Protection of ischemic post conditioning against transient focal ischemia-induced brain damage is associated with inhibition of neuroinflammation via modulation of TLR2 and TLR4 pathways

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.

Toll-Like Receptors 2, -3 and -4 Prime Microglia but not Astrocytes Across Central Nervous System Regions for ATP-Dependent Interleukin-1β Release

“…Microglia express functional TLR229 and TLR330 in addition to TLR4. TLR signaling pathways may be involved in neurodegenerative disorders31, including motor neuron disease32, cerebral hypoxia-ischemia151633 and blood-spinal cord barrier dysfunction after ischemia/reperfusion injury34, along with microglial TLR229 and TLR330 in preclinical pain models. For these experiments zymosan and Pam3CSK4 (TLR2 activators)35 and poly(I:C), an activator of TLR336 were used.…”

“…Within this context, the recruitment of TLRs contributes to inflammation by amplifying pro-inflammatory cytokine and other mediator release. TLRs thus play a central role in inflammation's impact on neuronal cell health, and their participation in neuroinflammation and neurological diseases is an area of growing interest, encompassing not only acute and chronic neurodegenerative disorders151632333448, but also neuropathic pain49 and even mood disorders50. ATP appears to be one of the most powerful stimuli to enhance and accelerate IL-1β release, via activation of P2X 7 R and caspase 12223.…”

Alpha-Lipoic Acid Preconditioning and Ischaemic Postconditioning Synergistically Protect Rats from Cerebral Injury Induced by Ischemia and Reperfusion Partly via Inhibition TLR4/MyD88/ NF-κB Signaling Pathway

“…On the one hand, previous studies have shown that IPC suppresses the generation of ROS and the synthesis of pro-inflammatory cytokines during the reperfusion period and decreases cerebral-induced apoptosis [35,36]. Previous studies suggested that IPC reduced post-ischemic release of the cytokines TNF-α and IL-8; accordingly, they indicated that may be a promising neuroprotective strategy achieved by the inhibition of TLR4 pathway mediated inflammatory response [37,38]. Our data agree with these results and confirm that IPC protects against cerebral I/RI through anti-inflammatory and antioxidant mechanisms.…”

Interleukin‐10 release from astrocytes suppresses neuronal apoptosis via the TLR2/NFκB pathway in a neonatal rat model of hypoxic‐ischemic brain damage

“…; Wang et al . ), whereas a study by Hua and colleagues (Hua et al . ) showed that TLR2 appears to be neuroprotective by enhancing the activation of protective signaling in response to cerebral ischemia/reperfusion.…”