Isoflurane preconditioning provides neuroprotection against stroke by regulating the expression of the TLR4 signalling pathway to alleviate microglial activation.

Abstract

Excessive microglial activation often contributes to inflammation-mediated neurotoxicity in the ischemic penumbra during the acute stage of ischemic stroke. Toll-like receptor 4 (TLR4) has been reported to induce microglial activation via the NF-κB pathway. Isoflurane preconditioning (IP) can provide neuroprotection and inhibit microglial activation. In this study, we investigated the roles of the TLR4 signalling pathway in IP to exert neuroprotection following ischemic stroke in vivo and in vitro. The results showed that 2% IP alleviated neurological deficits, reduced the infarct volume, attenuated apoptosis and weakened microglial activation in the ischemic penumbra. Furthermore, IP down-regulated the expression of HSP 60, TLR4 and MyD88 and up-regulated inhibitor of IκB-α expression compared with I/R group in vivo. In vitro, 2% IP and a specific inhibitor of TLR4, CLI-095, down-regulated the expression of TLR4, MyD88, IL-1β, TNF-α and Bax, and up-regulated IκB-α and Bcl-2 expression compared with OGD group. Moreover, IP and CLI-095 attenuated microglial activation-induced neuronal apoptosis, and overexpression of the TLR4 gene reversed the neuroprotective effects of IP. In conclusion, IP provided neuroprotection by regulating TLR4 expression directly, alleviating microglial activation and neuroinflammation. Thus, inhibiting the activation of microglial activation via TLR4 may be a new avenue for stroke treatment.

• Authors: Meiyan Sun, Bin Deng, Xiaoyong Zhao, Changjun Gao, Lu Yang, Hui Zhao, Daihua Yu, Feng Zhang, Lixian Xu, Lei Chen, Xude Sun
• Journal: Scientific reports (Sci Rep) Vol. 5 Pg. 11445 (Jun 18 2015) ISSN: 2045-2322 [Electronic] England
• PMID: 26086415 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Biomarkers
• Chaperonin 60
• I-kappa B Proteins
• Myeloid Differentiation Factor 88
• Neuroprotective Agents
• Nfkbia protein, rat
• Toll-Like Receptor 4
• Tumor Necrosis Factor-alpha
• NF-KappaB Inhibitor alpha
• Isoflurane

Topics

• Animals
• Apoptosis (drug effects)
• Biomarkers
• Brain Infarction (drug therapy, genetics, metabolism, pathology, physiopathology)
• Cells, Cultured
• Chaperonin 60 (metabolism)
• Disease Models, Animal
• Gene Expression
• Gene Expression Regulation (drug effects)
• I-kappa B Proteins (metabolism)
• Ischemic Preconditioning
• Isoflurane (administration & dosage, pharmacology)
• Male
• Microglia (drug effects, metabolism)
• Models, Molecular
• Myeloid Differentiation Factor 88 (metabolism)
• NF-KappaB Inhibitor alpha
• Neuroprotective Agents (administration & dosage, pharmacology)
• Rats
• Reperfusion Injury (drug therapy, genetics, metabolism)
• Signal Transduction (drug effects)
• Stroke (drug therapy, genetics, metabolism, pathology, physiopathology)
• Toll-Like Receptor 4 (genetics, metabolism)
• Tumor Necrosis Factor-alpha (genetics, metabolism)