Activation of Toll-like receptor 4 signaling contributes to hippocampal neuronal death following global cerebral ischemia/reperfusion

作者：Hua Fang; Ma Jing; Ha Tuanzhu; Xia Yeling; Kelley Jim; Williams David L; Kao Race L; Browder I William; Schweitzer John B; Kalbfleisch John H; Li Chuanfu^*

来源：Journal of Neuroimmunology, 2007, 190(1-2): 101-111.

DOI：10.1016/j.jneuroim.2007.08.014

• TLR4
• cerebral
• ischemia
• repel-fusion

Toll-like receptors (TLRs) play a critical role in the induction of innate immune responses which have been implicated in neuronal death induced by global cerebral ischemia/reperfusion (GCI/R). The present study investigated the role and mechanisms-of-action of TLR4 signaling in ischemia-induced hippocampal neuronal death. Neuronal damage, activation of the TLR4 signaling pathway, expression of pro-inflammatory cytokines and activation of the PI3K/Akt signaling pathway in the hippocampal formation (HF) were assessed in wild type (WT) mice and TLR4 knockout (TLR4(-/-)) mice after GCI/R. GCI/R increased expression of TLR4 protein in the hippocampal formation (HF) and other brain structures in WT mice. Phosphorylation of the inhibitor of kappa B (p-I kappa B) as well as activation of nuclear factor kappa B (NF kappa B) increased in the HF of WT mice. In contrast, there were lower levels of p-I kappa B and NF kappa B binding activity in TLR4(-/-) mice subjected to GCI/R. Pro-inflammatory cytokine expression was also decreased, while phosphorylation of Akt and GSK3 beta were increased in the HF of TLR4(-/-) mice after GCI/R. These changes correlated with decreased neuronal death/apoptosis in TLR4(-/-) mice following GCI/R. These data suggest that activation of TLR4 signaling contributes to ischemia-induced hippocampal neuronal death. In addition, these data suggest that modulation of TLR4 signaling may attenuate ischemic injury in hippocampal neurons.

• 出版日期2007-10