| Budget Amount *help |
¥3,500,000 (Direct Cost: ¥3,500,000)
Fiscal Year 2003: ¥1,400,000 (Direct Cost: ¥1,400,000)
Fiscal Year 2002: ¥2,100,000 (Direct Cost: ¥2,100,000)
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| Research Abstract |
The aim of this study is to determine whether neuroprotective agents (a selective thrombin inhibitor, argatroban, or immunosuppressant, FK506), would prevent neuronal cell death and whether extra-mildhypothermia (35℃) would enhance the neuroprotecive effect of a selective thrombin inhibitor following transient focal ischemia in rats. Sprague-Dawley rats were subjected to MCAo using an intraluminal suture technique for 2hrs. The rats were repeifused for 24h and decapitated for infarct and edema analysis. Argatroban-treated animals received a continuous injection of argatroban (3.0mg/kg) for 24 hrs by after the onset of ischemia, while vehide-treated groups received same dose of vehide. FK506-treated animals received a single injection of FK506 (0.3mg/kg) venously at 2 hours after isehemic induction, while vehide-treated groups received same dose of vehide. During ischemia, temporal muscle and rectal temperatures were monitored and maintained at 37℃ in the normothermic animals and at 35℃
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in the hypothermic animals. Animals were randomly divided into the following four groups (each, n=6): (I) vehicle-treated normothermic group (control) at 37℃ (rectal and temporalis muscle temperatures); (II) argatroban or FK506-treated normothermic group at 37℃; (III) vehicle-treated hypothermic group at 35℃; (IV) argatroban or FK506-treated hypothermic group at 35℃. Temporal muscle and rectal temperatures were maintained during ischemia at 37±0.2℃ (normothermic groups) or 35±0.2℃ (hypothermic groups). Argatroban (162±28mm^3) ameliorated the cortical ischemic damage compared with the control (205±55mm^3) significantly (p<0.05). Moreover, argatroban with mild hypothermia decreased the cortical infarct volume (114±28mm^3) significantly compared with those of groups I and III(170±27mm^3) (p<0.05). Furthermore, argatroban with mild hypothermia also decreased the cortical edema (29±11mm^3) volume significantly compared with those of groups I, II and III (68±23mm^3、52±13mm^3、61±16mm^3) (p<0.05). In the borderzone of cortex and striatum, argatroban reduced expression of the proapoptotic Bax protein, whereas increased upregulation of antiapoptotic protein Bcl. Moreover, TUNEL positive cells in the borderzone were decreased in the groups treated by argatroban Argatroban improved neurological symptoms significantly (p<0.05) and also improved survival rate. The combination of FK506 and mild hypothermia significantly reduced infarct volume (cortex,-61%;striatum,-31%) and edema volume (cortex,-57%;striatum,-41%), while mild hypothermia or FK506 alone failed to improve ischemic brain damage. These results demonstrate that extra-mild hypothermia (35℃) enhances neuroprotective effects of neuroprotective agents (a selective thrombin inhibitor, argatroban or immunosuppressant, FK506), suggesting that this combined therapy, extra-mild hypothermia (35℃) plus neuroprotective agents, may be a new therapeutic strategy for the treatment of acute stroke. Less
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