Activation of Mitogen-Activated Protein Kinases after Transient Forebrain Ischemia in Gerbil Hippocampus

Abstract

We investigated the expression, activation, and distribution of c-Jun N-terminal kinases (JNKs), p38 mitogen-activated protein kinases (p38s) and extracellular signal-regulated kinases (ERKs) using Western blotting and immunohistochemistry in gerbil hippocampus after transient forebrain ischemia to clarify the role of these kinases in delayed neuronal death (DND) in the CA1 subfield. Immunoblot analysis demonstrated that activities of JNK, p38, and ERK in whole hippocampus were increased after 5 min of global ischemia. We used an immunohistochemical study to elucidate the temporal and spatial expression of these kinases after transient global ischemia. The immunohistochemical study showed that active JNK and p38 immunoreactivities were enhanced at 15 min of reperfusion and then gradually reduced and disappeared in the hippocampal CA1 region. On the other hand, in CA3 neurons, active JNK and p38 immunoreactivities were enhanced at 15 min of reperfusion and peaked at 6 hr of reperfusion and then gradually reduced but was continuously detected 72 hr after ischemia. Active ERK immunoreactivity was observed transiently in CA3 fibers and dentate gyrus. Pretreatment with SB203580, a p38 inhibitor, but not with PD98059, an ERK kinase 1/2 inhibitor, reduced ischemic cell death in the CA1 region after transient global ischemia by inhibiting the activity of p38. These findings indicate that the p38 pathway may play an important role in DND during brain ischemia in gerbil. Components of the pathway are important target molecules for clarifying the mechanism of neuronal death.

Duplicate preconditioning with sevoflurane in vitro improves neuroprotection in rat brain via activating the extracellular signal-regulated protein kinase

“…Jiang et al [25] have reported that brain seizure tolerance involves p38 signaling pathways. In contrast, investigation by Sugino et al demonstrates that pretreatment with SB203580 could reduce ischemic cell death in the CA1 region after transient global ischemia, by inhibiting the activity of p38 MAPK [31] .…”

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

“…Brain p38 MAPK is activated within minutes of transient forebrain ischemia in vivo (Sugino et al, 2000) and induces tolerance to serious ischemic insult after a brief sublethal ischemic insult in the gerbil hippocampus (Nishimura et al, 2003). Another form of ischemic preconditioning in the brain can be elicited by volatile anesthetics (Kapinya et al, 2002;Zhao and Zuo, 2004;Bickler et al, 2005;Gray et al, 2005), which requires the activation of A 1 receptors (Liu et al, 2006) and p38 MAPK (Zheng and Zuo, 2004).…”

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.…”