Therapeutic time window of post-ischemic mild hypothermia and the gene expression associated with the neuroprotection in rat focal cerebral ischemia.
Hypothermia is the only neuroprotective therapy proven to be clinically effective. Identifying the molecules that play important roles in the efficacy of hypothermia, we developed a multi-channel computer-controlled system, in which the brain temperatures of freely moving rats were telemetrically monitored and maintained below 35 degrees C, and examined the time window necessary to exert its significant neuroprotective effects. Eight-week-old SD rats were subjected to a 2h middle cerebral artery occlusion (MCAO) with an intraluminal filament, and post-ischemic hypothermia was introduced at 0, 2, 4, or 6h after reperfusion until the rats were killed 2 days after MCAO. Since a significant protection was observed when hypothermia was started within 4h after reperfusion, it was concluded that the therapeutic time window of mild hypothermia lasts for 4h after reperfusion in our model. On the basis of the window, comprehensive gene expression analyses using oligonucleotide microarrays were conducted and identified potential genes related to the efficacy of hypothermia, which included inflammatory genes like osteopontin, early growth response-1, or macrophage inflammatory protein-3alpha. Therefore, the neuroprotective effects of post-ischemic mild hypothermia were strongly suggested to be mainly associated with the reduction of neuronal inflammation.
Ohta
Hiroyuki
H
Pharmacology Research Laboratories III, Pharmaceutical Research Division, Takeda Pharmaceutical Company Limited, 17-85, Jusohonmachi 2-Chome, Osaka, Japan.
Terao
Yasuko
Y
Shintani
Yasushi
Y
Kiyota
Yoshihiro
Y
D000818:Animals; D001831:Body Temperature / Q000502:physiology; D002545:Brain Ischemia / Q000235:genetics* / Q000378:metabolism / Q000628:therapy*; D002470:Cell Survival / Q000235:genetics; D002540:Cerebral Cortex / Q000378:metabolism / Q000503:physiopathology; D002544:Cerebral Infarction / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D054418:Chemokine CCL20; D019742:Chemokines, CC / Q000235:genetics / Q000378:metabolism; D019610:Cytoprotection / Q000235:genetics*; D004195:Disease Models, Animal; D051766:Early Growth Response Protein 1 / Q000235:genetics / Q000378:metabolism; D004660:Encephalitis / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy*; D015870:Gene Expression / Q000502:physiology*; D007036:Hypothermia, Induced / Q000379:methods* / Q000592:standards; D020244:Infarction, Middle Cerebral Artery / Q000235:genetics / Q000378:metabolism / Q000628:therapy; D018836:Inflammation Mediators / Q000378:metabolism; D019402:Macrophage Inflammatory Proteins / Q000235:genetics / Q000378:metabolism; D008297:Male; D009410:Nerve Degeneration / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D020411:Oligonucleotide Array Sequence Analysis; D053495:Osteopontin / Q000235:genetics / Q000378:metabolism; D051381:Rats; D015427:Reperfusion Injury / Q000503:physiopathology / Q000517:prevention & control / Q000628:therapy; D013997:Time Factors; D015854:Up-Regulation / Q000502:physiology
C486997:Ccl20 protein, rat; D054418:Chemokine CCL20; D019742:Chemokines, CC; D051766:Early Growth Response Protein 1; C486110:Egr1 protein, rat; D018836:Inflammation Mediators; D019402:Macrophage Inflammatory Proteins; D053495:Osteopontin