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.
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Abbreviations
- HbA1c:
-
Glycated hemoglobin
- LPL:
-
Lipoprotein lipase
- MCF:
-
Median corpuscular fragility
- RBC:
-
Red blood cells
- STZ:
-
Streptozotocin
- TBA:
-
Thiobarbituric acid
- TBAR:
-
Thiobarbituric acid reactive substances
- PPARs:
-
Peroxisome proliferator-activated receptors
- ZDF rat:
-
Zucker diabetic fatty rat
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This work was supported by VEGA 2/0005/2018, Slovak Research and Development Agency, under the contract NO. APVV-15-0455, SAS-Tubitak JRP 2015/7 and TUBITAK Project No: 215S19.
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MSP, LK, CK, and MS designed and performed research including behavioral and biochemical assays; participated in the interpretation of the results, writing and review of the manuscript. KS, SB and ZE performed behavioral and biochemical assays. All authors read and approved the manuscript.
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The study was approved by the Ethics Committee of the Institute of Experimental Pharmacology and Toxicology, CEM, SAS, and the State Veterinary and Food Administration of the Slovak Republic, and it was performed in accordance with the Principles of Laboratory Animal Care (NIH publication 83-25, revised 1985) and the Slovak law regulating animal experiments (Decree 289, Part 139, July 9, 2003).
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Prnova, M.S., Kovacikova, L., Svik, K. et al. 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. Naunyn-Schmiedeberg's Arch Pharmacol 393, 651–661 (2020). https://doi.org/10.1007/s00210-019-01769-1
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DOI: https://doi.org/10.1007/s00210-019-01769-1