The effects of 5-hydroxytryptamine 5-HT2 receptor antagonists on nerve conduction velocity and endoneurial perfusion in diabetic rats.
Reduced peripheral nerve perfusion participates in the aetiology of diabetic neuropathy. 5-Hydroxtryptamine causes vasa nervorum vasoconstriction and platelet aggregation, which are enhanced by diabetes. To assess whether these mechanisms could contribute to neuropathy, the effects of 5-hydroxytryptamine 5-HT2 receptor antagonist treatment were examined in streptozotocin-induced diabetic rats. One study determined the dose-response relationship for AT1015 (N-[2-[4-(5H-dibenzo[a,d]cyclohepten-5-ylidene)piperidino]ethyl]-1-formyl-4-piperidinecarboxamide monohydrochloride monohydrate). Two weeks AT1015 treatment after 6 weeks of diabetes dose-dependently corrected 19.7%, 54.1%, and 15.7% deficits in sciatic nerve motor conduction velocity and blood flow, and saphenous nerve sensory conduction: ED50 values were 0.52, 0.74 and 0.15 mg/kg(-1)/day(-1), respectively. In a second study, high-dose AT1015 (3 mg/kg(-1)/day(-1)) actions were compared with those of the 5HT2 receptor antagonists, ritanserin (10 mg/kg(-1)/day(-1)) and sarpogrelate (100 mg/kg(-1)/day(-1)), and the anti-platelet phosphodiesterase III inhibitor, cilostazol (100 mg/kg(-1)/day(-1)). Two weeks treatment with these drugs produced a marked correction (82.6-99.7%) of a 19.8% sciatic motor conduction deficit in diabetic rats. Similarly, 44.7% and 14.9% reductions in sciatic endoneurial blood flow and saphenous sensory conduction velocity were completely reversed. Thus, 5-HT2 receptor antagonists had marked beneficial effects in experimental diabetic neuropathy, and AT1015 appears suitable for further evaluation in clinical trials.
Department of Biomedical Sciences, Institute of Medical Sciences, University of Aberdeen, Foresterhill, AB25 2ZD Aberdeen, Scotland, UK. n.e.cameron@abdn.ac.uk
Norman E
NE
Cameron
Mary A
MA
Cotter
D000818:Animals; D003921:Diabetes Mellitus, Experimental / Q000503:physiopathology*; D004305:Dose-Response Relationship, Drug; D008297:Male; D009431:Neural Conduction / Q000187:drug effects* / Q000502:physiology; D010525:Peripheral Nerves / Q000098:blood supply / Q000187:drug effects / Q000502:physiology; D051381:Rats; D017207:Rats, Sprague-Dawley; D044348:Receptors, Serotonin, 5-HT2 / Q000502:physiology; D012584:Sciatic Nerve / Q000098:blood supply / Q000187:drug effects* / Q000502:physiology; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists / Q000494:pharmacology*
D044348:Receptors, Serotonin, 5-HT2; D058830:Serotonin 5-HT2 Receptor Antagonists; D012702:Serotonin Antagonists