship between behavioral abnormalities and pathological changes in the brain of mice following exposure to allylnitrile. Exposure to allylnitrile (63, 84, and 112 mg/kg, p.o.) resulted in dose-dependent changes in behavioral abnormalities, including increased locomotor activity, circling, retropulsion, head twitching, and alteration in reflexive behavior, which appeared at day 2 postdosing and were persistent throughout the experimental period (60 days) at the higher dose levels. Allylnitrile produced neuronal retraction including hyperchromasia of the nuclei in the raphe nuclei, cerebral cortex, hypothalamus, hippocampal CA1 and dentate gyrus later than 30 days. No gliosis was observed in these regions. Not all but a significant number of neurons in the hippocampal CA1, medial habenula and raphe nuclei were immunoreactive to CPP32 (Caspase-3) even at day 2. These neurons were also positive to Hoechst 33258 staining, indicating allylnitrile caused apoptotic changes in specific neurons when neuronal behaviors became apparent. These apoptotic changes were persistent even in the area without neuronal contraction such as medial habenula. However, almost all neurons in these areas were also positive to terminal deoxynucleotidyl transferase mediated dUTP-biotin nick end labeling (TUNEL). It is conceivable that allylnitrile caused apoptotic changes in neurons but did not always lead them to cell death immediately. Moreover, even when neuronal contraction resulted in retention of behavioral abnormalities, onset of these abnormalities seems to be associated with the impairment in the habenulo-raphe relay due to activation of apoptotic cascade in neurons. Received: 2 June 1998 / Accepted: 14 December 1998     

Behavioral changes induced in developing rats by an early postnatal exposure to lindane

The purpose of this study was to determine whether the behavioral developmental pattern was altered by an early postnatal exposure to lindane. Male and female offspring of Wistar rats were daily orally administered with a nonconvulsant dose of lindane (10 mg/kg) during 7 days either the 1st or the 2nd postnatal week days. Effects on pups were evaluated with a reduced developmental neurotoxicological test battery. Body weight evolution, neuromotor reflexes (surface righting, cliff avoidance and tail hang reflex) and spontaneous motor activity were analyzed from day 1 after birth up to day 28. The body weight pattern was unaffected by treatment with lindane and no signs of overt toxicity were observed. Lindane-treated pups showed an increased positive response of the neuromotor reflexes. Furthermore, lindane produced hyperactivity, especially manifested between days 12 and 16. A peak of activity was reached at day 16 in lindane-treated groups, while control animals had a maximum between days 20 and 24. These results suggest that low nonconvulsant doses of lindane may induce behavioral changes in developing rats.     

Vestibular toxicity of cis-2-pentenenitrile in the rat

cis-2-Pentenenitrile, an intermediate in the synthesis of nylon and other products, causes permanent behavioral deficits in rodents. Other low molecular weight nitriles cause degeneration either of the vestibular sensory hair cells or of selected neuronal populations in the brain. Adult male Long-Evans rats were exposed to cis-2-pentenenitrile (0, 1.25, 1.50, 1.75, or 2.0mmol/kg, oral, in corn oil) and assessed for changes in open field activity and rating scores in a test battery for vestibular dysfunction. Surface preparations of the vestibular sensory epithelia were observed for hair cell loss using scanning electron microscopy. A separate experiment examined the impact of pre-treatment with the universal CYP inhibitor,1-aminobenzotriazole, on the effect of cis-2-pentenenitrile on vestibular rating scores. The occurrence of degenerating neurons in the central nervous system was assessed by Fluoro-Jade C staining. cis-2-Pentenenitrile had a dose-dependent effect on body weight. Rats receiving 1.50mmol/kg or more of cis-2-pentenenitrile displayed reduced rearing activity in the open field and increased rating scores on the vestibular dysfunction test battery. Hair cell loss was observed in the vestibular sensory epithelia and correlated well with the behavioral deficits. Pre-treatment with 1-aminobenzotriazole blocked the behavioral effect. Fluoro-Jade C staining did not reveal significant neuronal degeneration in the central nervous system apart from neurite labeling in the olfactory glomeruli. We conclude that cis-2-pentenenitrile causes vestibular toxicity in a similar way to allylnitrile, cis-crotononitrile and 3,3'-iminodipropionitrile (IDPN), and also shares other targets such as the olfactory system with these other nitriles. The present data also suggest that CYP-mediated bioactivation is involved in cis-2-pentenenitrile toxicity.     

Naloxone reduces diuretic responses induced by water, alcohol or congenital lack of vasopressin in rats.

The effects of naloxone (2 and 10 mg kg-1 s.c.) were compared in several kinds of experimental polyuria: alcohol- or water-loaded rats and Brattleboro rats (i.e. animals with congenital lack of vasopressin). In normal rats, both water and alcohol increased urine flow and decreased urinary osmolality. Alcohol induced a more marked diuretic response than water. In normally hydrated rats, naloxone (2 and 10 mg kg-1 s.c.) failed to modify urine flow, urinary osmolality, Na+ and K+ urinary excretion, and urine creatinine concentration. The two doses of naloxone decreased urine flow and increased osmolality in both water- and alcohol-loaded rats. In Brattleboro rats, naloxone (10 mg kg-1 s.c.) reduced urine flow and urinary creatine whereas the low dose (2 mg kg-1 s.c.) was without effect. Since it is well known that the mechanism of water- or alcohol-induced diuresis is an inhibition of vasopressin release, the present results suggest that naloxone could prevent this inhibition. They indicate that endogenous opioid peptides may exert an inhibitory control on vasopressin release.     

Behavioral and neurochemical effects induced by subchronic exposure to 40 ppm toluene in rats

Chronic toluene inhalation at concentrations above occupational exposure limits (e.g., 100 ppm; NIOSH) has been repeatedly shown to induce neurotoxic effects. In contrast, although few clinical and experimental data are available on the effects of toluene exposure at concentrations below occupational exposure standards, some of these data may support adverse effects of long-term exposure to low toluene concentrations. To test this hypothesis, we investigated the neurobehavioral and neurochemical effects of 40 ppm inhaled toluene in a rat model of 16-week subchronic exposure, examining locomotor and rearing activities; adaptation/sensitization to narcosis produced by acute exposure to toluene at high concentration; and tyrosine hydroxylase and tryptophan hydroxylase activities, and dopamine (DA) and serotonin (5-HT) turnovers in the caudate-putamen, nucleus accumbens, hippocampus, prefrontal cortex, and cerebellum. Our results mainly show that subchronic exposure to 40 ppm toluene significantly resulted in a sensitization to toluene-induced narcosis, a decrease in rearing activity, and alterations in DA and 5-HT transmissions. This demonstrates that subchronic toluene exposure at a low concentration may lead to adverse changes in neurobehavioral and neurochemical functioning, and further questions in a public health perspective the actual neurotoxic potential of toluene and other organic compounds, because deficits in functioning are generally viewed as precursors of more serious adverse effects.     

Behavioral teratogenicity induced by nonforced maternal nicotine consumption.

Prenatal nicotine exposure (PNE) has been associated with increased prevalence of attention deficit hyperactivity disorder (ADHD), major depressive disorder (MDD) and substance abuse in exposed children and adolescents. Whether these syndromes are caused by nicotine exposure, or genetic and psychosocial adversities associated with maternal smoking is not completely clear. Animal models suggest a direct impact of PNE. However, the fact that nicotine is forcefully administrated in these paradigms raises some questions about the specificity of these findings. Pregnant C57BI/6J mice were allowed to choose drinking saccharin/nicotine solutions or pure water. Controls could choose saccharin solutions or pure water. Offspring were tested in spontaneous locomotion, fear-associated learning (trace conditioning), addictive (conditioned place preference), and depression-like (learned helplessness) behaviors. There was no significant difference in weight or pup number between the prenatal treatment groups. A significant effect of PNE was observed on spontaneous locomotion, preference for a cocaine-associated place, and latency to escape in the learned helplessness paradigm. Surprisingly, PNE mice exhibited an increased learning of trace-conditioned fear-associated cues. The hyperlocomotive behavior reported in animal models of PNE is not likely an artifact of forceful nicotine administration. The increased prevalence of ADHD, MDD and substance abuse observed in PNE children and adolescents is probably caused by direct behavioral teratogenic effects of PNE. The role of PNE as a risk factor of syndromes associated to increased learning of fear-associated cues such as post-traumatic stress disorder (PTSD) warrants further evaluation.     

Neurological deficits induced by malathion, DEET, and permethrin, alone or in combination in adult rats

Malathion (O,O-dimethyl-S-[1,2-carbethoxyethyl]phosphorodithionate), DEET (N,N-diethyl-m-toluamide), and permethrin [(+/-)-cis/trans-3-(2,2-dichloroethenyl)-2,2-dimethylcyclopropane carboxylic acid (3-phenoxyphenyl) methyl ester] are commonly used pesticides. To determine the effects of the dermal application of these chemicals, alone or in combination, the sensorimotor behavior, central cholinergic system, and histopathological alterations were studied in adult male Sprague-Dawley rats following a daily dermal dose of 44.4 mg/kg malathion, 40 mg/kg DEET, and 0.13 mg/kg permethrin, alone and in combination for 30 d. Neurobehavioral evaluations of sensorimotor functions included beam-walking score, beam walk time, inclined plane, and grip response assessments. Twenty-four hours after the last treatment with each chemical alone or in combination all behavioral measures were impaired. The combination of DEET and permethrin, malathion and permethrin, or the three chemicals together resulted in greater impairments in inclined performance than permethrin alone. Only animals treated with a combination of DEET and malathion or with DEET and permethrin exhibited significant increases in plasma butyrlcholinesterase (BChE) activity. Treatment with DEET or permethrin alone, malathion and permethrin, or DEET and permethrin produced significant increases in cortical acetylcholinesterase (AChE) activity. Combinations of malathion and permethrin or of DEET and permethrin produced significant decreases in midbrain AChE activity. Animals treated with DEET alone exhibited a significant increase in cortical m2 muscarinic ACh receptor binding. Quantification of neuron density in the dentate gyrus, CA1 and CA3 subfields of the hippocampus, midbrain, brainstem, and cerebellum revealed significant reductions in the density of surviving neurons with various treatments. These results suggest that exposure to real-life doses of malathion, DEET, and permethrin, alone or in combination, produce no overt signs of neurotoxicity but induce significant neurobehavioral deficits and neuronal degeneration in brain.     

Attenuation of iminodipropionitrile induced behavioral syndrome by sodium salicylate in rats

Iminodipropionitrile (IDPN) produces irreversible behavioral abnormalities characterized by excitation with choreiform and circling movements (ECC) syndrome in rodents. Concomitant exposure to drugs or environmental chemicals has been shown to alter IDPN-induced neurobehavioral toxicity. This investigation was undertaken to study the effect of sodium salicylate (SS) on IDPN-induced behavioral abnormalities in rats. The animals were exposed to IDPN (100 mg/kg ip) daily for 8 days. SS was administered daily 30 min before IDPN in the doses of 50, 100 and 200 mg/kg ip for 12 days. The animals were observed for neurobehavioral abnormalities including dyskinetic head movements, circling, tail hanging, air righting reflex and contact inhibition of the righting reflex. Horizontal and vertical locomotor activities and forelimbs grip strength were also measured. After behavioral studies, the animals were sacrificed, and the cerebrum and temporal bones were collected for glutathione analysis and inner ear histopathology, respectively. The onset of ECC syndrome was observed on Day 9 in the IDPN-alone group with 100% incidence on Day 12. Cotreatment with salicylate dose-dependently delayed the onset time and significantly attenuated the incidence and severity of IDPN-induced neurobehavioral signs. IDPN alone significantly increased horizontal motor activity and reduced vertical motor activity and forelimbs grip strength; these effect were significantly reversed by salicylate treatment. Treatment with salicylate also attenuated IDPN-induced depletion of GSH in the cerebrum, suggesting its free radical scavenging property.