| Budget Amount *help |
¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 1998: ¥700,000 (Direct Cost: ¥700,000)
Fiscal Year 1997: ¥700,000 (Direct Cost: ¥700,000)
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| Research Abstract |
To clarify the ability of diabetic nerves to regenerate in diabetic neuropathy, we evaluated nerve regeneration after nerve crush and degeneration after nerve transection in diabetic (DM) and age-matched control rats. In nerve crush model, electrophysical examination indicated that the elongation rate of regenerative nerves and their velocity was slower in DM.Morphologically, the number of regenerative nerve was significantly decreased and its diameter was smaller in DM.In nerve transection model, morphometric analysis indicated that WD was delayed in DM.Immunoblot analysis showed a delay in the degradation of neurofilaments (NFs) in DM during WD.Moreover, phosphorylated NFs detected by SMI31 were more recognized in intact diabetic nerves in comparison with control, while the opposite was true for unphosphorylated NFs detected by SMI32.
These results suggest that nerve regeneration is impaired in DM.This impairment, in part, might be due to delay of WD, because WD is prerequisite for nerve regeneration. Since it is known that the sensitivity of NF to calpain-mediated proteolysis is modulated by its carboxyl-terminal phosphorylation state and phosphorylated NFs are resistant to calpains, we concluded that abnormal NF phosphorylation state in diabetes could be one of the mechanisms by which axonal degeneration was delayed.
The excessive NF phosphorylation in STZ-diabetic rats could be due to an increase in kinase activity. Proline-directed protein kinases, such as Cdk5/p35, GSK3 beta JNK, ERK, and p38, are potential candidates for NF kinases. We confirmed the existence of Cdk5/p35, JNK, and ERK using immunoblot and immunohistochemistry. Moreover, both JNK and ERK were activated in DRG and sciatic nerve of 12 weeks STZ-diabetic rats. These results suggest that JNK and ERK make an important role in hyperphosphorylation of NF in diabetic rats.
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