Alcoholic Neuropathy: Involvement of Multifaceted Signalling Mechanisms.

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.

Anti-inflammatory and anti-hyperalgesic effect of all-trans retinoic acid in carrageenan-induced paw edema in Wistar rats: involvement of peroxisome proliferator-activated receptor-ß/δ receptors.

OBJECTIVE: In this study, we investigated the role of peroxisome proliferator-activated receptors (PPAR)-ß/δ receptors in carrageenan-induced inflammation and in the anti-inflammatory effects of all-trans retinoic acid (ATRA). MATERIALS AND METHODS: The λ-carrageenan (0.1 ml of 1% w/v) was injected into intra-plantar (i.pl.) region of the hind paw to produce acute inflammation. Paw volume was measured by using the mercury plethysmography. Further, mechanical and thermal hyperalgesia (TH) were assessed by using the dynamic plantar aesthesiometer and plantar test apparatus, respectively. In addition, markers of oxido-nitrosative stress were assessed spectrophotometrically in the hind paw tissue 5 h post-carrageenan. RESULTS: An i.pl injection of carrageenan has produced a marked mechanical hyperalgesia (MH) and TH in ipsilateral paw, which was associated with significant elevated oxido-nitrosative stress. Treatment with ATRA (5 mg/kg/p.o/4 days) and GW0742, a selective PPAR-ß/δ receptor agonist (0.1 mg/kg/i.p/4 days), significantly decreased the paw volume, mechanical and TH as compared to vehicle control. Administration of GSK0660, selective PPAR-ß/δ receptor antagonist, at a dose of (0.3 mg/kg/i.p/4 days), did not produce a significant effect on carrageenan-induced paw edema, MH and TH. However, co-administration of GSK0660 (0.3 mg/kg/i.p/4 days) along with both ATRA (5 mg/kg/p.o/4 days) and GW0742 (0.1 mg/kg/i.p/4 days), significantly reverse the decreased paw edema, MH, and TH. These observed ameliorative effects on inflammatory pain symptoms are correlated with the extent of reduction of oxido-nitrosative stress. CONCLUSION: From above findings, it can be concluded that ATRA exerts anti-inflammatory and anti-hyperalgesic effect, possibly through activation of PPAR-ß/δ and subsequent reduction of oxido-nitrosative stress.

Possible involvement of caveolin in attenuation of cardioprotective effect of ischemic preconditioning in diabetic rat heart.

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.