tropisetron and Diabetic-Neuropathies

Diabetic peripheral neuropathy (DPN) is a common nerve disorder of diabetes. The aim of this study was to explore the protective effects of tropisetron in DPN. Type 1 diabetes was created by a single injection of streptozotocin (50 mg/kg, ip). Tropisetron (3 mg/kg, ip) was administered daily for 2 weeks. Our analysis showed that nerve fibers and their myelin sheaths were thinned with decreased myelinated fiber number in diabetic animals. The intensity of Bcl-2 staining decreased and the intensity of Bax staining increased in the sciatic nerves of diabetic rats by using immunohistochemical staining. Furthermore, diabetes significantly increased tumor necrosis factor-alpha, interleukin 1-β (TNFα and IL-1β) and Bax/Bcl-2 ratio in sciatic nerves of rats. However, intraperitoneal injection of tropisetron significantly reversed these alterations induced by diabetes. These findings suggest that tropisetron attenuates diabetes-induced peripheral nerve injury through its anti-inflammatory and anti-apoptotic effects, and may provide a novel therapeutic strategy to ameliorate the process of peripheral neuropathy in diabetes.

Topics: Animals; Anti-Inflammatory Agents; Apoptosis; bcl-2-Associated X Protein; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Inflammation; Interleukin-1; Rats; Streptozocin; Tropisetron; Tumor Necrosis Factor-alpha

Tiapride dose-dependently attenuated the biphasic nociceptive responses induced by s.c. injection of formalin to the hindpaw of mice, and its activity on the first (ED50 = 110 mg/kg p.o.) and the second (ED50 = 32.0 mg/kg p.o.) phases paralleled that on the nociceptive response to intrathecal injection of substance P (ED50 = 190 mg/kg p.o.) and somatostatin (ED50 = 56.0 mg/kg p.o.), respectively. Moreover, a similar antinociceptive activity was observed in streptozotocin-induced diabetic or genetically diabetic (db/db) mice. The effects of tiapride (100 mg/kg p.o.) on both phases of the formalin test in normal mice were abolished by pretreatment with p-chlorophenylalanine (800 x 2 mg/kg p.o.), a 5-hydroxytryptamine (5-HT) depletor, or pindolol (1 mg/kg i.p.), a 5-HT1 antagonist, but were scarcely affected by 3-tropanyl-indole-3-carboxylate, a 5-HT3 antagonist. Ketanserin (1 mg/kg i.p.), a 5-HT2 antagonist, attenuated the effect of tiapride on the second phase but not on the first phase. This study on the antinociceptive mechanism of action of tiapride (that blocks painful neuropathy in diabetic patients) has led us to hypothesize that the drug attenuates pain transmission through an indirect activation of central 5-HT1 and 5-HT2 receptors.

Topics: Animals; Central Nervous System; Diabetes Mellitus, Experimental; Diabetic Neuropathies; Dopamine Antagonists; Female; Fenclonine; Indoles; Injections, Spinal; Ketanserin; Male; Mice; Nociceptors; Pain; Pain Measurement; Pindolol; Serotonin; Serotonin Antagonists; Somatostatin; Substance P; Synaptic Transmission; Tiapamil Hydrochloride; Tropisetron