Hippocampal injury and neurobehavioral deficits following hyperglycemic cerebral ischemia: effect of theophylline and ZM 241385.
OBJECTIVE
The effects of the adenosine receptor antagonists theophylline (for A1 and A2) and ZM 241385 (for A2A) on hippocampal injury and Morris water maze (MWM) performance in rats were investigated following normoglycemic and hyperglycemic cerebral ischemia (induced by four vessel occlusion for 10 minutes).


METHODS
Theophylline (36 mg/kg), ZM 241385 (1 mg/kg), or an equivalent volume of saline was administered to rats intraperitoneally 30 minutes before ischemia was induced. Moderate hyperglycemia was achieved by intraperitoneal administration of D-glucose (3 g/kg, 15 minutes before induction of ischemia). Morris water maze trials were performed on the 6th. 7th, and 8th days after ischemic insult. After the conclusion of the performance tests, the rat brains were cut into 8-microm sections, stained with cresyl violet and acid fuchsin, and evaluated in a blinded fashion to determine the extent of injury. Theophylline worsened injury in the hippocampus following normoglycemic and hyperglycemic ischemia. Moreover, theophylline significantly (p < 0.05, six animals) worsened latency and learning index (LI) scores during the MWM trials in both normoglycemic and hyperglycemic animals. On the other hand, ZM 241385 had no effect on either ischemic injury or MWM performance in normoglycemic animals. In the animals in the hyperglycemic ischemia group, however, ZM 241385 significantly (p < 0.05, five animals) reduced injury in the CA1 (94.6 +/- 1.7% compared with 79.2 +/- 10.9%), CA3 (26 +/- 12.5% compared with 11.2 +/- 4.3%), and hilum (22.4 +/- 8.1% compared with 11 +/- 5.5%) regions. In addition, ZM 241385 significantly improved latency (52 +/- 29.7 seconds compared with 24.8 +/- 11.2 seconds, p < 0.05) and LI scores (203.2 +/- 33.3 compared with 152.1 +/- 31.8, p < 0.05) in the MWM trials. A statistically significant correlation was also found between hippocampal injury (CA1, CA3, and hilum) and MWM performance.


CONCLUSIONS
The results of this study provide further evidence for a neuromodulatory role of adenosine during normoglycemic and hyperglycemic ischemia.
Higashi
Hisato
H
Department of Neurological Surgery, University of Washington, Seattle 98104, USA.
Meno
Joseph R
JR
Marwaha
Amitoj S
AS
Winn
H Richard
HR
D000241:Adenosine / Q000502:physiology; D000818:Animals; D001786:Blood Glucose / Q000378:metabolism*; D016923:Cell Death / Q000187:drug effects; D002544:Cerebral Infarction / Q000473:pathology*; D004924:Escape Reaction / Q000187:drug effects* / Q000502:physiology; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007274:Injections, Intraperitoneal; D008297:Male; D018782:Maze Learning / Q000187:drug effects* / Q000502:physiology; D009474:Neurons / Q000187:drug effects / Q000473:pathology; D058915:Purinergic P1 Receptor Antagonists; D051381:Rats; D017208:Rats, Wistar; D018047:Receptors, Purinergic P1 / Q000502:physiology; D013806:Theophylline / Q000494:pharmacology*; D014227:Triazines / Q000494:pharmacology*; D014230:Triazoles / Q000494:pharmacology*
D001786:Blood Glucose; D058915:Purinergic P1 Receptor Antagonists; D018047:Receptors, Purinergic P1; D014227:Triazines; D014230:Triazoles; C097270:ZM 241385; D013806:Theophylline; D000241:Adenosine