Triglyceride-lowering effect of the aldose reductase inhibitor cemtirestat-another factor that may contribute to attenuation of symptoms of peripheral neuropathy in STZ-diabetic rats.

Abstract

Hyperglycemia is considered a key risk factor for development of diabetic complications including neuropathy. There is strong scientific evidence showing a primary role of aldose reductase, the first enzyme of the polyol pathway, in the cascade of metabolic imbalances responsible for the detrimental effects of hyperglycemia. Aldose reductase is thus considered a significant drug target. We investigated the effects of cemtirestat, a novel aldose reductase inhibitor, in the streptozotocin-induced rat model of uncontrolled type 1 diabetes in a 4-month experiment. Markedly increased sorbitol levels were recorded in the erythrocytes and the sciatic nerve of diabetic animals. Osmotic fragility of red blood cells was increased in diabetic animals. Indices of thermal hypoalgesia were significantly increased in diabetic rats. Tactile allodynia, recorded in diabetic animals in the early stages, turned to mechanical hypoalgesia by the end of the experiment. Treatment of diabetic animals with cemtirestat (i) reduced plasma triglycerides and TBAR levels; (ii) did not affect the values of HbA1c and body weights; (iii) reversed erythrocyte sorbitol accumulation to near control values, while sorbitol in the sciatic nerve was not affected; (iv) ameliorated indices of the erythrocyte osmotic fragility; and (v) attenuated the symptoms of peripheral neuropathy more significantly in the middle of the experiment than at the end of the treatment. Taking into account the lipid metabolism as an interesting molecular target for prevention or treatment of diabetic peripheral neuropathy, the triglyceride-lowering effect of cemtirestat should be considered in future studies. The most feasible mechanisms of triglyceride-lowering action of cemtirestat were suggested.

• Authors: Marta Soltesova Prnova, Lucia Kovacikova, Karol Svik, Stefan Bezek, Zübeyir Elmazoğlu, Cimen Karasu, Milan Stefek
• Journal: Naunyn-Schmiedeberg's archives of pharmacology (Naunyn Schmiedebergs Arch Pharmacol) Vol. 393 Issue 4 Pg. 651-661 (04 2020) ISSN: 1432-1912 [Electronic] Germany
• PMID: 31802170 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Blood Glucose
• Hypoglycemic Agents
• Indoleacetic Acids
• Sulfhydryl Compounds
• Triglycerides
• cemtirestat
• Aldehyde Reductase

Topics

• Aldehyde Reductase (antagonists & inhibitors)
• Animals
• Blood Glucose (drug effects)
• Diabetes Mellitus, Experimental (blood, drug therapy)
• Diabetic Neuropathies (blood, drug therapy)
• Hypoglycemic Agents (pharmacology, therapeutic use)
• Indoleacetic Acids (pharmacology, therapeutic use)
• Male
• Osmotic Fragility (drug effects)
• Rats, Wistar
• Sulfhydryl Compounds (pharmacology, therapeutic use)
• Triglycerides (blood)