1-methylnicotinamide (MNA) in prevention of diabetes-associated brain disorders.

Tamara Kuchmerovska, Ihor Shymanskyy, Stefan Chlopicki, Arkady Klimenko

Index: Neurochem. Int. 56(2) , 221-8, (2010)

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Abstract

The present study has been designed to establish the potential benefits from 1-methylnicotinamide (MNA) treatment on brain disorders associated with type 1 diabetes. All experiments were carried out after 6 weeks of streptozotocin-induced diabetes (60 mg/kg of body weight, i.p.) in male Wistar rats treated for 5 weeks with or without MNA (100 mg/kg of body weight, per os in drinking water) after 1 week of diabetes induction. Diabetes was shown to reduce monoamine neurotransmitter serotonin transporters activity, as assessed by significant inhibition of [2-(14)C]serotonin uptake, that was accompanied by elevation of spontaneous mediator release in rat brain synaptosomes. Treatment with MNA slightly attenuated diabetes-induced changes in brain serotoninergic system. The precise mechanism underlying MNA action on central serotonin neurotransmission is not known, but appears to be linked to metabolic and signalling pathways involved in controlling synaptic function rather than being associated with direct modulation of serotonin transporters. In particular, MNA action was associated with its partial normalizing effects on such biochemical indices of neuropathy development as decrease in synaptosomal Na(+),K(+)-ATPase activity and plasma membrane depolarization of synaptic endings. Elevated sorbitol formation in brain and NAD(+) deficits resulted from diabetes as major metabolic imbalances were remarkably countered by MNA treatment. However, diabetes-induced decrease in cytosolic NAD(+) to NADH ratio in brain remained unchanged. Notably, MNA supplementation to diabetic rats caused a slight lowering effect on blood glucose level. Accordingly, our findings indicate that neuroprotective properties of MNA are linked to modulation of synaptic activity through multiple mechanisms. In conclusion, we suggest that 1-methylnicotinamide might be a useful agent for treating brain failures related to diabetes.Copyright 2009 Elsevier Ltd. All rights reserved.