Cerebral ischemia model with conscious mice. Involvement of NMDA receptor activation and derangement of learning and memory ability.
During anesthesia in mice, both common carotid arteries were tied loosely with an overhand knot suture (an occluder), while two snares (releasers) were placed in the knot so that it could be repeatedly tightened to occlude the arteries and loosened again to allow for reperfusion while the mice were conscious and unrestrained. The incidence of mortality as well as impairment of brain metabolism depended upon the length of cerebral ischemia. Cortical electroencephalogram (EEG) clearly reflected the regional ischemia as evidenced by electrical quiescence. Less mortality was observed with ischemic mice treated with dextrorphan (30 mg/kg p.o.). On day 1 (24 hr after ischemia), there were impairments in complex motor coordination, multichoice swim performance, and step-through or thermal pain-motivated avoidance responses. Thereafter, the battery of tests progressively improved. This improvement depended on the period of resumption of cerebral blood flow; the 7-day, postischemic lapse significantly reduced the deficit observed. Reduction in the degree of habituation of exploratory activity was also clearly observed following ischemic insult. Dextrorphan (1-30 mg/kg i.p.) given to ischemic mice was effective in the habituation and step-through-type passive avoidance test paradigms. In conclusion, 1) the decline in cognition as observed with ischemic mice is due to the temporal and reversible derangement of their neuronal networks; 2) excessively released glutamate is probably of major pathogenic importance in the consequences of cerebral ischemia based on the positive results of the N-methyl-D-aspartate receptor antagonist, dextrorphan; 3) the simple technique could be useful in elucidating the pathophysiologic mechanisms of ischemically elicited derangement of the cerebral organization; and 4) the model could be used to assess the efficiency of drugs with high clinical predictivity.
Himori
N
N
Department of Pharmacology, Nippon Roche Research Center, Kamakura, Japan.
Watanabe
H
H
Akaike
N
N
Kurasawa
M
M
Itoh
J
J
Tanaka
Y
Y
D000818:Animals; D001362:Avoidance Learning / Q000502:physiology; D001522:Behavior, Animal / Q000187:drug effects; D002545:Brain Ischemia / Q000378:metabolism / Q000503:physiopathology* / Q000523:psychology; D004195:Disease Models, Animal; D004569:Electroencephalography; D004734:Energy Metabolism; D006185:Habituation, Psychophysiologic / Q000502:physiology; D007858:Learning / Q000502:physiology*; D008297:Male; D008568:Memory / Q000502:physiology*; D051379:Mice; D008813:Mice, Inbred ICR; D008815:Mice, Inbred Strains; D009043:Motor Activity / Q000187:drug effects; D010146:Pain / Q000503:physiopathology; D011597:Psychomotor Performance / Q000502:physiology; D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter / Q000502:physiology*; D013550:Swimming
D016194:Receptors, N-Methyl-D-Aspartate; D017981:Receptors, Neurotransmitter