The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling
pathway on ischemic brain injury in rat hippocampal CA1 region.
Pan J, Zhang QG, Zhang GY.
Research Center for Biochemistry and Molecular Biology, Xuzhou Medical College,
84 West Huai-hai Road, Xuzhou 221002, Jiangsu, PR China.
It has been well documented that the activation of c-Jun N-terminal protein
kinase (JNK) pathway and caspase-3 signal are involved in the delayed neuronal
cell death in cerebral ischemia. In this study, we first detected the activation
pattern of JNK signaling including mixed lineage kinase (MLK)3, mitogen-activated
protein kinase kinase (MKK)7 and JNK3 in hippocampal CA1 and CA3/DG regions at
various time points after 15 min of ischemia. These results indicated that
cerebral ischemia induced the continuous activation of MLK3/MKK7/JNK3 cascade,
which all had two active waves only in the CA1 region. We also detected the
phosphorylation of JNK substrates c-Jun and Bcl-2, and the activation of a key
protease of caspase-3 in CA1 region, which only had one active peak,
respectively. Because K252a has recently been shown to be a potent inhibitor of
MLK3 activity both in vivo and in vitro, we further examined the possible
effects and mechanism of this interesting drug in cerebral ischemia. In our
present paper, we found that administration of K252a 20 min prior to ischemia
inhibited MLK3/MKK7/JNK3 signaling, Bcl-2 phosphorylation, the activation of
c-Jun and caspase-3, but had no significant effects on these protein
expressions. Additionally, pretreatment of K252a significantly increased the
number of the surviving CA1 pyramidal cells at 5 days of reperfusion. Our
results suggest that K252a play a neuroprotective role in ischemic injury via
inhibition of the JNK pathway, involving the death effector of caspase-3. Thus,
JNK signaling may eventually emerge as a prime target for novel therapeutic
approaches to treatment of ischemic stroke, and K252a may serve as a potential
and important neuroprotectant in therapeutic aspect in ischemic stroke.
Publication Types:
Research Support, Non-U.S. Gov't
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