Baicalin Inhibits TLR2/4 Signaling Pathway in Rat Brain Following Permanent Cerebral Ischemia
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Baicalin Inhibits TLR2/4 Signaling Pathway in Rat Brain Following Permanent Cerebral Ischemia Xian-kun Tu,1,2 Wei-zhong Yang,1,2,4 Song-sheng Shi,1 Ye Chen,3 Chun-hua Wang,2 Chun-mei Chen,1 and Zhen Chen1
Abstract—Recent work from our laboratory demonstrated that baicalin attenuates inflammatory reaction and cerebral ischemia injury in rats. Toll-like receptor 2 and 4 (TLR2/4) and the downstream nuclear factor-kappa B (NF-κB) signaling pathway, which mediate the inflammatory reaction, are involved in the pathophysiological processes of cerebral ischemia. In this study, we investigated whether baicalin inhibits TLR2/4 signaling pathway in a rat model of permanent focal cerebral ischemia. Adult Sprague–Dawley rats underwent permanent middle cerebral artery occlusion (MCAO). Baicalin was administered by intraperitoneally injected twice at 2 and 12 h after the onset of ischemia. Cerebral infarct area and infarct volume were measured 24 h after MCAO. Expression of TLR2/4, NF-κB, inducible nitric oxide synthase (iNOS), and cyclooxygenase-2 (COX-2) were determined by RT-PCR or western blot. NO and PGE2 production in rat brain were measured 24 h after MCAO. Serum content of tumor necrosis factor-alpha (TNF-α) and interleukin-1β (IL-1β) were detected by ELISA. Baicalin reduced cerebral infarct area and infarct volume. Baicalin reduced the expression of TLR2/4 and NF-κB, decreased the expression and activity of iNOS and COX-2 in rat brain. Baicalin also attenuated the serum content of TNF-α and IL-1β. Our results suggest that baicalin inhibits the TLR2/4 signaling pathway in cerebral ischemia, which may be a mechanism underlying the baicalin’s neuroprotection. KEY WORDS: baicalin; cerebral ischemia; cyclooxygenase-2; inducible nitric oxide synthase; inflammation; interleukin-1β; nuclear factor-kappa B; toll-like receptors; tumor necrosis factor-α.
apoptosis (subacute phase, hours to days), and repair and regeneration (chronic phase, days to months) [2, 3]. Accumulating evidence showed that post-ischemic inflammation in the subacute phase of cerebral ischemia contributes to the expansion of cerebral infarction [4, 5]. Toll-like receptors (TLRs), which mediate the inflammatory reaction [6], are involved in the pathophysiological processes of ischemic brain injury [7–11]. Among the family of Toll-like receptors (TLRs), TLR2, and TLR4 are the focus of particular interest because they have been demonstrated to initiate the cerebral inflammation related to Alzheimer’s disease, Parkinson’s disease, brain injury, and ischemic stroke [12–14]. TLR2 and TLR4 (TLR2/4) activate a common signaling pathway leading to the activation of nuclear factorkappa B (NF-κB) transcription factor [6]. As a downstream transcription factor of TLR2/4 signaling pathway, NF-κB is a key regulator involved the inducible expression of proinflammatory mediators such as indu-
INTRODUCTION Stroke is one of the leading causes of morbidity and mortality worldwide in adults [1]. Ischemia-induced brain injury can be separated into three serial phases: excitotoxicity and b
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