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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

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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.

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Abbreviations

AKR1B1:

: Human aldose reductase encoded by AKR1B1 gene

AGE:

: Advanced glycation endproducts

BHT:

: Butylated hydroxytoluene

CEM:

: Centre of Experimental Medicine

HbA1c:

: Glycated hemoglobin

MDA:

: Malondialdehyde

RAGE:

: Receptor for AGE

SAS:

: Slovak Academy of Sciences

TBA:

: Thiobarbituric acid

TBARS:

: Thiobarbituric acid reactive substances

TCA:

: Trichloroacetic acid

ZDF:

: Zucker diabetic fatty

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Acknowledgements

This work was supported by SAS-Tubitak JRP 2015/7, Slovak Research and Development Agency under the Contract No. APVV-15-0455, VEGA 2/0005/2018, and TUBITAK Project No: 215S19.

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Authors and Affiliations

  1. Department of Biochemical Pharmacology, Institute of Experimental Pharmacology and Toxicology, CEM, Slovak Academy of Sciences, Dubravska cesta 9, 84104, Bratislava, Slovakia

    Marta Soltesova Prnova, Karol Svik, Stefan Bezek, Lucia Kovacikova & Milan Stefek

  2. Department of Medical Pharmacology, Faculty of Medicine, Gazi University, 06510, Beşevler, Ankara, Turkey

    Cimen Karasu

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  1. Marta Soltesova Prnova
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Correspondence to Milan Stefek.

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Soltesova Prnova, M., Svik, K., Bezek, S. et al. 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. Neurochem Res 44, 1056–1064 (2019). https://doi.org/10.1007/s11064-019-02736-1

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