Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0004134 (ataxia)
 15,886 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Leptophos (O-[4-bromo-2,5 dichlorophenyl] O-methyl phenylphosphonothioate) (PhosvelR) was administered orally to chickens and rats in doses of 0.5 and 5.0 mg/kg/day for 26 weeks. Hens fed 5.0 mg/kg, except one, showed ataxia and became paralysed in the legs at varying times from 8 to 19 weeks. A fifth hen showed ataxia early in the experiment but recovered fully for the remainder of the experiment. Rats fed both doses and chickens fed 0.5 mg/kg showed no signs of delayed neurotoxicity. All hens fed 5.0 mg/kg stopped laying by about the third week. Animals of both species fed 5.0 mg/kg either lost weight (chickens) or gained less weight (rats) than the others. Erythrocyte acetylcholinesterase (AChE) of the chickens given both doses was significantly depressed at first, then increased, and later dropped to control levels. AChE of rats fed 0.5 mg/kg was significantly inhibited but soon recovered to within control levels. On the other hand, the AChE of rats fed 5.0 mg/kg was inhibited throughout the experiment. Plasma cholinesterase (ChE) of both species was first inhibited and then recovered erratically for both insecticide concentrations. Histological alterations in the spinal cord of paralysed hens included axon and myelin degeneration in the ventral, lateral and posterior columns. In the paralysed hens, 79% of the neurotoxic esterase in the brain were inhibited, whereas in the non-paralysed hens (including the one non-paralysed hen receiving 5.0 mg/kg/day) and all rats only about half as much was inhibited.
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PMID:Neurotoxic effects of leptophos (PhosvelR) in chickens and rats following chronic low-level feeding. 8 38

Male Sprague-Dawley rats injected sc with a single sublethal dose of the organophosphate nerve agent, soman (100 micrograms/kg), had motor limbic seizures within 5-15 min. Pretreatment with a single dose of memantine HCl (MEM, 18 mg/kg, sc), alone or in combination with atropine sulfate (ATS, 16 mg/kg, sc), before soman prevented seizures without sedation or ataxia. Rats appeared normal or demonstrated increased exploratory activity. Excessive salivation, a peripheral manifestation of soman intoxication, was decreased by ATS, but pretreatment with ATS alone did not prevent seizures. After seizure onset, MEM +/- ATS, but not ATS, abolished seizures. Acetylcholinesterase (AChE) activity in several brain regions (cortex, stem, striatum, and hippocampus) was markedly reduced by soman, but not by MEM, ATS, or MEM + ATS. Preadministration of MEM + ATS in vivo significantly protected AChE from inhibition by soman. Memantine reduced inhibition of AChE activity in crude brain homogenates by soman, but not by edrophonium (anionic site inhibitor) or decamethonium (peripheral site inhibitor). Thus, MEM may bind to a different modulatory site, not yet characterized, to protect AChE. When given after onset of soman-induced seizures, treatment with MEM +/- ATS did not reactivate AChE although seizures were controlled, suggesting additional anticonvulsant mechanisms of action. At concentrations (10(-4) to 5 x 10(-4) M) which did not significantly alter the spontaneous firing of action potentials (APs), MEM limited sustained high frequency repetitive firing (SRF) induced by depolarization of spinal cord (mouse and rat) and neocortical (mouse) neurons in monolayer-dissociated cell culture. In the same range of concentrations, ATS both limited SRF and suppressed spontaneous activity, suggesting toxicity. In addition, MEM and ATS reversibly produced use-dependent block of depolarizing responses to acetylcholine (ACh) applied by pressure ejection to spinal cord neurons. Thus, the anticonvulsant efficacy of MEM, with or without ATS, may have resulted from a combination of actions, including protection of AChE from inhibition by soman, limitation of high frequency firing of APs, and blockade of excitatory postsynaptic responses to ACh.
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PMID:Prophylactic and therapeutic efficacy of memantine against seizures produced by soman in the rat. 173 53

Cerebrospinal fluid (CSF) amino acid neurotransmitters, related compounds, and their precursors, choline levels, and acetylcholinesterase activity were measured in the CSF of patients with cerebellar ataxia during a randomized, double-blind, crossover, placebo-controlled clinical trial of physostigmine salicylate. The CSF gamma-aminobutyric acid, methionine, and choline levels, adjusted for age, were significantly lower in patients with cerebellar ataxia compared with controls. Physostigmine selectively reduced the level of CSF isoleucine and elevated the levels of phosphoethanolamine. No change occurred in CSF acetylcholinesterase activity and in the levels of plasma amino compounds in patients with cerebellar ataxia when compared with controls. Median ataxia scores did not statistically differ between placebo and physostigmine nor did functional improvement occur in any of the patients.
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PMID:Cerebrospinal fluid as a reflector of central cholinergic and amino acid neurotransmitter activity in cerebellar ataxia. 197 60

An equimolal single dose (1 mmole/kg) of leptophos or cyanofenphos was given orally to chickens to assay the clinical and biochemical neurotoxic effects of these two organophosphorus insecticides. Parathion and TOCP at 2 and 1000 mg/kg of chicken body weight were tested in the same manner as negative and positive neurotoxicants, respectively. Three birds of each of five groups tested were sacrificed 1,2,3,7,14,21 and 28 days after treatment and the brains were taken for the biochemical tests. Acetylcholinesterase (AChE) and neurotoxic esterase (NTE) activities were determined in the brain microsomal fractions. In addition, the AChE activity in the brain soluble fractions was measured. Clinical observations indicated that leptophos-, cyanofenphos- and parathion-treated chickens became acutely poisoned but recovered from the typical cholinergic signs in a day or two. However, about 10 to 15 days later leptophos- and cyanofenphos-treated chickens developed the characteristic leg weakness and unrecoverable ataxia seen in birds given TOCP. The biochemical results indicated that cyanofenphos followed by leptophos and parathion produced more in vivo AChE inhibition than that produced by TOCP in both chicken brain soluble and microsomal fractions. Results suggested that there are no correlations between the in vivo effect of TOCP, leptophos and cyanofenphos on AChE and phenyl valerate-total hydrolyzing activities and the ability of these chemicals to produce neuropathy in hens. The results obtained from this study of the in vivo effect of the tested compounds on chicken brain NTE activity present an acceptable correlation between the inhibition of this enzyme and the ability of these chemicals to induce neuropathy. The mechanism and explanation for this correlation are presented. The in vivo effect of the tested compounds on the chicken brain NTE activity was determined using the indirect and a new direct method. The data presented in this report suggested that the new direct technique of assaying NTE activity using 4-nitrophenyl valerate (4-NPV) as substrate, can be useful in the in vivo screening studies of organophosphates for their ability to induce neuropathy in hens.
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PMID:In vivo inhibition of chicken brain acetylcholinesterase and neurotoxic esterase in relation to the delayed neurotoxicity of leptophos and cyanofenphos. 243 15

The effects of desbromoleptophos, fenitrothion, and fenthion on brain acetylcholinesterase (AChE), brain neurotoxic esterase (NTE), and walking were investigated in immature chicks, below the age of organophosphorus ester-induced delayed neurotoxicity (OPIDN). Seventy-five milligrams per kilogram of the delayed neurotoxicant desbromoleptophos (DBL) and 100 mg/kg of the nonneurotoxicant fenithrothion (FTR) were given orally to 8-d-old chicks. Five milligrams per kilogram of the suspected neurotoxicant fenthion (FEN) was administered topically for 7 d, in 4 different age groups. Behavioral testing was performed for treated and control chicks on various days after treatment. Brain NTE and AChE assays were carried out for treated and control chicks on each day of behavioral testing. NTE and AChE inhibition were around 80 and 50%, respectively, 24 h after treatment, for the chicks treated with DBL. NTE returned to normal levels by 20 d and AChE by 6 d after treatment. FTR caused 56% AChE inhibition but not NTE inhibition 24 h after treatment. NTE inhibition for the FEN-treated chicks never exceeded 25% during the whole period of the experiment, whereas 65 and 54% inhibition of AChE was seen in two age groups. DBL and FEN significantly altered the gait of treated chicks, but the non-OPIDN-inducing FTR did not. FEN-treated chicks developed an atypical ataxia at the normal age for onset of sensitivity to OPIDN. Minimal NTE inhibition, long latency for the development of ataxia, and immaturity of the chicks at treatment distinguish FEN-induced functional deficits from classical OPIDN.
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PMID:Acute and delayed effects of fenthion in young chicks. 243 99

Certain biochemical and behavioral effects of carbaryl were investigated in chicks. Six-day-old birds received 100 mg/kg body weight (bw) per day carbaryl for 7 d. Brain acetylcholinesterase (AChE) and neuropathy target esterase (NTE) were measured at 24 h after the first, third, and fifth dose during the 1 wk of treatment, and then at d 1, 3, 6, 10, 20, 30, and 40 after the last dose. Gait analysis was evaluated on each posttreatment day. No significant reduction in both NTE and AChE activities was noticed throughout the experiment. However, carbaryl altered the locomotion of the chicks from d 1 until d 40 after last treatment. The stride length of the treated birds was significantly shorter than that of the controls. A significant increase in the stride width and sine of the angle of placement was noticeable throughout the period of the experiment. Thus, treated chicks walked with abnormal gait. Delayed ataxia and paralysis occurred 20 d after the last treatment and lasted until the end of the experiment or eventually death.
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PMID:Enzyme and behavioral changes in young chicks as a result of carbaryl treatment. 249 47

Organophosphate-induced delayed polyneuropathy (OPIDP) is initiated by inhibition/aging of more than 70-75% of neuropathy target esterase (NTE). Di-n-butyl-2,2-dichlorovinyl phosphate (DBDCVP) (1 mg/kg s.c.) inhibited 96%, 86% and 83% of NTE in brain, spinal cord and peripheral nerve, respectively, and induced a typical central peripheral distal axonopathy in hens. A lower dose (0.45 mg/kg s.c.) caused 90%, 83% and 54% NTE inhibition in the same organs; by contrast, hens developed a spastic ataxia with axonal degeneration in spinal cord but not in peripheral nerve. With a dose of 0.2 mg/kg s.c., a suprathreshold inhibition of NTE was produced in brain (78%) but not in spinal cord (56%) and peripheral nerve (33%) and no morphological or clinical signs of neuropathy developed in hens. With doses up to 4.0 mg/kg s.c., acetylcholinesterase (AChE) inhibition was similar throughout the nervous system. In vitro time-course inhibition studies showed a different sensitivity to DBDCVP of NTE from peripheral nerve (ka = 5.4 x 10(6)) relative to that from spinal cord (ka = 13.9 x 10(6)) or brain (ka = 20.6 x 10(6)). In vitro I50s of DBDCVP for AChE were similar in brain, spinal cord and peripheral nerve (11-17 nM). These data support the hypothesis that the critical target for initiation of OPIDP is located in the nerve fiber, possibly in the axon and also suggest that peripheral nerve NTE has a different sensitivity to DBDCVP than the brain enzyme.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:In vivo and in vitro regional differential sensitivity of neuropathy target esterase to di-n-butyl-2,2-dichlorovinyl phosphate. 261 60

Tri-o-cresyl phosphate (TOCP), which produces a delayed neurotoxic syndrome in humans and some animal species, was given to Fischer 344 (F344) male (18 week old) rats to determine if it causes biochemical, sensorimotor, and neuropathological effects. Animals were given TOCP by gavage in doses ranging from 10 to 100 mg of TOCP/kg daily for a period of 63 days. The rats were subjected to a series of neurobehavioral tests including fore- and hindlimb grip strength, motor activity, tremor, and latency to respond to a thermal stimulus. Central and peripheral nervous tissues were examined for damage characteristic of organophosphorous compound-induced delayed neurotoxicity (OPIDN). Brain neurotoxic esterase and acetylcholinesterase activities were inhibited in a dose-dependent fashion. A group of three chickens treated with 100 mg of TOCP/kg/day for 18 days was included as the positive control for enzymatic and histopathological alterations associated with OPIDN. Rats showed no consistent neurobehavioral changes or evidence of neuropathological damage in nervous tissues associated with treatment. In contrast, chickens treated with TOCP developed delayed neurotoxicity characterized by ataxia, which progressed to paralysis. These neurological changes included swelling, fragmentation, and degeneration of the axon and myelin in both central and peripheral nervous tissues. This study concludes that the F344 rat is not sensitive to the delayed neurotoxic effects of TOCP. When studying OPIDN in rats, care must be exercised in choosing the experimental animal since some strains, e.g., F344, are not sensitive.
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PMID:Lack of delayed neurotoxic effect after tri-o-cresyl phosphate treatment in male Fischer 344 rats: biochemical, neurobehavioral, and neuropathological studies. 335 6

The changes in brain acetylcholinesterase (AChE), acid phosphatase (APase), and 2',3'-cyclic nucleotide-3'-phosphohydrolase (CNP), and plasma butyrylcholinesterase (BuChE) activities were investigated in hens treated with a single, dermal dose (100-1000 mg/kg) of S,S,S-tri-n-butyl phosphorotrithioate (DEF). Three control groups consisted of hens left untreated, given a single, dermal dose of 500 mg/kg tri-o-cresyl phosphate (TOCP, positive control for organophophorous compound-induced delayed neurotoxicity), or 10 mg/kg O,O-diethyl O-4-nitrophenyl phosphorothioate (parathion, negative control). Brain AChE activity, determined 28 days after application, was significantly inhibited in hens given 500-1,000 mg/kg DEF and in TOCP- and parathion-treated hens. In contrast, brain APase and CNP activities were significantly higher in all treatments as compared with those of the untreated hens. Parathion, however, caused the least increase in these enzymatic activities as compared to DEF or TOCP. A single, dermal dose of DEF or TOCP also caused an initial decrease in plasma BuChE activity with maximum depression of enzymatic activity observed 1 to 7 days after administration. This decrease was dose dependent and the enzymatic activity showed partial recovery with time. Hens treated with single, dermal doses of DEF, ranging from 250 to 1000 mg/kg, developed ataxia which progressed to paralysis in some hens. Histopathologic examination revealed axon and myelin degeneration of the spinal cord and peripheral nerves of some hens. The severity and frequency of the neuropathologic lesions were dose dependent. Neurologic dysfunctions and neuropathologic lesions seen in DEF-treated hens were similar to those exhibited in TOCP-treated hens. While parathion produced acute cholinergic effects, it did not cause delayed neurotoxicity. The changes in brain and plasma enzymes are discussed in relation to their role in the pathogenesis of DEF-induced delayed neurotoxicity.
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PMID:Brain acetylcholinesterase, acid phosphatase, and 2',3'-cyclic nucleotide-3'-phosphohydrolase and plasma butyrylcholinesterase activities in hens treated with a single dermal neurotoxic dose of S,S,S-tri-n-butyl phosphorotrithioate. 395 29

The sensitivity of the mouse to organophosphorus-induced delayed neurotoxicity (OPIDN) has been investigated. One group of five mice received two single 1000-mg/kg po doses of tri-o-cresyl phosphate (TOCP) at a 21-day interval (on Days 1 and 21 of the study); a second group of five mice was given 225 mg/kg of TOCP daily for 270 days. A third group of five animals served as an untreated control. All animals were killed 270 days after the start of the experiment. Daily po dosing of 225 mg/kg TOCP caused a decrease in body weight gain, muscle wasting, weakness, and ataxia which progressed to severe hindlimb paralysis at termination. On the other hand, po administration of two single 1000-mg/kg doses of TOCP at a 21-day interval produced no observable adverse effects. Brain acetylcholinesterase (AChE) and neurotoxic esterase (NTE) activity were 35 and 10% of the control, respectively, in daily dosed animals while AChE and NTE in mice receiving two single 1000-mg/kg doses of TOCP were not significantly altered from the control group. Plasma butyrylcholinesterase activity was 12% of the control group in daily dosed animals. Hepatic microsomal enzyme activities of aniline hydroxylase and p-chloro-N-methylaniline demethylase and NADPH-cytochrome P-450 content in daily dosed animals were increased (141 to 161% of the control group) when compared to controls and mice receiving two single 1000-mg/kg doses of TOCP; the latter being not significantly different from each other. Degeneration of the axon and myelin of the spinal cord and sciatic fascicle were observed and were consistent with OPIDN. This study demonstrates that chronic dosing of TOCP produces OPIDN and induces hepatic microsomal enzyme activity in mice. It is concluded that while the mouse is susceptible to OPIDN, it is a less sensitive and a less appropriate test animal for studying this effect when compared to the adult hen.
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PMID:Characterization of delayed neurotoxicity in the mouse following chronic oral administration of tri-o-cresyl phosphate. 404 9


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