HOME HELP FEEDBACK SUBSCRIPTIONS ARCHIVE SEARCH TABLE OF CONTENTS		QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) Purchase Article View Shopping Cart Alert me when this article is cited Alert me if a correction is posted Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Price, S. A. Articles by Tomlinson, D. R. Search for Related Content PubMed PubMed Citation Articles by Price, S. A. Articles by Tomlinson, D. R. Social Bookmarking                What's this?

Mitogen-Activated Protein Kinase p38 Mediates Reduced Nerve Conduction Velocity in Experimental Diabetic Neuropathy

Interactions With Aldose Reductase

From the Division of Neuroscience, School of Biological Sciences, University of Manchester, Manchester, U.K

This study examined the role of p38 mitogen-activated protein (MAP) kinase in transducing high glucose into deficits in nerve conduction velocity (NCV) that are characteristic of diabetic neuropathy. p38 activation and NCV were measured in streptozocin-induced diabetic rats treated with a p38 inhibitor, an aldose reductase inhibitor, and insulin. Dorsal root ganglia (DRG) from diabetic animals showed marked activation of p38 at 12 weeks of diabetes. Insulin treatment for the last 4 of 12 weeks of diabetes normalized p38 activation. Furthermore, activation was completely prevented by 12 weeks’ treatment with the aldose reductase inhibitor, fidarestat. Immunocytochemistry localized activation of p38 to the nuclei of virtually all sensory neuronal phenotypes in the DRG, and activation was clear in diabetes, as was inhibition by fidarestat and by the p38 inhibitor SB 239063. In the ventral horn of the spinal cord, p38 was present in motoneuron cell bodies; and again, activation in diabetes and fidarestat inhibition was clear. Treatment of diabetic animals with a specific inhibitor of p38 (SB 239063), fidarestat, or insulin also prevented reductions in both motor and sensory NCV. These findings suggest that increased polyol pathway flux in diabetic animals leads to the activation of p38. This activation can mediate changes in gene transcription and cellular phenotype that are likely to underlie the NCV deficits. Insulin and aldose reductase inhibitors can prevent excess polyol pathway flux, and hence these agents may prevent NCV deficits by preventing p38 MAP kinase activation.

Abbreviations: ChAT, choline acetyltransferase; DRG, dorsal root ganglia; MAP, mitogen-activated protein; MNCV, motor nerve conduction velocity; NCV, nerve conduction velocity; SNCV, sensory NCV; STZ, streptozocin

CiteULike    Del.icio.us    Digg    Reddit    Technorati    What's this?

This article has been cited by other articles:

				M. J. Stevens, F. Li, V. R. Drel, O. I. Abatan, H. Kim, D. Burnett, D. Larkin, and I. G. Obrosova Nicotinamide Reverses Neurological and Neurovascular Deficits in Streptozotocin Diabetic Rats J. Pharmacol. Exp. Ther., January 1, 2007; 320(1): 458 - 464. [Abstract] [Full Text] [PDF]

				A. Pladzyk, A. B. M. Reddy, U. C. S. Yadav, R. Tammali, K. V. Ramana, and S. K. Srivastava Inhibition of Aldose Reductase Prevents Lipopolysaccharide-Induced Inflammatory Response in Human Lens Epithelial Cells Invest. Ophthalmol. Vis. Sci., December 1, 2006; 47(12): 5395 - 5403. [Abstract] [Full Text] [PDF]

				V. R. Drel, N. Mashtalir, O. Ilnytska, J. Shin, F. Li, V. V. Lyzogubov, and I. G. Obrosova The Leptin-Deficient (ob/ob) Mouse: A New Animal Model of Peripheral Neuropathy of Type 2 Diabetes and Obesity Diabetes, December 1, 2006; 55(12): 3335 - 3343. [Abstract] [Full Text] [PDF]

				E. C.M. Ho, K. S.L. Lam, Y. S. Chen, J. C.W. Yip, M. Arvindakshan, S.-I. Yamagishi, S. Yagihashi, P. J. Oates, C. A. Ellery, S. S.M. Chung, et al. Aldose Reductase-Deficient Mice Are Protected From Delayed Motor Nerve Conduction Velocity, Increased c-Jun NH2-Terminal Kinase Activation, Depletion of Reduced Glutathione, Increased Superoxide Accumulation, and DNA Damage. Diabetes, July 1, 2006; 55(7): 1946 - 1953. [Abstract] [Full Text] [PDF]

				E. K. Wittmack, A. M. Rush, A. Hudmon, S. G. Waxman, and S. D. Dib-Hajj Voltage-Gated Sodium Channel Nav1.6 Is Modulated by p38 Mitogen-Activated Protein Kinase J. Neurosci., July 13, 2005; 25(28): 6621 - 6630. [Abstract] [Full Text] [PDF]

				S. K. Srivastava, K. V. Ramana, and A. Bhatnagar Role of Aldose Reductase and Oxidative Damage in Diabetes and the Consequent Potential for Therapeutic Options Endocr. Rev., May 1, 2005; 26(3): 380 - 392. [Abstract] [Full Text] [PDF]

				F. Li, V. R. Drel, C. Szabo, M. J. Stevens, and I. G. Obrosova Low-Dose Poly(ADP-Ribose) Polymerase Inhibitor-Containing Combination Therapies Reverse Early Peripheral Diabetic Neuropathy Diabetes, May 1, 2005; 54(5): 1514 - 1522. [Abstract] [Full Text] [PDF]

				I. G. Obrosova, P. Pacher, C. Szabo, Z. Zsengeller, H. Hirooka, M. J. Stevens, and M. A. Yorek Aldose Reductase Inhibition Counteracts Oxidative-Nitrosative Stress and Poly(ADP-Ribose) Polymerase Activation in Tissue Sites for Diabetes Complications Diabetes, January 1, 2005; 54(1): 234 - 242. [Abstract] [Full Text] [PDF]