Diabetes-induced impairments of the exocytosis process and the effect of gabapentin: the link with cholesterol level in neuronal plasma membranes.

Abstract

Diabetic neuropathy represents one of the most prevalent complications of diabetes mellitus. The aim of this study was to investigate the effect of diabetes-induced disturbances in neurons on the Ca(2+)-triggered membrane fusion process in cell-free system in relation to plasmalemma cholesterol level. The gabapentin therapy on the exocytosis process was also studied. The diabetes in rats was induced by streptozotocin (60 mg/kg of body weight, i.p.). After 4 weeks of diabetes induction the one group of diabetic rats was treated with gabapentin (50 mg/kg, i.p.) during 1 month. Fusion experiments were performed in the cell-free model system using fluorescent dye octadecylrhodamine B. The [2-(14)C]serotonin preloaded synaptosomes were used for assay of stimulated neurotransmitter release. The synaptosomal plasma membrane cholesterol level in diabetic rats was on 12 % higher than in control and was decreased on 5 % after gabapentin therapy. The rate of synaptic vesicles fusion with plasma membranes in the presence of Ca(2+) and synaptosomal cytosolic proteins was decreased to 14.5 % in diabetic rats as compared to control (23 %) and after gabapentin administration to diabetic rats was raised to 18 %. At diabetes the stimulated synaptosomal serotonin release was increased in 1.7-2 folds and was partially normalized by gabapentin therapy. Together, these findings suggest that elevated cholesterol content in neuronal plasma membranes at diabetes impairs the membrane fusion process in neurons that can induce the development of neuropathy. Diabetes-evoked impairments of the exocytotic process can be attenuated by gabapentin therapy.