Restoring adenine nucleotides in a brain slice model of cerebral reperfusion.
Tissue adenine nucleotides are depleted during cerebral ischemia, impeding recovery after reperfusion. Although prior studies have attempted to prevent the initial loss of adenylates, the present study tests the hypothesis that stimulating synthesis of adenine nucleotides, through either adenosine kinase or adenine phosphoribosyltransferase, would result in significant cerebroprotection. To study the effects on neurons and glia directly while avoiding the influence of the cerebral vasculature, hippocampal brain slices were used for the model of transient ischemia with reperfusion. The standard brain slice insult of brief exposure to anoxia with aglycemia was modified based on studies which showed that a 30-minute exposure to air with 1 mmol/L glucose produced a stable, moderate reduction in ATP during the insult and that, 2 hours after return to normal conditions, there was moderate depletion of tissue adenine nucleotides and histologic injury. Treatments with 1 mmol/L adenosine, AMP, or adenine were equivalent in partially restoring adenine nucleotides. Despite this, only adenosine afforded histologic protection, suggesting a protective role for adenosine receptors. There also was evidence for metabolic cycling among adenine nucleotides, nucleosides, and purines. Adenosine may exert direct cerebroprotective effects on neural tissue as well as indirect effects through the cerebral vasculature.
Newman
G C
GC
Department of Neurology, State University of New York at Stony Brook 11794-8121, USA.
Hospod
F E
FE
Trowbridge
S D
SD
Motwani
S
S
Liu
Y
Y
D000225:Adenine / Q000494:pharmacology; D000227:Adenine Nucleotides / Q000378:metabolism*; D000241:Adenosine / Q000494:pharmacology; D000249:Adenosine Monophosphate / Q000494:pharmacology; D000818:Animals; D002245:Carbon Dioxide / Q000008:administration & dosage; D005947:Glucose / Q000494:pharmacology; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism*; D066298:In Vitro Techniques; D002546:Ischemic Attack, Transient / Q000378:metabolism*; D007700:Kinetics; D008297:Male; D008954:Models, Biological; D009584:Nitrogen / Q000008:administration & dosage; D010100:Oxygen / Q000008:administration & dosage; D051381:Rats; D017207:Rats, Sprague-Dawley; D015424:Reperfusion
D000227:Adenine Nucleotides; D002245:Carbon Dioxide; D000249:Adenosine Monophosphate; D005947:Glucose; D000225:Adenine; D000241:Adenosine; D009584:Nitrogen; D010100:Oxygen