Abstract
Background and purposeIschemic postconditioning has been demonstrated to be a protective procedure to brain damage caused by transient focal ischemia/reperfusion. However, it is elusive whether the protection of postconditioning against brain damage and neuroinflammation is via regulating TLR2 and TLR4 pathways. In the present study, we examined the protection of ischemic postconditioning performed immediately prior to the recovery of cerebral blood supply on brain damage caused by various duration of ischemia and tested the hypothesis that its protection is via inhibition of neuroinflammation by modulating TLR2/TLR4 pathways.MethodsBrain damage in rats was induced by using the middle cerebral artery occlusion (MCAO) model. Ischemic postconditioning consisting of fivecycles of ten seconds of ischemia and reperfusion was performed immediately following theischemic episode Theduration of administration of ischemic postconditioning was examined by comparing its effects on infarction volume, cerebral edema and neurological function in 2, 3, 4, 4.5and 6 hour ischemia groups. The protective mechanism of ischemic postconditioning was investigated by comparing its effects on apoptosis, production of the neurotoxic cytokine IL-1β and the transcription and expression of TLR2, TLR4 and IRAK4 in the 2 and 4.5 hour ischemia groups.ResultsIschemic postconditioning significantly attenuated cerebral infarction, cerebral edema and neurological dysfunction in ischemia groups of up to 4 hours duration, but not in 4.5and 6 hour ischemia groups. It also inhibited apoptosis, production of IL-1β, abnormal transcription and expression of TLR2, TLR4 and IRAK4 in the 2 hour ischemia group, but not in the 4.5 hour ischemia group.ConclusionsIschemic postconditioning protected brain damage caused by 2, 3 and 4 hours of ischemia, but not by 4.5 and 6 hours of ischemia. The protection of ischemic postconditioning is associated with its inhibition of neuroinflammation via inhibition of TLR2 and TLR4 pathways.
Highlights
Cerebral damage due to reperfusion following ischemia has been proven to be an important factor affecting the prognosis of revascularization of occluded blood vessels [1]
Neuroinflammation mediated by Toll-like receptor 2 (TLR2) or TLR4 was proved to play an active role in aggravating brain damage caused by ischemia/reperfusion
TLR2 and TLR4 are both found to be expressed on neurons and glial cells such as microglia and astrocytes and would be activated when they are attached to their corresponding ligands such as heat-shock proteins (HSPs) and high mobility group box 1 (HMGB1) [9]
Summary
Cerebral damage due to reperfusion following ischemia has been proven to be an important factor affecting the prognosis of revascularization of occluded blood vessels [1]. Ahmad et al found that the expressional levels of neurotoxic cytokines TNF-α and IL-1β induced by traumatic brain injury was mitigated in TLR4 knockout mice [11]. These studies showed that inhibition of TLR2- or TLR4- mediated neuroinflammation would exert protection on ischemia/reperfusion-induced brain damage. We examined the protection of ischemic postconditioning performed immediately prior to the recovery of cerebral blood supply on brain damage caused by various duration of ischemia and tested the hypothesis that its protection is via inhibition of neuroinflammation by modulating TLR2/TLR4 pathways
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