This chapter covers the identification of mitogen-activated protein kinases as early stage transducers of the damaging effects of glucose on peripheral nerves. They are activated by several metabolic consequences of hyperglycemia, in particular oxidative stress, osmotic stress, and advanced glycation end products. Inhibition of one group of mitogen-activated protein kinases—the p38 group—prevents the development of reduced nerve conduction velocity in experimental diabetes; such inhibition can also be achieved by an aldose reductase inhibitor, giving an explanation for the mechanism underlying the damaging effect of the polyol pathway. The effect of treatment is also described with sonic hedgehog in preventing reduced nerve conduction velocity and normalising expression of genes coding for endoskeletal proteins, which may be instrumental in preserving the integrity of the distal axon.
Key Words: Sonic hedgehog; p38 MAP kinase; nerve conduction; gene expression; axonal endoskeleton.
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