MATSUMOTO Mishiya Yamaguchi Univ., Graduate School of Medicine, Associate Professor (60243664)
MIZUKAMI Youichi Yamaguchi Univ., Science Research Center, Associate Professor (80274158)
HIRATA Takao Yamaguchi Univ., Hospital, Assistant Professor (40420533)
森本 康裕 山口大学, 医学部附属病院, 講師 (60325230)
福田 志朗 山口大学, 医学部附属病院, 助手 (70322245)
|Budget Amount *help
¥16,060,000 (Direct Cost: ¥14,800,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2007: ¥5,460,000 (Direct Cost: ¥4,200,000、Indirect Cost: ¥1,260,000)
Fiscal Year 2006: ¥4,600,000 (Direct Cost: ¥4,600,000)
Fiscal Year 2005: ¥6,000,000 (Direct Cost: ¥6,000,000)
We have previously demonstrated that repeated hyperbaric oxygen (HBO) exposure (3.5 absolute atmosphere (ATA)) prior to ischemia significantly reduced loss of hippocampal CAl neurons after transient forebrain ischemia. The present study examined 1) the effects of different pressure level of HBO, 2) neuroprotective mechanism (by using microarray technology), and 3) biological verification (by using protein synthesis inhibitor).
Rats were subjected to forebrain ischemia (8 min)at 12 hours after five sessions of 100% oxygen exposure (100% 02 group) and HBO (at 2 ATA or 3.5 MA, (HBO-2ATA, -3.5ATA group, respectively)) or sham treatment (sham group). 3.5ATA-HBO maximally protected hippocampal CAl neurons (survived neurons : 68%) against ischemic damage(sham group : 2.7%, 100% 02 group : 13.5%, 2 ATA-HBO group : 44%).
Microarray data showed significant up-regulation in p75^<NTR>, C/EBP δ, CD74, whose time-course expressions corresponded to HBO-induced neuroprotection. The protein levels were a
lso significantly increased (2.9, 2.0, and 7.9, respectively). Further, we examined the modulation of neuroprotection by administering protein synthesis inhibitor, anisomycin (AM) or cycloheximide (CY) prior to HBO exposure, both of which inhibited HBO-induced neuroprotection, survived neuron being 2.1 and 8.9% in the rats treated with AM and CY, respectively. With administration of p38 MAP kinase inhibitor, SB203580 (SB), before each treatment with AM-HBO, HBO-induced neuroprotection was resumed. In contrast, with administration of SB before each treatment with CY-HBO, HBO-induced neuroprotection was only marginal. Because AM, but not CY, has been known to have activating property of p38 mitogen-activated protein (p38MAP) kinase, our results suggest that the mechanism of HBO-induced neuroprotection is involved in suppression of p38 MAP kinase.
In conclusion, HBO induced neuroprotection against the neuronal damage in the hippocampal CAl following forebrain ischemia is mediated by de novo protein synthesis relevant to neurotrophin and inflammatory-immune system and to suppression of p38 MAP kinase. Less