2-benzylidene-3-(cyclohexylamino)-2-3-dihydro-1h-inden-1-one and Encephalitis

Activation of mitogen-activated protein kinases (MAPKs), particularly c-jun-N-terminal kinases (JNK) and p38 exacerbates stroke injury by provoking pro-apoptotic and pro-inflammatory cellular signaling. MAPK phosphatase-1 (MKP-1) restrains the over-activation of MAPKs via rapid de-phosphorylation of the MAPKs. We therefore examined the role of MKP-1 in stroke and studied its inhibitory effects on MAPKs after experimental stroke.. Male mice were subjected to transient middle cerebral artery occlusion (MCAO). MKP-1 knockout (KO) mice and a MKP-1 pharmacological inhibitor were utilized. We utilized flow cytometry, immunohistochemistry (IHC), and Western blots analysis to explore MKP-1 signaling and its effects on apoptosis/inflammation in the brain and specifically in microglia after stroke.. MKP-1 was highly expressed in the nuclei of both neurons and microglia after stroke. MKP-1 genetic deletion exacerbated stroke outcome by increasing infarct, neurological deficits and hemorrhagic transformation. Additionally, delayed treatment of the MKP-1 pharmacological inhibitor worsened stroke outcome in wild type (WT) mice but had no effect in MKP-1 KO mice. Furthermore, MKP-1 deletion led to increased c-jun-N-terminal kinase (JNK) activation and microglial p38 activation after stroke. Finally, MKP-1 deletion or inhibition increased inflammatory and apoptotic response as evidenced by the increased levels of interleukin-6 (IL-6), tumor necrosis factor α (TNFα), ratio of p-c-jun/c-jun and cleaved caspase-3 following ischemia.. We have demonstrated that MKP-1 signaling is an endogenous protective mechanism in stroke. Our data imply that MKP-1 possesses anti-apoptotic and anti-inflammatory properties by simultaneously controlling the activities of JNK and microglial p38.

Topics: Animals; Brain Injuries; Cyclohexylamines; Disease Models, Animal; Dose-Response Relationship, Drug; Dual Specificity Phosphatase 1; Encephalitis; Enzyme Activation; Enzyme Inhibitors; Gene Expression Regulation, Enzymologic; Indenes; Infarction, Middle Cerebral Artery; Male; MAP Kinase Kinase 4; Mice, Knockout; Neurologic Examination; p38 Mitogen-Activated Protein Kinases