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

Noradrenergic locus coeruleus (LC) is involved in pain regulation. We studied whether response properties of LC neurons or coeruleospinal antinociception are changed 10-14 days following development of experimental neuropathy. Experiments were performed in spinal nerve-ligated, sham-operated and unoperated male rats under sodium pentobarbital anesthesia. Recordings of LC neurons indicated that responses evoked by noxious somatic stimulation were enhanced in nerve-injured animals, while the effects of nerve injury on spontaneous activity or the response to noxious visceral stimulation were not significant. Microinjection of glutamate into the central nucleus of the amygdala produced a dose-related inhibition of the discharge rate of LC neurons in nerve-injured animals but no significant effect on discharge rates in control groups. Assessment of the heat-induced hind limb withdrawal latency indicated that spinal antinociception induced by electrical stimulation of the LC was significantly weaker in nerve-injured than control animals. The results indicate that peripheral neuropathy induces bidirectional changes in coeruleospinal inhibition of pain. Increased responses of LC neurons to noxious somatic stimulation are likely to promote feedback inhibition of neuropathic hypersensitivity, while the enhanced inhibition of the LC from the amygdala is likely to suppress noradrenergic pain inhibition and promote neuropathic pain. It is proposed that the decreased spinal antinociception induced by direct stimulation of the LC may be explained by pronociceptive changes in the non-noradrenergic systems previously described in peripheral neuropathy. Furthermore, we propose the hypothesis that emotions processed by the amygdala enhance pain due to increased inhibition of the LC in peripheral neuropathy.
 ...
PMID:Influence of peripheral nerve injury on response properties of locus coeruleus neurons and coeruleospinal antinociception in the rat. 1744 89

Peripheral neurotoxicity is a major complication associated with the use of chemotherapeutic agents such as platinum compounds, taxanes and vinca alkaloids. The neurotoxicity of chemotherapy depends not only on the anticancer agent(s) used, the cumulative dose and the delivery method, but also on the capacity of the nerve to cope with the nerve-damaging process. The sensory and motor symptoms and signs of neurotoxicity are disabling, and have a significant impact on the quality of life of cancer patients. Moreover, the risk of cumulative toxicity may limit the use of highly effective chemotherapeutic agents. Therefore, prophylaxis and treatment of peripheral neurotoxicity secondary to chemotherapy are major clinical issues. Acetyl-L-carnitine (ALC), the acetyl ester of L-carnitine, plays an essential role in intermediary metabolism. Some of the properties exhibited by ALC include neuroprotective and neurotrophic actions, antioxidant activity, positive actions on mitochondrial metabolism, and stabilisation of intracellular membranes. ALC has demonstrated efficacy and high tolerability in the treatment of neuropathies of various aetiologies, including chemotherapy-induced peripheral neuropathy (CIPN). In several experimental settings, the prophylactic administration of ALC prevented the occurrence of peripheral neurotoxicity commonly induced by chemotherapeutic agents. In animal models of CIPN, ALC administration promoted the recovery of nerve conduction velocity, restored the mechanical nociceptive threshold, and induced analgesia by up-regulating the expression of type-2 metabotropic glutamate receptors in dorsal root ganglia. These results, plus the favourable safety profile of ALC in neuropathies of other aetiologies, have led to the effects of ALC on CIPN being investigated in cancer patients. Preliminary results have confirmed the reasonably good tolerability profile and the efficacy of ALC on CIPN. The present studies support the use of ALC in cancer patients with persisting neurotoxicity induced by paclitaxel or cisplatin treatment.
 ...
PMID:Acetyl-L-carnitine for the treatment of chemotherapy-induced peripheral neuropathy: a short review. 1769 92

Familial transthyretin amyloidosis (ATTR), caused by mutant transthyretin deposition, is mainly characterized by peripheral neuropathy, autonomic dysfunction, and cardiomyopathy. There are few reports among the Chinese population. We previously described the TTR mutation (Val30Ala) in the first Hong Kong Chinese family with ATTR. In this study, we report the progress of this family and describe another three unrelated Chinese kinships newly diagnosed with ATTR. The second proband presented mainly with peripheral neuropathy, and genetic analysis of the TTR gene showed alanine-to-serine substitution at amino acid 97. The third proband complained of autonomic dysfunction, and a novel missense mutation of glycine-to-glutamate substitution at amino acid 67 was found. The fourth patient presented with peripheral neuropathy and diastolic cardiomyopathy with the mutation threonine-to-lysine at codon 59. Diagnosis was delayed for more than 2 years. We performed DNA analysis in 46 subjects and detected a total of 21 patients, including the four probands, affected with ATTR, 15 of whom were still at a symptom-free stage at the time of writing. We conclude that ATTR remains largely underdiagnosed in the Chinese population. A high clinical suspicion is crucial for a timely diagnosis and can thus lead to a significant decrease in morbidity and mortality.
 ...
PMID:Identification of a novel TTR Gly67Glu mutant and the first case series of familial transthyretin amyloidosis in Hong Kong Chinese. 1796 90

Spinocerebellar ataxia type 1 (SCA1) is a late onset neurodegenerative disease characterized by cerebellar ataxia with variable degrees of ophthalmoplegia, pyramidal and extrapyramidal signs, and peripheral neuropathy. SCA1 is caused by the toxic effects triggered by an expanded polyglutamine (polyQ) within the protein ataxin 1 (Atxn1) resulting in variable degrees of neurodegeneration in the cerebellum, brainstem, and spinocerebellar tracts. The toxic gain-of-function mechanisms by which the polyQ expansion induces neuronal cell death are not fully understood and no effective therapies are yet available. Alterations in transcriptional regulation, calcium homeostasis, glutamate signaling/excitotoxicity, and impaired protein degradation are few recurrent events in the pathogenesis in SCA1. However, elucidating the molecular routes regulated by ataxin 1 is leading to the discovery of new pathways that are implicated in SCA1. This suggests that dominant-negative effects exerted by the mutant protein, rather than just gain-of-function mechanisms, might be also implicated in SCA1 pathogenesis. The challenge now is to determine how these responses account for the clinical manifestation of the disease symptoms and, ultimately, how this knowledge can be translated into the development of therapeutic strategies. Herein, we review the phenotype and most recent advances in our understanding of the physiopathological mechanisms of neurodegeneration in SCA1.
 ...
PMID:Clinical, genetic, molecular, and pathophysiological insights into spinocerebellar ataxia type 1. 1841 61

Peripheral neuropathy has been associated with structural and functional changes of the amygdala, a key player in emotions. Here we study whether peripheral neuropathy influences pain regulation by the amygdala. For this purpose, we determined discharge rates of presumably pro- and antinociceptive pain-regulatory neurons in the rostral ventromedial medulla (RVM) following microinjection of various glutamatergic compounds into the central nucleus of the amygdala. RVM neurons were recorded in pentobarbitone-anesthetized rats with a peripheral nerve injury or sham-operation. In a separate behavioral experiment, we determined whether the influence of amygdaloid administration of a glutamatergic compound on affective pain-related behavior, as assessed by an aversive place-conditioning test, is changed by neuropathy. While glutamate or an NMDA receptor antagonist in the amygdala failed to induce marked changes in discharge rates of RVM cells, amygdaloid administration of DHPG, a group I metabotropic glutamate receptor (mGluR) agonist acting on mGluR(1) and mGluR(5), increased discharge rates of presumably pronociceptive RVM ON-cells in nerve-injured but not sham-operated animals. This pronociceptive effect of DHPG was reversed by MPEP (mGluR(5) antagonist) and CPCCOEt (mGluR(1) antagonist). CHPG, an mGluR(5) agonist, failed to influence ON-cell activity and DHPG failed to influence activity of presumably antinociceptive RVM OFF-cells. Amygdaloid administration of DHPG increased and that of CPCCOEt decreased affective pain-related behavior in nerve-injured animals. The results suggest that following nerve injury, the amygdaloid group I mGluR, particularly subtype mGluR(1), has an enhanced pronociceptive effect providing a potential mechanism for emotional enhancement of pain in peripheral neuropathy.
 ...
PMID:Enhanced pronociception by amygdaloid group I metabotropic glutamate receptors in nerve-injured animals. 1909 88

Toxic peripheral neuropathy is still a significant limiting factor for chemotherapy with paclitaxel (PAC), although glutamate and its closely related amino acid glutamine were claimed to ameliorate PAC neurotoxicity. This pilot trial aimed to evaluate the role of glutamate supplementation for preventing PAC-induced peripheral neuropathy in a randomized, placebo-controlled, double-blinded clinical and electro-diagnostic study. Forty-three ovarian cancer patients were available for analysis following six cycles of the same PAC-containing regimen: 23 had been supplemented by glutamate all along the treatment period, at a daily dose of three times 500 mg (group G), and 20 had received a placebo (group P). Patients were evaluated by neurological examinations, questionnaires and sensory-motor nerve conduction studies. There was no significant difference in the frequency of signs or symptoms between the two groups although neurotoxicity symptoms presented mostly with lower scores of severity in group G. However, this difference reached statistical significance only with regard to reported pain sensation (P = 0.011). Also the frequency of abnormal electro-diagnostic findings showed similarity between the two groups (G: 7/23 = 30.4%; P: 6/20 = 30%). This pilot study leads to the conclusion that glutamate supplementation at the chosen regimen fails to protect against peripheral neurotoxicity of PAC.
 ...
PMID:Long-term glutamate supplementation failed to protect against peripheral neurotoxicity of paclitaxel. 1967 75

Chemotherapy is the most common method to treat cancer. The use of certain antineoplastic drugs, however, is associated with the development of peripheral neuropathy that can be dose-limiting. Excitotoxic glutamate release, leading to excessive glutamatergic neurotransmission and activation of N-methyl-D-aspartate (NMDA) receptors, is associated with neuronal damage and death in several nervous system disorders. N-Acetyl-aspartyl-glutamate (NAAG) is an abundant neuropeptide widely distributed in the central and peripheral nervous system which is physiologically hydrolyzed by the enzyme glutamate carboxypeptidase into N-Acetyl-aspartyl (NAA) and glutamate. Pharmacological inhibition of glutamate carboxypeptidase results in decreased glutamate and increased endogenous NAAG and has been shown to provide neuroprotection in several preclinical models. Here, we report the neuroprotective effect of an orally available glutamate carboxypeptidase inhibitor on three well-established animal models of chemotherapy (cisplatin, paclitaxel, bortezomib)-induced peripheral neuropathy. In all cases, glutamate carboxypeptidase inhibition significantly improved the chemotherapy-induced nerve conduction velocity deficits. In addition, morphological and morphometrical alterations induced by cisplatin and bortezomib in dorsal root ganglia (DRG) were improved by glutamate carboxypeptidase inhibition. Our data support a novel approach for the treatment of chemotherapy-induced peripheral neuropathy.
 ...
PMID:Glutamate carboxypeptidase inhibition reduces the severity of chemotherapy-induced peripheral neurotoxicity in rat. 1976 34

Glutamate neurotransmission is highly regulated, largely by glutamate transporters. In the spinal cord, the glutamate transporter GLT-1 is primarily responsible for glutamate clearance. Downregulation of GLT-1 can occur in activated astrocytes, and is associated with increased extracellular glutamate and neuroexcitation. Among other conditions, astrocyte activation occurs following repeated opioids and in models of chronic pain. If GLT-1 downregulation occurs in these states, GLT-1 could be a pharmacological target for improving opioid efficacy and controlling chronic pain. The present studies explored whether daily intrathecal treatment of rats with ceftriaxone, a beta-lactam antibiotic that upregulates GLT-1 expression, could prevent development of hyperalgesia and allodynia following repeated morphine, reverse pain arising from central or peripheral neuropathy, and reduce glial activation in these models. Ceftriaxone pre-treatment attenuated the development of hyperalgesia and allodynia in response to repeated morphine, and prevented associated astrocyte activation. In a model of multiple sclerosis (experimental autoimmune encephalomyelitis; EAE), ceftriaxone reversed tactile allodynia and halted the progression of motor weakness and paralysis. Similarly, ceftriaxone reversed tactile allodynia induced by chronic constriction nerve injury (CCI). EAE and CCI each significantly reduced the expression of membrane-bound, dimerized GLT-1 protein in lumbar spinal cord, an effect normalized by ceftriaxone. Lastly, ceftriaxone normalized CCI- and EAE-induced astrocyte activation in lumbar spinal cord. Together, these data indicate that increasing spinal GLT-1 expression attenuates opioid-induced paradoxical pain, alleviates neuropathic pain, and suppresses associated glial activation. GLT-1 therefore may be a therapeutic target that could improve available treatment options for patients with chronic pain.
 ...
PMID:Spinal upregulation of glutamate transporter GLT-1 by ceftriaxone: therapeutic efficacy in a range of experimental nervous system disorders. 2054 13

Wernicke encephalopathy is a neurological disorder commonly observed in chronic alcohol abuse, in patients with AIDS, and in other conditions of compromised nutritional status. The underlying cause of the disorder is thiamine deficiency. The present review highlights data focusing on alcohol-thiamine interactions and their relationship to the pathogenesis of Wernicke encephalopathy. Recent findings on the effects of alcohol on thiamine absorption and storage and on thiamine phosphorylation to the enzyme co-factor form (thiamine diphosphate) are discussed with regard to the postulated "biochemical lesion" of Wernicke encephalopathy. Also discussed are new findings on the molecular genetics of the thiamine-dependent enzyme transketolase in patients with Wernicke encephalopathy. A discussion of the hypotheses regarding the mechanisms underlying the phenomenon of selective neuronal cell death observed in this disorder including cerebral energy deficit, focal lactic acidosis, glutamate excitotoxicity, increased expression of immediate-early genes, free radicals and perturbations of the blood-brain barrier are presented. Finally, the possible role of thiamine deficiency in alcoholic peripheral neuropathy is reviewed.
 ...
PMID:Alcohol-thiamine interactions: an update on the pathogenesis of Wernicke encephalopathy. 2057 93

A substantial body of data was reported between 1984 and 2000 demonstrating that the neuropeptide N-acetylaspartylglutamate (NAAG) not only functions as a neurotransmitter but also is the third most prevalent transmitter in the mammalian nervous system behind glutamate and GABA. By 2005, this conclusion was validated further through a series of studies in vivo and in vitro. The primary enzyme responsible for the inactivation of NAAG following its synaptic release had been cloned, characterized and knocked out. Potent inhibitors of this enzyme were developed and their efficacy has been extensively studied in a series of animal models of clinical conditions, including stroke, peripheral neuropathy, traumatic brain injury, inflammatory and neuropathic pain, cocaine addiction, and schizophrenia. Considerable progress also has been made in defining further the mechanism of action of these peptidase inhibitors in elevating synaptic levels of NAAG with the consequent inhibition of transmitter release via the activation of pre-synaptic metabotropic glutamate receptor 3 by this peptide. Very recent discoveries include identification of two different nervous system enzymes that mediate the synthesis of NAAG from N-acetylaspartate and glutamate and the finding that one of these enzymes also mediates the synthesis of a second member of the NAAG family of neuropeptides, N-acetylaspartylglutamylglutamate.
 ...
PMID:Advances in understanding the peptide neurotransmitter NAAG and appearance of a new member of the NAAG neuropeptide family. 2164 97


<< Previous 1 2 3 4 5 Next >>