Abstract
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.
Footnotes
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This work was supported by the Juvenile Diabetes Research Foundation, by the National Institutes of Health, and by the Department of Veterans Affairs.
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Article, publication date, and citation information can be found at http://jpet.aspetjournals.org.
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doi:10.1124/jpet.106.115550.
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ABBREVIATIONS: CP-316,819, [R-R*,S*]-5-chloro-N-[2-hydroxy-3-(methoxymethylamino)-3-oxo-1-(phenylmethyl)propyl]-1H-indole-2-carboxamide; DAB, 1,4-dideoxy-1,4-imino-d-arabinitol; MOR-14, N-methyl-1-deoxynojirimycin; EEG, electroencephalogram; MSO, methionine sulfoximine.
- Received October 14, 2006.
- Accepted January 16, 2007.
- The American Society for Pharmacology and Experimental Therapeutics
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