Protective Effects of Cyclooxygenase-2 Gene Inactivation against Peripheral Nerve Dysfunction and Intraepidermal Nerve Fibers Loss in Experimental Diabetes

Abstract

Objective. Activation of the cyclooxygenase (COX) pathway with secondary neurovascular deficits are implicated in the pathogenesis of experimental diabetic peripheral neuropathy.

Objective. The aim of this study was to explore the interrelationships between hyperglycemia, activation of the COX-2 pathway, oxidative stress and inflammation in mediating peripheral nerve dysfunction and whether COX-2 gene inactivation attenuates nerve fiber loss in long term experimental diabetes.

Research Design and Methods. Motor and sensory digital nerve conduction velocities, sciatic nerve indices of oxidative stress, prostaglandins content, markers of inflammation, and intraepidermal nerve fibers (IENF) density were measured after 6 months in control and diabetic COX-2 deficient (COX-2^-/-) and littermate, wild-type (COX-2^+/+) mice. The effects of a selective COX-2 inhibitor, celecoxib, on these markers were also investigated in diabetic rats.

Results. Under normal conditions, there were no differences in blood glucose, peripheral nerve electrophysiology, markers of oxidative stress, inflammation, and IENF density between COX-2^+/+ and COX-2^-/- mice. After 6 months, diabetic COX-2^+/+ mice experienced significant deterioration in nerve conduction velocities and IENF density and developed important signs of increased oxidative stress and inflammation as compared with nondiabetic mice. Diabetic COX-2^-/- mice were protected against functional and biochemical deficits of experimental DPN and against nerve fibers loss. In diabetic rats, selective COX-2 inhibition replicated this protection.

Conclusions. These data suggests that selective COX-2 inhibition may be useful for preventing or delaying diabetic neuropathy.