1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) Urea Exerts Neuro-Protective Effects Against Ischemic Injury via Suppressing JNK/p38 MAPK-Mediated Mitochondrial Apoptosis Pathway
Journal of Stroke and Cerebrovascular Diseases(2021)
Abstract
Background: 1-trifluoromethoxyphenyl-3-(1-propionylpiperidin-4-yl) urea (TPPU) is a novel soluble epoxide hydrolase inhibitor which can protect against cerebral ischemic injury in middle cerebral artery occlusion rat model. However, the effects and poten-tial mechanisms of TPPU on mitochondrial dysfunction are poorly understood. Materi-als and Methods: In oxygen-glucose deprivation/reperfusion (OGD/R)-induced cortical neurons, the effect of TPPU on cell viability was measured by MTT assay and apoptosis was evaluated using TUNEL assay. Mitochondria were observed by transmission elec-tron microscopy and Mitotracker green staining assay, mitochondrial membrane poten-tial was determined by JC-1 staining assay, activities of mitochondrial respiratory chain complexes (MRCC) I-IV and ATPase were measured by MRCC Activity Assay Kits and spectrophotometer. Western blot was used to investigate the effects of TPPU on apoptosis-related proteins. Results: TPPU treatment demonstrated significant protective effect on the OGD/R-induced cortical neurons by reducing cell death and number of apoptotic cells, stabilizing mitochondrial ultrastructure and morphology, increasing mitochondrial membrane potential and activities of MRCC I-IV and ATPase. Further-more, TPPU treatment might effectively reverse the upregulation of caspase-3, Bax, p38 mitogen-activated protein kinase (MAPK) and c-Jun N-terminal protein kinase (JNK), alleviate the inhibition of Bcl-2 in OGD/R-induced cortical neurons. Conclusions: TPPU exerts a marked neuroprotective effect against mitochondrial dysfunction after cerebral ischemia potentially via suppressing JNK/p38 MAPK-mediated mitochondrial apopto-sis signal pathway, it may be a promising neuroprotective agent for cerebral ischemia.
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Key words
TPPU-Ischemic,stroke-Mitochondrial,dysfunction-Neuronal,apoptosis-p38-JNK-OGD,R-Neuroprotective
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