Edaravone Dexborneol Alleviates Cerebral Ischemic Injury via MKP-1-Mediated Inhibition of MAPKs and Activation of Nrf2

Abstract

The edaravone and dexborneol concentrated solution for injection (edaravone-dexborneol) is a medication used clinically to treat neurological impairment induced by ischemic stroke. This study was aimed at investigating the preventive effects and the underlying mechanisms of edaravone-dexborneol on cerebral ischemic injury. A rat four-vessel occlusion (4-VO) model was established, and the neuronal injury and consequent neurological impairment of rats was investigated. Brain tissue malondialdehyde (MDA), myeloperoxidase (MPO), and nitric oxide (NO) levels were determined. The levels of proteins in mitogen-activated protein kinases (MAPKs), nuclear factor erythroid 2-related factor 2 (Nrf2), and nuclear factor-κB (NF-κB) signaling pathways were determined by western immunoblotting. The function of mitogen-activated protein kinase phosphatase 1 (MKP-1) was investigated using both western blot and immunofluorescence methods, and the effect of the MKP-1 inhibitor, (2E)-2-benzylidene-3-(cyclohexylamino)-3H-inden-1-one (BCI), was investigated. The results indicated that edaravone-dexborneol alleviated neurological deficiency symptoms and decreased apoptosis and neuron damage in the hippocampal CA1 area of the ischemic rats. Edaravone-dexborneol increased the MKP-1 level; decreased the phosphorylation of extracellular signal-regulated kinase (ERK), c-Jun N-terminal kinase (JNK), and p38 mitogen-activated protein kinase (p38 MAPK); inhibited NF-κB p65 activation; and boosted Nrf2 activation, all of which were partially reversed by the MKP-1 inhibitor, BCI. The above results indicated that the upregulation of MKP-1 contributed to the protective effects of edaravone-dexborneol against ischemic brain injury. Our findings support the hypothesis that edaravone-dexborneol can alleviate cerebral ischemic injury via the upregulation of MKP-1, which inhibits MAPKs and activates Nrf2.