Gene/Protein Disease Symptom Drug Enzyme Compound
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Query: UMLS:C0031117 (peripheral neuropathy)
 10,577 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Neurotoxic effects of the combined exposure of rats to carbon disulphide (CS2) and ethanol (EtOH) were studied. Biochemical and ultrastructural evaluation of the central nervous system (CNS) and peripheral nervous system (PNS) was performed. Male Wistar rats were exposed to CS2 vapour (0.8 mg/l air) and to 10% alcohol in the drinking water for 8 months. EtOH elevated the increase in beta-glucuronidase activity caused by CS2 in the hippocampus and in the cerebral cortex. No effect on the high-affinity synaptosomal uptake of L-glutamate and GABA was observed and no marked ultrastructural changes in the tested brain regions were found. In the peripheral nerves CS2 alone evoked axonal degeneration whereas CS2 combined with EtOH caused disturbances in myelin. Ultrastructural changes preceded biochemical alterations in the PNS and the biochemical indicators of peripheral neuropathy such as beta-glucuronidase activity and cholesterol ester content were not significantly affected. It is suggested that CS2 and EtOH combined affect both PNS and CNS to a higher extent than each of these substances alone.
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PMID:Neurotoxic effects of the combined exposure to carbon disulphide and ethanol in rats. 373 35

This review examines the interaction of pyridoxal phosphate with select neuroendocrine and neuropharmacological systems and their health related therapeutic implications. Vitamin B6 and its vitamers can be involved in many interactions with a number of drugs as well as the actions of various endocrines and neurotransmitters. Nutritional deficiencies, particularly of vitamins and proteins, can affect the manner in which drugs undergo biotransformation and thus may modify the therapeutic efficacy of certain drugs. In addition to pyridoxine deficiency adversely affecting drug actions, improper supplementation with viatmin B6 can in some instances also adversely affect drug efficacy. A decrease by pyridocxine in the efficacy of levodopa used in the treatment of Parkinsonism is an example. The interrelationships and enzymatic interconversions amony pyridoxine vitamers, both phosphorylated and nonphosphorylated, are briefly discussed, particularly concerning their pharmacokinetic properties. The chronic administration of isoniazid for the prevention or treatment of tuberculosis can produce peripheral neuropathy which can be prevented by the concurrent administration of pyridoxine. An acute toxic overdose of isoniazid causes generalized convulsions, and the intravenous administration of pryidoxine hydrochloride prevents or stops these seizures. The acute ingestion of excessive monosodium glutamate will, in some persons, cause a group of symptoms, including headache, weakness, stiffness, and heartburn, collectively known as the "Chinese Restaurant Syndrome." These symptoms can be prevented by prior supplementation with vitamin B6. It is postulated that the intestinal absorption of zinc is facilitated by picolinic acid, a metabolite of tryptophan. The derivation of picolinic acid from tryptophan depends on the action of the enzyme kynureninase, which is dependent on pyridoxal phosphate. Therefore, the adequate absorption of zinc is indirectly dependent on an adequate supply of vitamin B6. The formation of pyridoxal phospate appears to be indirectly dependent on Zn2++ which activates pyridoxal kinase. Treatment with daily pyridoxine can reverse a state of depression induced in women who take oral contraceptives (OCs). 1 hypothesis to explain this effect is that the OC is somehow causing a deficiency of seroton serotonin in the brain and that the vitamin B6 helps to overcome this deficiency through the stimulation of 5-hydroxytryptophan decarboxylase by pyridoxal phosphate. In sum, the stimulation of 5-hydroxytryptophan decarboxylase by pyridoxal phosphate. In sum, pyridoxal phosphate in physiological concentrations seems to function as an endogenous "down regulator" of several receptor sites, including estrogen, progesterone, and androgen.
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PMID:Drug-pyridoxal phosphate interactions. 608 25

Zinc deficiency results in defective central nervous system function and in peripheral neuropathy. Calcium serves as second messenger in both pre- and postsynaptic membranes. Presynaptic uptake of calcium occurs via voltage-gated channels, whereas postsynaptic uptake occurs by way of a glutamate-activated channel, the N-methyl-D-aspartate (NMDA) receptor-channel. This study was designed to determine the effect of zinc status on calcium uptake by synaptic membranes prepared from guinea pigs deprived of zinc. Within each group of three guinea pigs, one animal was allowed to consume a low zinc (< 1 mg/kg) diet ad libitum (-ZN), one an adequate zinc (100 mg/kg) diet ad libitum (+AL), and one the adequate zinc diet restricted (+RF). When the -ZN guinea pig within a group developed clinical signs of deficiency, synaptosomes were prepared from brain cortices and calcium uptake measured by use of 45Ca. Both high potassium- and glutamate-stimulated calcium uptakes by synaptosomes from zinc-deficient guinea pigs were significantly lower than those of controls, with the glutamate-stimulated uptake 40% lower. In vitro addition of either magnesium or zinc resulted in lower uptake in synaptosomes from all dietary groups. Regardless of in vitro conditions, calcium uptake was impaired by zinc deficiency. The impaired function of calcium channels may explain the neurological disturbances observed in zinc-deficient animals.
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PMID:Low zinc status in guinea pigs impairs calcium uptake by brain synaptosomes. 790 39

Glutamate is a major neurotransmitter of fine afferent fibers to the spinal cord. Neuropeptides are also released by the same fibers. We explored, by quantitative immunocytochemistry, the effects of two experimental manipulations of peripheral nerves on the levels of these two classes of mediators. Glutamate levels in the superficial dorsal horn of rats increased after chronic loose ligature of the sciatic nerve, a model for hyperpathic peripheral neuropathy. A similar increase was observed acutely, after stimulation of C fibers, but not A fibers, in the sciatic nerve. In contrast, immunostaining for substance P and calcitonin gene-related peptide decreased in the same region with both manipulations. The decrease in immunocytochemical levels of peptides is in agreement with previous observations and can result from activity-related depletion. We propose that the increase in glutamate levels reflects differences in the regulation and kinetics of amino acid versus peptide neuromediators.
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PMID:Glutamate immunocytochemistry in the dorsal horn after injury or stimulation of the sciatic nerve of rats. 809 61

The dose-limiting toxicity of the chemotherapeutic agent vincristine is peripheral neuropathy, for which there is no established therapy. The amino acid glutamate has been proposed as a neuroprotectant for vincristine, but a full preclinical evaluation of its efficacy, safety and mechanism of action has been hampered by a lack of suitable animal models. We report the development of a Dark Agouti rat model of sensorimotor peripheral neuropathy, to investigate the neurotoxicity of cytotoxic drugs. Neuropathy was manifested as gait disturbance in 100% of vincristine-treated animals (n = 12), significant elevation of the tail-flick threshold (5.1 +/- 2 sec) and significantly impaired mean Rotarod times (55 +/- 41 sec) developing after administration of 1.5 mg/kg vincristine over 2 weeks. Among vincristine-treated animals supplemented p.o. with sodium glutamate (500 mg/kg/day in drinking water) from 24 hr before vincristine treatment, only one (8%, P = .01) developed gait disturbance, the tall-flick threshold was not significantly different from controls and the mean Rotarod score was 188 +/- 18 sec (P = .004). Glutamate thus significantly protected against both sensory and motor neuropathy. We observed no intrinsic neurotoxicity with glutamate and no interference with the cytotoxic efficacy of vincristine against a transplantable rat mammary adenocarcinoma grown s.c. in Dark Agouti rats. Our findings suggest that glutamate is likely to be a safe and effective neuroprotectant for patients receiving vincristine, and it warrants further clinical evaluation. The mechanism of this selective neuroprotection by glutamate remains to be elucidated. Our rat model may be of use in determining whether glutamate offers protection from other neurotoxic drugs.
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PMID:Glutamate ameliorates experimental vincristine neuropathy. 885 20

Feline immunodeficiency virus, like human immunodeficiency virus type 1, is a retrolentivirus causing neurological disease and immune suppression. Primary neurological complications, including human immunodeficiency virus encephalopathy and peripheral neuropathy, and neuropathological changes, including gliosis, neuronal injury and multinucleated giant cells, have been described for human immunodeficiency virus type 1 infection. Excitatory amino acids have been implicated as a basis for human immunodeficiency virus encephalopathy and the accompanying neuronal injury. Here, we test our hypothesis that feline immunodeficiency virus infection results in glial activation accompanied by enhanced glutamatergic activity, causing neuronal loss. Neurological signs observed in naturally and experimentally infected animals included ataxia, aggressivity and reduced motor activity. Neuropathological changes included gliosis, perivascular cuffing and neuronal dropout in the brains of both experimentally and naturally infected animals, but not in uninfected animals. Feline immunodeficiency virus antigen and genome were detected in the brains of all experimentally and naturally infected animals. Proton nuclear magnetic resonance spectroscopy revealed significantly increased glutamate levels in the feline immunodeficiency virus-infected animals. In contrast, glutamate decarboxylase levels in GABAergic neurons were reduced in feline immunodeficiency virus-infected animals. These findings provide direct in vivo evidence for enhanced glutamate levels in conjunction with neuronal loss, supporting the hypothesis of glutamate-mediated neurotoxicity as a major mechanism in the neuropathogenesis of retrolentiviral infections.
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PMID:Feline immunodeficiency virus causes increased glutamate levels and neuronal loss in brain. 913 Jul 96

A major toxic effect of the chemotherapeutic agents paclitaxel and cisplatin is peripheral neuropathy. We report the use of a rat model of cytotoxic neuropathy to evaluate the role of glutamate as a possible neuroprotectant for these two drugs. Neuropathy was manifest as gait disturbance in 100% of paclitaxel treated animals after 2 weeks and 100% of cisplatin treated animals after 8 weeks. Significant elevations of mean tail-flick threshold, a measure of sensory impairment, were observed in animals treated with both cytotoxics. Impaired rota-rod performance was observed in both light and dark with paclitaxel, indicating motor neuropathy. There was a trend towards impairment in the dark for cisplatin, suggesting proprioceptive loss. In cytotoxic treated animals supplemented with oral sodium glutamate (approx. 500 mg/kg/day in drinking water) from 24 h before chemotherapy, there was a significant delay in time to onset of gait disturbance allowing significantly higher mean doses to be tolerated. Mean tail-flick and rota-rod scores were unchanged from baseline for both drugs. Glutamate therefore protected against both sensory and motor neuropathy. Similar doses of glutamate did not impair the cytotoxic efficacy of paclitaxel or cisplatin against a transplantable rat mammary adenocarcinoma grown subcutaneously in rats. Our findings suggest that glutamate warrants clinical trial as a neuroprotectant in patients receiving paclitaxel or cisplatin.
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PMID:Amelioration of experimental cisplatin and paclitaxel neuropathy with glutamate. 1022 30

The concentration of plasma zinc is the generally accepted index of zinc status. Although low plasma zinc is an essential criterion of deficiency, alone it is inadequate. To supplement this index, we sought to determine the first limiting biochemical defect in animals fed zinc-deficient diets and concluded that the limiting function is associated with a posttranslational change in plasma membrane proteins. Among the signs of zinc deficiency in rats is a bleeding tendency associated with failure of platelet aggregation, a phenomenon that correlates with impaired uptake of Ca(2+) when stimulated. Zinc-deficient guinea pigs exhibit signs of peripheral neuropathy, and their brain synaptic vesicles exhibit impaired Ca(2+) uptake when they are stimulated with glutamate. Red cells from zinc-deficient rats show increased osmotic fragility associated with decreased plasma membrane sulfhydryl concentration. Both phenomena are readily reversed (2 d) by dietary zinc repletion. Volume recovery is dependent on Ca-dependent K channels and the sulfhydryl redox state. Both the impaired aggregation and calcium uptake of zinc-deficient platelets are corrected by in vitro incubation of blood with glutathione. Considering the fact that plasma membranes from several cell types show impaired function that is associated with a decreased rate of calcium uptake, it is postulated that a defect in calcium channels is the first limiting biochemical defect in zinc deficiency. The calcium uptake defect and consequent impaired second-messenger function likely results from an abnormal sulfhydryl redox state in the membrane channel protein.
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PMID:Role of zinc in plasma membrane function. 1080 56

The most frequent localization of amyloid in transthyretin (TTR) mutations is in the peripheral nerve, causing familial amyloidpolyneuropathy (FAP). It is generally accompanied by involvement of other organs such as the myocardium and kidney. To date, over 70 TTR point mutations have been reported in literature, with different phenotypes depending on the location of the mutation in the TTR gene. This paper deals with a point mutation in exon 2 position 47 of the TTR gene, encoding the substitution of glycine with glutamate. The mutation was found in an Italian family with 5 patients over 3 generations. The phenotype was characterised by peripheral neuropathy and autonomic dysfunction, associated in some patients with cardiomyopathy and renal involvement. The symptoms were very severe and the patients did not survive long, thus suggesting the aggressive nature of the pathological process. Moreover, in the succeeding generations of this family, there was genetic anticipation in the age of onset of the disease.
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PMID:Familial amyloid polyneuropathy with genetic anticipation associated to a gly47glu transthyretin variant in an Italian kindred. 1200 Jan 96

Riluzole is a presynaptic inhibitor of glutamate release with neuroprotective properties. In order to evaluate the effects of riluzole on motor activity in post-traumatic peripheral neuropathy (PTPN), the sciatic nerve of Wistar male rats was exposed monolaterally and subjected to crushing for one min by a surgical forceps. Animals received an intraperitoneal treatment with riluzole (2, 4 or 8 mg/kg per day), diclofenac (5, 10 or 20 mg/kg) or with vehicle for 3 days. Motor activity and coordination was evaluated in a circular open field and in the rotorod test. The treatment with riluzole stimulated ambulation in PTPN rats and improved their motor performance and coordination. The effect of treatment with riluzole on locomotor activity was greater than that of treatment with diclofenac and was dose-dependent. Furthermore, in contrast to vehicle- and diclofenac-treated rats, animals treated with riluzole showed a long-lasting improvement of locomotor activity as it was assessed 7 days after the end of treatment. These findings suggest that riluzole may improve motor performance in PTPN, and this does not depend on its antinociceptive activity. Its neuroprotective properties are possibly involved in this effect.
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PMID:Riluzole restores motor activity in rats with post-traumatic peripheral neuropathy. 1501 29


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