The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region

J. Pan, Quanguang Zhang, G. Y. Zhang

Research output: Contribution to journalArticle

48 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)147-159
Number of pages13
JournalNeuroscience
Volume131
Issue number1
DOIs
StatePublished - Feb 9 2005
Externally publishedYes

Fingerprint

Hippocampal CA1 Region
Neuroprotective Agents
Brain Injuries
Caspase 3
Brain Ischemia
Ischemia
Stroke
Phosphorylation
Effector Caspases
JNK Mitogen-Activated Protein Kinases
Pyramidal Cells
Reperfusion
Proteins
Peptide Hydrolases
Cell Death
staurosporine aglycone
protein kinase N
Wounds and Injuries
Therapeutics
Pharmaceutical Preparations

Keywords

  • JNK3
  • K252a
  • MKK7
  • MLK3
  • c-Jun
  • cerebral ischemia

ASJC Scopus subject areas

  • Neuroscience(all)

Cite this

The neuroprotective effects of K252a through inhibiting MLK3/MKK7/JNK3 signaling pathway on ischemic brain injury in rat hippocampal CA1 region. / Pan, J.; Zhang, Quanguang; Zhang, G. Y.

In: Neuroscience, Vol. 131, No. 1, 09.02.2005, p. 147-159.

Research output: Contribution to journalArticle

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