title: Inhibition of adenosine kinase during oxygen-glucose deprivation in rat cortical neuronal cultures.
abstract: 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.
authors.affiliation: Neurological and Urological Diseases Research, Pharmaceutical Products Division, Abbott Laboratories, Abbott Park, IL 60064-3500, USA. james.j.lynch@abbott.com
authors.forename: J J
authors.initials: JJ
authors.lastname: Lynch
authors.forename: K M
authors.initials: KM
authors.lastname: Alexander
authors.forename: M F
authors.initials: MF
authors.lastname: Jarvis
authors.forename: E A
authors.initials: EA
authors.lastname: Kowaluk
mesh_terms: 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
chemical_list: D004791:Enzyme Inhibitors; D058915:Purinergic P1 Receptor Antagonists; C053907:8-cyclopentyl-1,3-dimethylxanthine; D013806:Theophylline; D000248:Adenosine Kinase; D005947:Glucose; D000241:Adenosine