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1.
Curr Mol Pharmacol ; 14(1): 2-10, 2021.
Article in English | MEDLINE | ID: mdl-32394849

ABSTRACT

BACKGROUND: Alcoholic neuropathy is a chronic disorder caused by the excessive consumption of alcohol. Damage to the nerves results in unusual sensations in the limbs, decreased mobility and loss of some body functions. OBJECTIVE: Alcohol is considered a major cause for exclusively creating the debilitating condition of the neuropathic state. This review critically examines the key mediators involved in the pathogenesis of alcoholic neuropathy and the targets, which, upon selective inhibition, alleviate the progression of alcoholic neuropathy. METHODS: A thorough study of research and review articles available on the internet from PubMed, MEDLINE, and concerned sites was performed on alcoholic neuropathy. RESULT: Impairment in axonal transportation is quite common with the progression of alcoholic neuropathy. Nutritional deficiencies lead to axonal neuropathies that escalate a variety of complications that further worsen the state. PKC and PKA play a significant role in the pathogenesis of alcoholic neuropathy. PKC plays a marked role in modulating NMDA receptor currents, manifesting excitations in neurons. MMPs are involved in the number of pathologies that destroy the CNS and reduction in the level of endogenous antioxidants like α-tocopherol, vitamin E with ethanol, promotes oxidative stress by generating free radicals and lipid peroxidation. CONCLUSION: Oxidative stress is implicated in the activation of MMPs, causing disruption in the blood-brain barrier, the latter are involved in the trafficking and passage of molecules in and out of the cell. Chronic alcohol consumption leads to the downregulation of CNS receptors, consequently precipitating the condition of alcoholic neuropathy.


Subject(s)
Alcoholic Neuropathy/metabolism , Ethanol/adverse effects , Animals , Antioxidants/metabolism , Cytokines/metabolism , Dopamine/metabolism , Endocannabinoids/metabolism , Ethanol/metabolism , Free Radicals/metabolism , Humans , Lipid Peroxidation , Oxidative Stress , Protein Kinases/metabolism , Signal Transduction , Tocopherols/metabolism , Vitamin E/metabolism
2.
BMC Cardiovasc Disord ; 11: 43, 2011 Jul 12.
Article in English | MEDLINE | ID: mdl-21745415

ABSTRACT

BACKGROUND: Nitric oxide (NO) has been noted to produce ischemic preconditioning (IPC)-mediated cardioprotection. Caveolin is a negative regulator of NO, which inhibits endothelial nitric oxide synthase (eNOS) by making caveolin-eNOS complex. The expression of caveolin is increased during diabetes mellitus (DM). The present study was designed to investigate the involvement of caveolin in attenuation of the cardioprotective effect of IPC during DM in rat. METHODS: Experimental DM was induced by single dose of streptozotocin (50 mg/Kg, i.p,) and animals were used for experiments four weeks later. Isolated heart was mounted on Langendorff's apparatus, and was subjected to 30 min of global ischemia and 120 min of reperfusion. IPC was given by four cycles of 5 min of ischemia and 5 min of reperfusion with Kreb's-Henseleit solution (K-H). Extent of injury was measured in terms of infarct size by triphenyltetrazolium chloride (TTC) staining, and release of lactate dehydrogenase (LDH) and creatin kinase-MB (CK-MB) in coronary effluent. The cardiac release of NO was noted by measuring the level of nitrite in coronary effluent. RESULTS: IPC- induced cardioprotection and release of NO was significantly decreased in diabetic rat heart. Pre-treatment of diabetic rat with daidzein (DDZ) a caveolin inhibitor (0.2 mg/Kg/s.c), for one week, significantly increased the release of NO and restored the attenuated cardioprotective effect of IPC. Also perfusion of sodium nitrite (10 µM/L), a precursor of NO, significantly restored the lost effect of IPC, similar to daidzein in diabetic rat. Administration of 5-hydroxy deaconate (5-HD), a mito KATP channel blocker, significantly abolished the observed IPC-induced cardioprotection in normal rat or daidzein and sodium nitrite perfused diabetic rat heart alone or in combination. CONCLUSIONS: Thus, it is suggested that attenuation of the cardioprotection in diabetic heart may be due to decrease the IPC mediated release of NO in the diabetic myocardium, which may be due to up -regulation of caveolin and subsequently decreased activity of eNOS.


Subject(s)
Caveolin 1/physiology , Diabetes Mellitus, Experimental/metabolism , Diabetes Mellitus, Experimental/prevention & control , Ischemic Preconditioning, Myocardial/methods , Myocardial Ischemia/metabolism , Myocardial Ischemia/prevention & control , Animals , Caveolin 1/antagonists & inhibitors , Caveolin 1/biosynthesis , Diabetes Mellitus, Experimental/enzymology , Female , Male , Myocardial Ischemia/enzymology , Myocardium/enzymology , Myocardium/metabolism , Myocardium/pathology , Nitric Oxide/antagonists & inhibitors , Nitric Oxide/biosynthesis , Nitric Oxide/metabolism , Nitric Oxide Synthase Type III/antagonists & inhibitors , Nitric Oxide Synthase Type III/biosynthesis , Rats , Rats, Wistar
3.
Indian J Pharmacol ; 42(4): 219-23, 2010 Aug.
Article in English | MEDLINE | ID: mdl-20927246

ABSTRACT

OBJECTIVE: The cardioprotective potential of human recombinant erythropoietin (alpha) (Epo) against ischemia-reperfusion-induced injury is well known. But, the underlying mechanisms are not well elucidated. The aim of this study was to characterize the mechanism involved in the cardioprotective effect of Epo-induced preconditioning in isolated rat heart. MATERIALS AND METHODS: The heart was mounted on a Langendorff apparatus. After 10 min of stabilization, four cycles of ischemic preconditioning (IPC) were given followed by 30 min of global ischemia and 120 min of reperfusion. Epo preconditioning was induced by four cycles of 5-min perfusion of K-H solution containing Epo (1.0 U/ml) followed by 5 min perfusion with K-H solution. Myocardial infarct size was estimated macroscopically using the triphenyltetrazolium chloride staining technique. The extent of myocardial injury was measured by release of lactate dehydrogenase and creatine kinase-MB in the coronary effluent. RESULTS: The present study demonstrates that Epo preconditioning was almost as effective as IPC. Administration of Wortmannin (100 nM), a PI-3K inhibitor, or Chelerythrine (1 µM), a protein kinase-C (PKC) inhibitor, or AG490 (5 µM), a JAK-2 inhibitor, significantly attenuated the cardioprotective effects of Epo-induced preconditioning. CONCLUSION: Our result suggest that the cardioprotective potential of Epo-induced preconditioning in isolated rat heart was due to an interplay of the JAK-2, PI-3K and PKC pathways. Inhibition of any one of the three pathways was sufficient to block the cardioprotective effect of Epo-induced preconditioning in isolated rat heart.

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