Protein kinase C effects on nerve function, perfusion, Na + ,K + -ATPase activity and glutathione content in diabetic rats

Abstract

Changes in protein kinase (PK) C activity have been implicated in the complications of diabetes mellitus.In retina, blood vessels, kidney and heart, PKC activity is increased [1], perhaps due to raised de novo synthesis of diacylglycerol (DAG). A recent study has shown that PKC inhibitor treatment prevented the development of impaired retinal blood flow, renal glomerular hyperfiltration and microalbuminuria in diabetic rats [2] and this is compatible with the notion that PKC activation contributes to the aetiology of retinopathy and nephropathy.In another complication-prone tissue, peripheral nerve, PKC activity is reduced or unchanged [3±6]. Moreover, one neurochemical explanation of neuro- Diabetologia (1999) AbstractAims//hypothesis. Increased protein kinase C activity has been linked to diabetic vascular complications in the retina and kidney, which were attenuated by protein kinase C antagonist treatment. Neuropathy has a vascular component, therefore, the aim was to assess whether treatment with WAY151 003 or chelerythrine, inhibitors of protein kinase C regulatory and catalytic domains respectively, could correct nerve blood flow, conduction velocity, Na + ,K + -ATPase, and glutathione deficits in diabetic rats. Methods. Diabetes was induced by streptozotocin. Sciatic nerve conduction velocity was measured in vivo and sciatic endoneurial perfusion was monitored by microelectrode polarography and hydrogen clearance. Glutathione content and Na + ,K + -ATPase activity were measured in extracts from homogenised sciatic nerves. Results. After 8 weeks of diabetes, sciatic blood flow was 50 % reduced. Two weeks of WAY151 003 (3 or 100 mg/kg) treatment completely corrected this deficit and chelerythrine dose-dependently improved nerve perfusion. The inhibitors dose-dependently corrected a 20 % diabetic motor conduction deficit, however, at high doses ( > 3.0 mg/kg WAY151003; > 0.1 mg/kg chelerythrine) conduction velocity was reduced towards the diabetic level. Sciatic Na + ,K + -ATPase activity, 42 % reduced by diabetes, was partially corrected by low but not high dose WAY151 003. In contrast, only a very high dose of chelerythrine partially restored Na + ,K + -ATPase activity. A 30 % diabetic deficit in sciatic glutathione content was unchanged by protein kinase C inhibition. The benefits of WAY151 003 on blood flow and conduction velocity were blocked by nitric oxide synthase inhibitor co-treatment. Conclusion/interpretation. Protein kinase C contributes to experimental diabetic neuropathy by a neurovascular mechanism rather than through Na + ,K + -ATPase defects. [Diabetologia (1999

Role of Poly(ADP-Ribose) Polymerase Activation in Diabetic Neuropathy

“…All three mechanisms contribute to enhanced oxidative and nitrosative stress (4,5,7,9 -11) resulting from imbalance between production and neutralization of reactive oxygen species. Enhanced oxidative stress has been documented in peripheral nerve (4,5,8,(12)(13)(14), dorsal root and sympathetic ganglia (15), and vasculature (16,17) of the peripheral nervous system and has been implicated in neurovascular dysfunction and motor and sensory nerve conduction velocity (MNCV and SNCV) deficits, impaired neurotrophic support, nerve metabolic and signal transduction changes, and morphologic abnormalities characteristic for diabetes (4,5,12,14,16 -20). Evidence for the pathophysiologic role of reactive nitrogen species in PDN is also emerging (16,21).…”

“…Improved blood glucose control reduces the risk of peripheral diabetic neuropathy (PDN), thereby implicating hyperglycemia as a leading causative factor. Diabetic hyperglycemia causes PDN via several mechanisms, among which increased aldose reductase (AR) activity (2)(3)(4)(5), nonenzymatic glycation/glycoxidation (6,7), and activation of protein kinase C (2,8) are the best studied. All three mechanisms contribute to enhanced oxidative and nitrosative stress (4,5,7,9 -11) resulting from imbalance between production and neutralization of reactive oxygen species.…”

Evaluation of orally active poly(ADP-ribose) polymerase inhibitor in streptozotocin-diabetic rat model of early peripheral neuropathy

“…These concentrations were not affected by PJ34 treatment in control or diabetic rats. [17] and PKC [22], with antioxidants [23] and with other agents, all indicating that consequences of diabetic hyperglycaemia such as increased sorbitol pathway activity, oxidative stress and PKC activation do not cause irreversible changes in the peripheral nervous system, at least in the early stage of PDN. More recently, it has been shown that intervention even further downstream than hyperglycaemia, at the level of oxidative-stress-initiated, mitogen-activated protein kinase signalling cascade, successfully restores normal nerve function [24].…”

“…In contrast, the effect of PARP inhibitor on nerve perfusion, manifested by a 17% increase in NBF and the absence of a significant increase in vascular conductance, was modest. While studies from several groups [17,22,23,27,28,36], including one from our laboratory [17], suggest that vascular factor plays an important role in MNCV and SNCV deficits in PDN, growing evidence indicates that the aetiology of diabetes-induced nerve dysfunction is far more complex, and involves both vascular and non-vascular mechanisms. In particular, in diabetic and galactosaemic transgenic mice overexpressing aldose reductase (AR) specifically in the Schwann cells of the peripheral nerve under the control of the rat myelin protein zero promoter, there was a significantly greater reduction in MNCV than in the corresponding groups of non-transgenic mice with normal AR content [37].…”

O papel da proteína quinase C no desenvolvimento das complicações vasculares do diabetes mellitus

“…Como o aumento da atividade da PKC nos vasa nervorum leva à maior resposta contrátil e redução da vasodilatação, foram realizados estudos utilizando inibidores da PKC, os quais demonstraram efeito positivo sobre a condução nervosa, o que se atribuiu à melhora do fluxo sangüíneo aos nervos (42,43).…”