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Journal of Pharmacology And Experimental Therapeutics Fast Forward
First published on October 4, 2006; DOI: 10.1124/jpet.106.109702

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Received for publication June 21, 2006.
Revised October 3, 2006.
Accepted for publication October 3, 2006.

NICOTINAMDE REVERSES NEUROLOGICAL AND NEUROVASCULAR DEFICITS IN STREPTOZOTOCIN DIABETIC RATS

Martin John Stevens 1*, Fei Li 2, Viktor Drel 2, Omrola Abatan 2, Howard Kim 2, Dianna Burnett 2, Dennis Larkin 2, Irina G Obrosova 3

1 University of Birmingham 2 University of Michigan 3 Lousianna State University

* Address correspondence to: E-mail: martin.stevens{at}heartofengland.nhs.uk

Abstract

In diabetes, activation of the nuclear enzyme poly(ADP- ribose) polymerase (PARP) is an important effector of oxidative-nitrosative injury which contributes to the development of experimental diabetic peripheral neuropathy (DPN). However, the potential toxicity of complete PARP inhibition necessitates the utilization of weaker PARP inhibitors with additional therapeutic properties. Nicotinamide (vitamin B3), is a weak PARP inhibitor, antioxidant, calcium modulator and can improve energy status and inhibit cell death in ischemic tissues. We report the dose-dependent effects of nicotinamide in an established model of early DPN. Control and streptozotocin-diabetic (STZ-D) rats were treated with 200-400 mg kg-1d-1 nicotinamide (i.p.) for 2 weeks after 2 weeks of untreated diabetes. Sciatic endoneurial nutritive blood flow was measured by microelectrode polarography and hydrogen clearance, and sciatic motor and hind-limb digital sensory nerve conduction velocities and thermal and mechanical algesia by standard electrophysiological and behavioral tests. Malondialdehyde plus 4-hydroxyalkenal concentration in the sciatic nerve and amino acid- (4)-hydroxynonenal adduct and poly(ADP-ribosyl)ated protein expression in human Schwann cells were assessed by a colorimetric method with N-methyl-2-phenyl indole and Western blotting, respectively. Nicotinamide corrected increased sciatic nerve lipid peroxidation in concert with nerve perfusion deficits, and dose-dependently attenuated nerve conduction slowing as well as mechanical and thermal hyperalgesia. 25 mM nicotinamide prevented high (30 mmol/l) glucose-induced overexpression of amino acid- (4)-hydroxynonenal adducts and poly(ADP-ribosyl)ated proteins in human Schwann cells. In conclusion, nicotinamide deserves consideration as an attractive, non-toxic therapy for the treatment of DPN.


Key words: Diabetes, Neuropathy, Nicotinamide, Rat, Schwann Cell, oxidative stress


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 Am. J. Physiol. Endocrinol. Metab.Home page
I. G. Obrosova, V. R. Drel, C. L. Oltman, N. Mashtalir, J. Tibrewala, J. T. Groves, and M. A. Yorek
Role of nitrosative stress in early neuropathy and vascular dysfunction in streptozotocin-diabetic rats
Am J Physiol Endocrinol Metab, December 1, 2007; 293(6): E1645 - E1655.
[Abstract] [Full Text] [PDF]


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