Protective effects of cyclooxygenase-2 gene inactivation against peripheral nerve dysfunction and intraepidermal nerve fiber loss in experimental diabetes.
OBJECTIVE
Activation of the cyclooxygenase (COX) pathway with secondary neurovascular deficits are implicated in the pathogenesis of experimental diabetic peripheral neuropathy (DPN). The aim of this study was to explore the interrelationships between hyperglycemia, activation of the COX-2 pathway, and oxidative stress and inflammation in mediating peripheral nerve dysfunction and whether COX-2 gene inactivation attenuates nerve fiber loss in long-term experimental diabetes.


METHODS
Motor and sensory digital nerve conduction velocities, sciatic nerve indexes of oxidative stress, prostaglandin content, markers of inflammation, and intraepidermal nerve fiber (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 compared with nondiabetic mice. Diabetic COX-2(-/-) mice were protected against functional and biochemical deficits of experimental DPN and against nerve fiber loss. In diabetic rats, selective COX-2 inhibition replicated this protection.


CONCLUSIONS
These data suggest that selective COX-2 inhibition may be useful for preventing or delaying DPN.
Kellogg
Aaron P
AP
University of Michigan, Department of Internal Medicine, 5570D MSRB II, 1150 W. Medical Center Dr., Ann Arbor, MI 48109, USA.
Wiggin
Tim D
TD
Larkin
Dennis D
DD
Hayes
John M
JM
Stevens
Martin J
MJ
Pop-Busui
Rodica
R
D000818:Animals; D051546:Cyclooxygenase 2 / Q000172:deficiency* / Q000235:genetics*; D052246:Cyclooxygenase 2 Inhibitors / Q000627:therapeutic use*; D003921:Diabetes Mellitus, Experimental / Q000150:complications*; D003929:Diabetic Neuropathies / Q000517:prevention & control*; D051379:Mice; D009046:Motor Neurons / Q000187:drug effects / Q000502:physiology; D009412:Nerve Fibers / Q000187:drug effects / Q000502:physiology*; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology; D010525:Peripheral Nerves / Q000503:physiopathology
D052246:Cyclooxygenase 2 Inhibitors; D051546:Cyclooxygenase 2