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Research ArticleArticle

Polyol Pathway Hyperactivity Is Closely Related to Carnitine Deficiency in the Pathogenesis of Diabetic Neuropathy of Streptozotocin-Diabetic Rats

Jiro Nakamura, Naoki Koh, Fumihiko Sakakibara, Yoji Hamada, Tomohiro Hara, Hiromitsu Sasaki, Sadao Chaya, Taku Komori, Eitaro Nakashima, Keiko Naruse, Koichi Kato, Naohide Takeuchi, Yasuhide Kasuya and Nigishi Hotta
Journal of Pharmacology and Experimental Therapeutics December 1998, 287 (3) 897-902;
Jiro Nakamura
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Naoki Koh
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Fumihiko Sakakibara
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Yoji Hamada
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Tomohiro Hara
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Hiromitsu Sasaki
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Sadao Chaya
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Taku Komori
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Eitaro Nakashima
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Keiko Naruse
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Koichi Kato
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Naohide Takeuchi
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Yasuhide Kasuya
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Nigishi Hotta
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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

  • 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.

  • ↵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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Journal of Pharmacology and Experimental Therapeutics
Vol. 287, Issue 3
1 Dec 1998
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Research ArticleArticle

Polyol Pathway Hyperactivity Is Closely Related to Carnitine Deficiency in the Pathogenesis of Diabetic Neuropathy of Streptozotocin-Diabetic Rats

Jiro Nakamura, Naoki Koh, Fumihiko Sakakibara, Yoji Hamada, Tomohiro Hara, Hiromitsu Sasaki, Sadao Chaya, Taku Komori, Eitaro Nakashima, Keiko Naruse, Koichi Kato, Naohide Takeuchi, Yasuhide Kasuya and Nigishi Hotta
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 897-902;

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Research ArticleArticle

Polyol Pathway Hyperactivity Is Closely Related to Carnitine Deficiency in the Pathogenesis of Diabetic Neuropathy of Streptozotocin-Diabetic Rats

Jiro Nakamura, Naoki Koh, Fumihiko Sakakibara, Yoji Hamada, Tomohiro Hara, Hiromitsu Sasaki, Sadao Chaya, Taku Komori, Eitaro Nakashima, Keiko Naruse, Koichi Kato, Naohide Takeuchi, Yasuhide Kasuya and Nigishi Hotta
Journal of Pharmacology and Experimental Therapeutics December 1, 1998, 287 (3) 897-902;
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