Abstract
To investigate the relationship between polyol pathway hyperactivity and altered carnitine metabolism in the pathogenesis of diabetic neuropathy, the effects of an aldose reductase inhibitor, [5-(3-thienyl) tetrazol-1-yl]acetic acid (TAT), and a carnitine analog, acetyl-l-carnitine (ALC), on neural functions and biochemistry and hemodynamic factors were compared in streptozotocin-diabetic rats. Significantly delayed motor nerve conduction velocity, decreased R-R interval variation, reduced sciatic nerve blood flow and decreased erythrocyte 2,3-diphosphoglycerate concentrations in diabetic rats were all ameliorated by treatment with TAT (administered with rat chow containing 0.05% TAT, ∼50 mg/kg/day) or ALC (by gavage, 300 mg/kg/day) for 4 weeks. Platelet hyperaggregation activity in diabetic rats was diminished by TAT but not by ALC. TAT decreased sorbitol accumulation and prevented not onlymyo-inositol depletion but also free-carnitine deficiency in diabetic nerves. On the other hand, ALC also increased the myo-inositol as well as the free-carnitine content without affecting the sorbitol content. These observations suggest that there is a close relationship between increased polyol pathway activity and carnitine deficiency in the development of diabetic neuropathy and that an aldose reductase inhibitor, TAT, and a carnitine analog, ALC, have therapeutic potential for the treatment of diabetic neuropathy.
Footnotes
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Send reprint requests to: Jiro Nakamura, M.D., The Third Department of Internal Medicine, Nagoya University School of Medicine, 65 Tsuruma-cho, Showa-ku, Nagoya 466-8550, Japan.
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↵1 This research was supported in part by a Diabetes Research grant from the Ministry of Health and Welfare of Japan.
- Abbreviations:
- ALC
- acetyl-l-carnitine
- MNCV
- motor nerve conduction velocity
- CVr-r
- coefficient of variation of the R-R interval
- SNBF
- sciatic nerve blood flow
- 2
- 3-DPG, 2,3-diphosphoglycerate
- PKC
- protein kinase C
- Received November 11, 1997.
- Accepted July 8, 1998.
- The American Society for Pharmacology and Experimental Therapeutics
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