Role For Pkc Activation

PKC includes a superfamily of isoenzymes, many of which are activated by 1,2-diacylglycerol in the presence of phosphatidylserine. PKC isoforms phosphorylate a wide variety of intracellular target proteins and have multiple functions in signal trans-duction-mediated cellular regulation. The role for PKC in the pathogenesis of PDN has been reviewed in detail (80). PKC is activated in vasa nervorum of diabetic rats (81), and vessel-rich epineurial vessels of diabetic mice (82). PKC has been reported decreased (83), unchanged (81), or increased (84) in the diabetic rat nerve, and decreased in endoneurial tissue of diabetic mouse nerve (82). PKC activity was markedly reduced in DRG neurons of the wild-type STZ-diabetic mice and furthermore, in the diabetic mice overexpressing human AR (85). These changes were associated with reduced expression and activity of the membrane PKC-a isoform that translocated to cytosol. The membrane PKC-IIP isoform expression was increased in AR-overexpressing diabetic transgenic mice, but not in the wild-type mice (85).

The experimental evidence obtained with various PKC inhibitors as well as the dia-cylglycerol complexing agent cremophor by several groups (81,86-88) suggests the detrimental role of PKC activation in vasa nervorum. The PKC inhibitors, WAY151003, chelerythrine, and LY333531 as well as cremophor prevented or reversed NBF and conduction deficits (81,86,87), and the PKC inhibitor Ws-indolylmaleimide-1HCl corrected acetylcholine-mediated vascular relaxation in epineurial arterioles in the STZ-diabetic rat model (88). The role for neural PKC in the pathogenesis of PDN remains unclear. However, recent findings suggest that neuronal PKC might be related to diabetes-associated changes in expression, phosphorylation, and function of the vanilloid receptor 1, known to play an important role in diabetic neuropathic pain (89). The novel PKC-P isoform selective inhibitor JTT-010 was found to ameliorate nerve conduction deficits, hyperalgesia (formalin test in its first phase), and hypoalgesia (formalin test in its second phase, tail flick test) in STZ-diabetic rats (90).

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