Inhibition of adenosine kinase during oxygen-glucose deprivation in rat cortical neuronal cultures.
Adenosine kinase (AK) inhibitors potentiate the actions of endogenous adenosine (ADO) and ameliorate cerebral ischemic damage in animal models. The present study examined the effects of the AK inhibitor, 5-iodotubercidin (5-IT) in an in vitro model of neuronal ischemia, specifically, combined oxygen-glucose deprivation of rat cortical mixed neuronal-glial cultures. Oxygen-glucose deprivation caused extensive neuronal loss which was accompanied by a marked increase in ADO release into the extracellular medium, was ameliorated by exogenous ADO (10 microM(-1) mM), and was exacerbated by a high concentration of the selective A1 receptor antagonist 8-cyclopentyl-1,3-dimethylxanthine (CPT; 10 microM). 5-IT (1 microM) had no effect on extracellular ADO levels nor on neuronal loss. However, AK activity in these cultures was markedly suppressed during oxygen-glucose deprivation. Taken together, these data demonstrate a marked down-regulation of AK activity during oxygen-glucose deprivation in this in vitro model, providing an endogenous mechanism contributing to the accumulation of extracellular ADO, which exerts neuroprotective effects by activating the ADO A1 receptor.
Lynch
J J
JJ
Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. james.j.lynch@abbott.com
Alexander
K M
KM
Jarvis
M F
MF
Kowaluk
E A
EA
D000241:Adenosine / Q000494:pharmacology; D000248:Adenosine Kinase / Q000037:antagonists & inhibitors*; D000818:Animals; D015687:Cell Hypoxia / Q000502:physiology*; D002478:Cells, Cultured; D004353:Drug Evaluation, Preclinical; D004791:Enzyme Inhibitors / Q000494:pharmacology*; D005947:Glucose / Q000172:deficiency*; D019579:Neocortex / Q000166:cytology / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017207:Rats, Sprague-Dawley; D013806:Theophylline / Q000031:analogs & derivatives / Q000494:pharmacology
D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; C053907:8-cyclopentyl-1,3-dimethylxanthine; D013806:Theophylline; D000248:Adenosine Kinase; D005947:Glucose; D000241:Adenosine