Activation of p38^MAPK in Microglia After Ischemia

Abstract

p38 MAPK has been implicated in the regulation of promflammatory cytokines and apoptosis in vitro. To understand its role in neurodegeneration, we determined the time course and localization of the dually phosphorylated active form of p38 MAPK in hippocampus after global forebrain ischemia. Phosphorylated p38 MAPK and mitogen-activated protein kinase-activated protein 2 activity increased over 4 days after ischemia. Phosphorylated p38 MAPK immunoreactivity was observed in microglia in regions adjacent to, but not in, the dying CAl neurons. In contrast, neither c-Jun N-terminal kinase 1 nor p42/p44M~activity was altered after ischemia. These results provide the first evidence for localization of activated p38 MAPK in the CNS and support a role for p38 MAPK in the microglial response to stress.

Deciphering of Mitochondrial Cardiolipin Oxidative Signaling in Cerebral Ischemia-Reperfusion

“…25 The late appearance of mediators from AA oxygenation could be related to the postischemic inflammatory response after global cerebral ischemia. 26 Alternatively, reperfusion-associated oxidation of phospholipids could produce their modified forms that might be metabolized by Ca 2+ -independent phospholipases, for example by iPLA 2γ in mitochondria. A specific feature of this pathway may be its selectivity toward a peroxidizable and subsequently hydrolyzable phospholipid substrate, a unique phospholipid of mitochondria, CL.…”

p38 Mitogen-Activated Protein Kinase Contributes to Adenosine A1Receptor-Mediated Synaptic Depression in Area CA1 of the Rat Hippocampus

“…Previous studies have found that the p38 MAPK pathway is activated after hypoxia/ischemia in brain tissue (Walton et al, 1998;. However, there is evidence that p38 MAPK activity is deleterious, mediating the cell death induced by hypoxia (Y. , oxygen glucose deprivation, magnesium withdrawal, and glutamate receptor agonist exposure (Legos et al, 2002).…”

Microglial Activation in Stroke: Therapeutic Targets

“…p38 MAPK promotes the stabilization and enhanced translation of mRNAs encoding proinflammatory proteins. 147 Activated (phosphorylated) p38 has been demonstrated in microglia in animal models of brain ischemia, 146,148,149 and pharmacological inhibition of p38 with the compound SD-282 decreased the number of activated microglia in ischemic brain. 150 The MAPK/ ERK signaling pathway may also regulate inflammation through its effects on PARP-1 activation, which (as detailed later in this review) is an important modulator of proinflammatory gene expression.…”