QUICK SEARCH:   [advanced] Author: Keyword(s): Year:  Vol:  Page:

This Article Full Text Full Text (PDF) All Versions of this Article: jpet.106.115550v1 321/1/45    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Suh, S. W. Articles by Swanson, R. A. Search for Related Content PubMed PubMed Citation Articles by Suh, S. W. Articles by Swanson, R. A.

NEUROPHARMACOLOGY

Astrocyte Glycogen Sustains Neuronal Activity during Hypoglycemia: Studies with the Glycogen Phosphorylase Inhibitor CP-316,819 ([R-R*,S*]-5-Chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide)

Department of Neurology, University of California, San Francisco and Department of Veterans Affairs Medical Center, San Francisco, California (S.W.S., J.P.B., C.M.A., R.A.S.); Departments of Cardiovascular and Metabolic Diseases, Pfizer Global Research and Development, Groton/New London Laboratories, Pfizer Inc., Groton, Connecticut (J.L.T.); and Pharmacological Research 2, MedChem Research, Hepatic Biochemistry, Discovery Management, Novo Nordisk A/S, Maaloev, Denmark (K.F.)

Glycogen in the brain is localized almost exclusively to astrocytes. The physiological function of this energy store has been difficult to establish because of the difficulty in manipulating brain glycogen concentrations in vivo. Here, we used a novel glycogen phosphorylase inhibitor, CP-316,819 ([R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide), that causes glycogen accumulation under normoglycemic conditions but permits glycogen utilization when glucose concentrations are low. Rats treated with CP-316,819 had an 88 ± 3% increase in brain glycogen content. When subjected to hypoglycemia, these rats maintained brain electrical activity 91 ± 14 min longer than rats with normal brain glycogen levels and showed markedly reduced neuronal death. These studies establish a novel approach for manipulating brain glycogen concentration in normal, awake animals and provide in vivo confirmation that astrocyte glycogen supports neuronal function and survival during glucose deprivation. These findings also suggest an approach for forestalling hypoglycemic coma and brain injury in diabetic patients.

Address correspondence to: Dr. Raymond A. Swanson, Neurology Service (127), Veterans Affairs Medical Center, 4150 Clement Street, San Francisco, CA 94121. E-mail: raymond.swanson{at}ucsf.edu

This article has been cited by other articles:

				G. Oz, A. Kumar, J. P. Rao, C. T. Kodl, L. Chow, L. E. Eberly, and E. R. Seaquist Human Brain Glycogen Metabolism During and After Hypoglycemia Diabetes, September 1, 2009; 58(9): 1978 - 1985. [Abstract] [Full Text] [PDF]