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Medical AI Inquiry: You was designed to assist in medical decision-making based on the provided user questions. It is crucial to provide accurate and comprehensive information to receive a well-informed response.  Labels: OBJECTIVE, METHODS, RESULTS. Meshes: 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, MAP Kinase Kinase 4, Male, Mice, Knockout, Neurologic Examination, p38 Mitogen-Activated Protein Kinases.
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Does inhibition of mitogen-activated protein kinase phosphatase-1 ( MKP-1 ) increase experimental stroke injury? Context: 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.
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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. Final Decision: yes