新生兒窒息腦病變是指出生前後因缺氧而引起的腦部損傷。這種傷害是造成嬰幼兒神經病變最常見的原因，其後遺症包括智力障礙、腦性麻痺、抽痙或是學習障礙。目前對此種窒息腦傷並無有效的治療方式。除了研發有效的治療方式之外，科學家也致力於一些“前置處理”(preconditioning)方面的研究。前置處理就是在一個致命的傷害之前事先給予一個非致命性的刺激，進而保護生物體對抗致命的傷害，使所受的傷害減少。這方面的研究可以提供一些可能的機制來預防及治療新生兒窒息腦傷。
　　我們的動物模式是將出生後七天的幼鼠在遭遇缺血缺氧傷害前24小時以腹腔注射給予一個低劑量的革蘭氏陰性菌細胞壁上的脂多醣體(Lipopolysaccharide，LPS)，並在其行為及病理上發現了明顯的神經保護效果。進一步研究其潛在機制後，發現LPS前處理可以在缺血缺氧傷害後減少活化態的Caspase-3，Caspase-9，被裂解的poly (ADP-ribose) polymerase (PARP)，自由基(Reactive oxygen species，ROS)的表現量，並且增加c-Inhibitor of apoptosis protein (cIAP)的表現量。在前置處理的早期機制方面我們發現TLR4扮演著重要的的角色；相較之下，Mitogen-activated protein kinases (MAPK)和ROS似乎就不是那麼的重要。
　　總而言之，在這份研究中我們先在新生鼠腦中建立了一個LPS前置處理的動物模式，並證實由LPS前置處理所達到的腦部保護作用機制包括減少ROS的產量及細胞的自我凋零(Apoptosis)，並增加抗自我凋零(anti-apoptosis)的蛋白質cIAP的表現量進而達到神經保護的作用；至於前置處理的早期的機制還有待釐清。我們的研究可以對新生兒窒息腦傷的治療方式提供一些可能的研究方向。

　　Perinatal hypoxic-ischemic (HI) brain injury is a major cause of neonatal mortality and long-term disability such as mental retardation, cerebral palsy, learning disability, and seizures. There are still no effective therapies against neonatal HI brain injury to date. A sublethal stress before a lethal injury can reduce the neuronal death, a phenomenon called “preconditioning”. Elucidating the underlying mechanisms of preconditioning may provide potential neuroprotective therapy for neonatal HI encephalopathy.
　　We first established a lipopolysaccharide (LPS) preconditioning model in neonatal rats by pretreating rat pups with a low dose of LPS 24 hours before HI injury on postnatal day 7. We found that the degree of brain injury of LPS-preconditioned rats were significantly less than that of NS-pretreated rats. The behavioral performance measured by Morris water maze of LPS-preconditioned rats was also significantly better than that of NS-pretreated rats. The expression levels of apoptosis markers, such as cleavaged form of caspase-3, caspase-9, poly (ADP-ribose) polymerase (PARP), and the production of reactive oxygen species (ROS) in the cortex were significantly lower in the LPS-preconditioned rats compared to NS-pretreated rats at 24 hours after HI injury.
　　Among the mitogen-activated protein kinases (MAPK) family, LPS preconditioning could increase the phosphorylation levels of extracellular signal-related kinase (ERK) instead of p38. However, inhibition of MAP kinase kinase (MEK) or p38 did not affect the neuroprotection induced by LPS preconditioning. We also observed that LPS could up-regulate ROS production up to 24 hours after LPS injection. However, ROS scavenger, N-(2-mercaptopropionyl) glycine (N-2-MPG), could not abolish the LPS induced neuroprotection. In contrast, toll-like receptor 4 (TLR4) was involved in the LPS-induced neuroprotection since LPS preconditioning could not be induced in the C3H/HeJ mice, a TLR4 deficient mice.
　　In conclusion, we established a LPS preconditioning model in immature rat brains, and the neuroprotection mechanisms in this model involved the down-regulation of ROS production and the reduction of apoptosis. The LPS-preconditioning mechanisms in the neonatal rat brain remain to be elucidated.

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