3-Mercapto-5H-1,2,4-Triazino[5,6-b]Indole-5-Acetic Acid (Cemtirestat) Alleviates Symptoms of Peripheral Diabetic Neuropathy in Zucker Diabetic Fatty (ZDF) Rats: A Role of Aldose Reductase

Peripheral neuropathy is the most prevalent chronic complication of diabetes mellitus. Good glycemic control can delay the appearance of neuropathic symptoms in diabetic patients but it is not sufficient to prevent or cure the disease. Therefore therapeutic approaches should focus on attenuation of pathogenetic mechanisms responsible for the nerve injury. Considering the role of polyol pathway in the etiology of diabetic neuropathy, we evaluated the effect of a novel efficient and selective aldose reductase inhibitor, 3-mercapto-5H-1,2,4-triazino[5,6-b]indole-5-acetic acid (cemtirestat), on symptoms of diabetic peripheral neuropathy in Zucker Diabetic Fatty (ZDF) rats. Since the age of 5 months, male ZDF rats were orally administered cemtirestat, 2.5 and 7.5 mg/kg/day, for two following months. Thermal hypoalgesia was evaluated by tail flick and hot plate tests. Tactile allodynia was determined by a von Frey flexible filament test. Two-month treatment of ZDF rats with cemtirestat (i) did not affect physical and glycemic status of the animals; (ii) partially inhibited sorbitol accumulation in red blood cells and the sciatic nerve; (iii) markedly decreased plasma levels of thiobarbituric acid reactive substances; (iv) normalized symptoms of peripheral neuropathy with high significance. The presented findings indicate that inhibition of aldose reductase by cemtirestat is not solely responsible for the recorded improvement of the behavioral responses. In future studies, potential effects of cemtirestat on consequences of diabetes that are not exclusively dependent on glucose metabolism via polyol pathway should be taken into consideration.

     

The high-energy diet affecting development of diabetes symptoms in Zucker diabetic fatty rats

The appropriate animal model of diabetes mellitus type 2 is Zucker diabetic fatty (ZDF) rats. The goal of this study was to analyse the effect of chronic high-energy diet on diabetes mellitus (DM) complications in ZDF rats. Male ZDF rats (n?=?20) and their lean controls (non-diabetic, n?=?10) in the age of 3 months were involved in the experiment. Rats were provided with water and diet on ad libitum base. Animals were divided into three groups as follows: lean untreated rats (C) fed by KKZ-P/M (10 MJ/kg), obese rats fed by KKZ-P/M (10 MJ/kg, E1) and obese rats fed by enriched high energy diet (E2, enriched KKZ-P/M, 20 MJ/kg). Glucose, ketones levels, the consumption of feed, water and the live weight was measured weekly during the whole experiment. At the end of the experiment rats were anesthetized and selected haematological parameters were measured. ZDF rats in E1 and E2 group developed obesity, hyperglycaemia, non-insulin dependent diabetes, aggravations in haematological parameters and accumulation of sorbitol in sciatic nerve and lens of rats. High-energy diet immediately induced hyperglycaemia followed by accelerating the secondary symptoms of diabetes complications expressed by disturbed haematology parameters. High-energy diet caused ketoacidosis what meant two cases of death. Extended research on diabetes is needed.