A1 adenosine receptors mediate hypoglycemia-induced neuronal injury.
The cellular mechanisms that lead to neuronal death following glucose deprivation are not known, although it is recognized that hypoglycemia can lead to perturbations in intracellular calcium ([Ca2+]i) levels. Recently, activation of A1 adenosine receptors (A1AR) has been shown to alter [Ca2+]i and promote neuronal death. Thus, we examined if A1AR activation contributes to hypoglycemia-induced neuronal injury using rat cortical neurons. First, we observed that hypoglycemia was associated with large increases in neuronal adenosine release. Next, decreased neuronal viability was seen with progressive reduction in glucose concentration (25, 6, 3, 0.75 and 0 mM). Using the calcium-sensitive dye, Fluo-3, we observed both acute and long-term changes in relative [Ca2+]i during hypoglycemic conditions. Demonstrating a role for adenosine in this process, both the loss in neuronal viability and the early changes in [Ca2+]i were reversed by treatment with A1AR antagonists (8-cyclopentyl, 1,3-dipropylxanthine; 9-chloro-2-(2-furyl)(1,2,4)-triazolo(1,5-c)quinazolin-5-amine; and N-cyclopentyl-9-methyladenine). We also found that hypoglycemia induced the expression of the pro-apoptotic enzyme, caspase-3, and that A1AR antagonism reversed hypoglycemia-induced caspase-3 activity. Collectively, these data show that hypoglycemia induces A1ARs activation leading to alterations in [Ca2+]i, which plays a prominent role in leading to hypoglycemia-induced neuronal death.
Turner
C P
CP
Department of Pediatrics, Yale Child Health Researh Center, 464 Congress Avenue, New Haven, Connecticut 06520, USA. scott.rivkees@yale.edu
Blackburn
M R
MR
Rivkees
S A
SA
D000241:Adenosine / Q000378:metabolism*; D058916:Adenosine A1 Receptor Antagonists; D000818:Animals; D002118:Calcium / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D002470:Cell Survival / Q000502:physiology*; D002540:Cerebral Cortex / Q000196:embryology; D004622:Embryo, Mammalian / Q000378:metabolism; D004789:Enzyme Activation / Q000502:physiology; D007003:Hypoglycemia / Q000503:physiopathology*; D009474:Neurons / Q000378:metabolism*; D051381:Rats; D017207:Rats, Sprague-Dawley; D043682:Receptor, Adenosine A1 / Q000378:metabolism*; D020196:Trauma, Nervous System / Q000503:physiopathology*; D014970:Xanthines / Q000494:pharmacology
D058916:Adenosine A1 Receptor Antagonists; D043682:Receptor, Adenosine A1; D014970:Xanthines; C505410:Casp3 protein, rat; D053148:Caspase 3; D020169:Caspases; D000241:Adenosine; D002118:Calcium