HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: db07-0740v1 56/12/2997    most recent Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Kellogg, A. P. Articles by Pop-Busui, R. Search for Related Content PubMed PubMed Citation Articles by Kellogg, A. P. Articles by Pop-Busui, R. Social Bookmarking                What's this?

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

¹ Department of Internal Medicine, University of Michigan, Ann Arbor, Michigan
² Department of Neurology, University of Michigan, Ann Arbor, Michigan
³ University of Birmingham, Birmingham, U.K

Address correspondence and reprint requests to Rodica Pop-Busui, MD, PhD, University of Michigan, Department of Internal Medicine, 5570D MSRB II, 1150 W. Medical Center Dr., Ann Arbor, MI 48109. E-mail: rpbusui{at}umich.edu

Abbreviations: COX, cyclooxygenase; DPN, diabetic peripheral neuropathy; DRG, dorsal root ganglia; GSH, glutathione; IENF, intraepidermal nerve fiber; MDA, malondialdehyde plus 4-hydroxyalkenals; MNCV, motor nerve conduction velocity; NF, nuclear factor; PG, prostaglandin; ROS, reactive oxygen species; SNCV, sensory nerve conduction velocity; STZ, streptozotocin; TNF, tumor necrosis factor; TXB, thromboxane B₂

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.

RESEARCH DESIGN AND 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.

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?