Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:2.7.7.49 (reverse transcriptase)
 31,746 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Whereas small-fibre sensory neuropathies might ultimately lead to cell death and loss of sensation, they first progress through a phase, which might last for years, characterized by the presence of analgesia-resistant neuropathic dysesthesias and pain. Much previous research has addressed these two phases as separate phenomena mediated by presumably discrete biochemical mechanisms. We hypothesized that activity in signalling pathways that ultimately lead to apoptosis plays a critical role in the generation of neuropathic pain, before death of sensory neurons becomes apparent. We have tested the hypothesis that activator and effector caspases, defining components of programmed cell death (apoptosis) signalling pathways, also contribute to pain-related behaviour in animals with small-fibre peripheral neuropathies and that the death receptor ligand, tumour necrosis factor-alpha, and its downstream second messenger, ceramide, also produce pain-related behaviour via this mechanism. In two models of painful peripheral neuropathy, HIV/AIDS therapy (induced by the nucleoside reverse transcriptase inhibitor, dideoxycytidine), and cancer chemotherapy (induced by vincristine) peripheral neuropathy, and for pain-related behaviour induced by tumour necrosis factor-alpha and its second messenger, ceramide, inhibition of both activator (1, 2, 8 and 9) and effector (3) caspases attenuates neuropathic pain-related behaviour, although has no effect in streptozotocin-diabetic neuropathy and control rats. We conclude that during a latent phase, before apoptotic cell death is manifest, the caspase signalling pathway can contribute to pain in small-fibre peripheral neuropathies, and that inflammatory/immune mediators also activate these pathways. This suggests that these pathways are potential targets for novel pharmacological agents for the treatment of inflammatory as well as neuropathic pain.
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PMID:Caspase signalling in neuropathic and inflammatory pain in the rat. 1557 43

This study aimed to correlate the onset of functional deficits in diabetic neuropathy with changes in gene expression in rat dorsal root ganglia (DRG). After 1, 4, or 8 weeks of streptozotocin-induced diabetes, sensory and motor nerve conduction velocities (NCV) were measured as an indicator of neuropathy and changes in gene expression were measured using Affymetrix oligonucleotide microarrays. No significant changes in NCV were found after 1 week of diabetes, but after 4 and 8 weeks, there was a significant reduction in both sensory and motor NCV. Global gene expression changes in diabetic rat DRG were evident from principal component analysis of microarray data after 1, 4, and 8 weeks. Expression changes in individual genes were relatively small in line with a gradual degenerative neuropathy indirectly resulting from diabetes. Sets of differentially expressed genes have been identified and quantitative reverse transcriptase-polymerase chain reaction has been used to confirm the microarray data for several genes. Gene ontology overrepresentation analysis was performed on the microarray data to identify biologic processes altered in diabetic DRG. The genes identified in this study may be responsible for causing the functional deficits and suggest pathways/processes that require further investigation as possible targets for therapeutic intervention.
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PMID:Identification of changes in gene expression in dorsal root ganglia in diabetic neuropathy: correlation with functional deficits. 1682 59

Peripheral neuropathies are extremely heterogeneous nosological entities. One of the most common symptoms is pain, the underlying mechanisms of which are numerous and complex. Inflammation, reparative processes, and anatomical and gene expression alterations lead to chronic pain, the persistence of which is sustained by peripheral and central sensitisation mechanisms. Treatment of peripheral neuropathies is targeted to its symptomatic and aetiological features. For pain relief, several types of drugs may be used, notably antidepressants (e.g. tricyclic antidepressants, selective serotonin reuptake inhibitors, and both serotonin and noradrenaline [norepinephrine] reuptake inhibitors), antiepileptic drugs (e.g. carbamazepine, phenytoin, lamotrigine, valproic acid, gabapentin, topiramate and pregabalin), NSAIDs and opioid analgesics. Aetiological therapy is aimed at modifying the pathophysiological mechanisms underlying the neuropathy, some of which are common in different neuropathic conditions. Certain drugs are known to exert more than one action on different pathophysiological mechanisms. This is the case with acetyl-L-carnitine (ALC), which can be considered both a symptomatic therapy that can be used in any kind of painful neuropathy, and an aetiological therapy, at least in diabetic neuropathy and neuropathies induced by nucleoside reverse transcriptase inhibitors and cancer chemotherapeutic agents. ALC acts via several mechanisms, inducing regeneration of injured nerve fibres, reducing oxidative stress, supporting DNA synthesis in mitochondria, and enhancing nerve growth factor concentrations in neurons.
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PMID:Overview on pathophysiology and newer approaches to treatment of peripheral neuropathies. 1769 88

A clearer understanding of the mechanisms underlying the development and progression of diabetic neuropathy is likely to indicate new directions for the treatment of this complication of diabetes. In the present study we investigated the expression of cannabinoid CB(1) receptors in models of diabetic neuropathy. PC12 cells were differentiated into a neuronal phenotype with nerve growth factor (NGF) (50 ng/ml) in varying concentrations of glucose (5.5-50 mM). CB(1) receptor expression was studied at the mRNA level by reverse transcriptase-polymerase chain reaction (RT-PCR) and at the protein level via immunohistochemical and Western blot analysis. CB(1) expression was also compared in dorsal root ganglia (DRG) removed from streptozotocin-induced diabetic rats versus control animals. Total neurite length induced by NGF was reduced in cells cultured in 20 to 50 mM glucose at day 6 (P < 0.01 versus 5.5 mM; n = 6). Cell viability assays conducted in parallel on day 6 confirmed that the total cell numbers were not significantly different among the various glucose concentrations (P = 0.86; n = 12). RT-PCR, immunohistochemical, and Western blot analysis all revealed down-regulation of the CB(1) receptor in cells treated with high glucose (P < 0.05; n = 4-5 for each), and in DRG removed from diabetic rats compared with controls (P < 0.01; n = 5 for immunohistochemistry, and n = 3 for Western blot). These results suggest that high glucose concentrations are associated with decreased expression of CB(1) receptors in nerve cells. Given the neuroprotective effect of cannabinoids, a decline in CB(1) receptor expression may contribute to the neurodegenerative process observed in diabetes.
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PMID:Expression of cannabinoid CB1 receptors in models of diabetic neuropathy. 1770 1