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.

Abstract

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.

• Authors: Marta Soltesova Prnova, Karol Svik, Stefan Bezek, Lucia Kovacikova, Cimen Karasu, Milan Stefek
• Journal: Neurochemical research (Neurochem Res) Vol. 44 Issue 5 Pg. 1056-1064 (May 2019) ISSN: 1573-6903 [Electronic] United States
• PMID: 30689163 (Publication Type: Journal Article)

Chemical References

• Blood Glucose
• Enzyme Inhibitors
• Akr1b1 protein, rat
• Aldehyde Reductase

Topics

• Aldehyde Reductase (drug effects, pharmacology)
• Animals
• Blood Glucose (drug effects, metabolism)
• Diabetic Neuropathies (drug therapy, metabolism)
• Enzyme Inhibitors (pharmacology)
• Hyperalgesia (drug therapy, metabolism)
• Neural Conduction (drug effects)
• Rats, Zucker
• Sciatic Nerve (drug effects)