Dissection of metabolic, vascular, and nerve conduction interrelationships in experimental diabetic neuropathy by cyclooxygenase inhibition and acetyl-L-carnitine administration.
Alterations in cyclooxygenase (COX) pathway activity have been implicated in the pathogenesis of experimental diabetic neuropathy (EDN). These studies explore the relationships between COX-mediated and acetyl-L-carnitine (ALC)-sensitive defects that contribute to functional, metabolic, and vascular abnormalities of EDN. The effects of nonselective COX inhibition with flurbiprofen were contrasted with selective COX-2 inhibition with meloxicam, administered alone and in combination with ALC in nondiabetic (ND) and streptozotocin-induced diabetic (STZ-D) rats. Flurbiprofen treatment of ND rats replicated many of the biochemical and physiological abnormalities of EDN, i.e., reduced motor nerve conduction velocity (MNCV), total and endoneurial nerve blood flow (NBF), Na,K-ATPase activity, and myo-inositol (MI) and taurine content. In STZ-D rats, however, flurbiprofen paradoxically prevented endoneurial NBF deficits but not MNCV slowing. Coadministration of 50 mg x kg(-1) x day(-1) ALC prevented reductions in MNCV, Na,K-ATPase activity, and endoneurial NBF in flurbiprofen-treated ND and STZ-D rats. In contrast, selective COX-2 inhibition with meloxicam was without effect on MNCV, NBF, or MI content in ND rats and prevented MNCV slowing and NBF deficits in STZ-D rats. Western blot analysis showed unchanged sciatic nerve COX-1 protein but increased COX-2 protein abundance in STZ-D versus ND rats. These results imply 1) a tonic role of the COX-1 pathway in the regulation of nerve osmolytes and Na,K-ATPase activity and the maintenance of NBF in ND animals and 2) activation of the COX-2 pathway as an important mediator of NBF and MNCV deficits in EDN.
Pop-Busui
Rodica
R
Division of Endocrinology and Metabolism, Department of Internal Medicine, Michigan Diabetes Research and Training Center, University of Michigan, Ann Arbor Veterans Administration Hospitals, 48109-0678, USA.
Marinescu
Victor
V
Van Huysen
Carol
C
Li
Fei
F
Sullivan
Kelli
K
Greene
Douglas A
DA
Larkin
Dennis
D
Stevens
Martin J
MJ
D000108:Acetylcarnitine / Q000494:pharmacology*; D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000494:pharmacology; D051546:Cyclooxygenase 2; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology*; D003921:Diabetes Mellitus, Experimental / Q000473:pathology / Q000503:physiopathology*; D003929:Diabetic Neuropathies / Q000503:physiopathology*; D004195:Disease Models, Animal; D005480:Flurbiprofen / Q000494:pharmacology*; D007527:Isoenzymes / Q000378:metabolism*; D008297:Male; D009431:Neural Conduction / Q000187:drug effects / Q000502:physiology*; D011451:Prostaglandin-Endoperoxide Synthases / Q000378:metabolism*; D051381:Rats; D012039:Regional Blood Flow / Q000187:drug effects; D012584:Sciatic Nerve / Q000098:blood supply / Q000473:pathology / Q000503:physiopathology; D000254:Sodium-Potassium-Exchanging ATPase / Q000378:metabolism; D013654:Taurine / Q000378:metabolism
D000894:Anti-Inflammatory Agents, Non-Steroidal; D052246:Cyclooxygenase 2 Inhibitors; D016861:Cyclooxygenase Inhibitors; D007527:Isoenzymes; D013654:Taurine; D005480:Flurbiprofen; D000108:Acetylcarnitine; D051546:Cyclooxygenase 2; D011451:Prostaglandin-Endoperoxide Synthases; D000254:Sodium-Potassium-Exchanging ATPase