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).
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.
Suh
Sang Won
SW
Department of Neurology, University of California, San Francisco, San Francisco, California, USA.
Bergher
Jennifer P
JP
Anderson
Christopher M
CM
Treadway
Judith L
JL
Fosgerau
Keld
K
Swanson
Raymond A
RA
D000818:Animals; D001253:Astrocytes / Q000187:drug effects / Q000378:metabolism*; D001921:Brain / Q000473:pathology; D001923:Brain Chemistry / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D002478:Cells, Cultured; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000378:metabolism; D006003:Glycogen / Q000378:metabolism / Q000494:pharmacology*; D024981:Glycogen Phosphorylase / Q000037:antagonists & inhibitors*; D007003:Hypoglycemia / Q000378:metabolism / Q000473:pathology*; D007211:Indoles / Q000494:pharmacology*; D008297:Male; D009474:Neurons / Q000187:drug effects*; D010654:Phenylbutyrates / Q000494:pharmacology*; D051381:Rats; D017207:Rats, Sprague-Dawley
C504712:3-(5-chloroindole-2-carbonyl)amino-2-hydroxy-4-phenylbutyric acid N-methyl-N-methoxyamide; D004791:Enzyme Inhibitors; D007211:Indoles; D010654:Phenylbutyrates; D006003:Glycogen; D024981:Glycogen Phosphorylase; D005947:Glucose