A self-developed MyD88 inhibitor across the blood-brain barrier fully reverses acute cerebral ischemia-reperfusion injury
Research Square (Research Square)(2022)
摘要
Background: The acute ischemia-reperfusion injury that occurs after an ischemic stroke is almost inevitable. In treating ischemic stroke, the prevention and treatment of cerebral ischemia-reperfusion injury (CIRI) is an undeniable difficulty clinically. Despite increasing studies being done on the subject, medicines showing effective neurological improvements after reperfusion is still minimal. This study aims to investigate the effects of a self-developed MyD88 inhibitor (TJ-M2010-5) on CIRI and its mechanism.Methods: The middle cerebral artery occlusion (MCAO) model was used to simulate CIRI in mice. BV-2 cells were cultured for the mechanism study by LPS stimulation in vitro. Neurological deficit score and cerebral infarction volume were studied. Immunofluorescence staining was used to measure neuronal damage and apoptosis in the brain. The anti-inflammation effect of TJ-M2010-5 was evaluated by analyzing the expression of inflammatory cytokines, activation of microglia and infiltration of peripheral myeloid cells. The expression of TLR4/Myd88/NF-κB signaling pathway protein was detected by Simple Western. The concentrations of TJ-M2010-5 in blood and brain were analyzed by LC-MS methods.Results: The cerebral infarction volume decreased in mice treated with TJ-M2010-5, with the most prominent decrease in approximately 80% of the original infarction volume. Moreover, the downregulation of apoptosis and NeuN protein expression in the brain of infarction area further indicated that neuronal damage was alleviated. TJ-M2010-5 treatment also reduced the infiltration ratio of peripheral myeloid cells in the cerebral infarction area and increased the proportion of inactive microglia. The inflammatory cytokines decreased after TJ-M2010-5 treatment in infarction area and supernatant. TJ-M2010-5 downregulated the expression of iNOS and inhibited TLR4/MyD88/NF-κB signaling pathway in vivo and in vitro. In addition, TJ-M2010-5 could freely pass through the blood-brain barrier.Conclusions: TJ-M2010-5 has shown to have an excellent therapeutic effect on CIRI by inhibiting TLR4/Myd88/NF-κB signaling pathway to decrease excessive inflammatory response, showing the potential to change the history that there is no effective medicine for the treatment of CIRI. and also has the potential to be utilized in brain neuroinflammatory diseases.
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关键词
myd88 inhibitor,blood-brain blood-brain barrier,self-developed,ischemia-reperfusion
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