Coactivation of GABA receptors inhibits the JNK3 apoptotic pathway via disassembly of GluR6-PSD-95-MLK3 signaling module in KA-induced seizure

Authors: Li, Chong; Xu, Bo; Wang, Wei-Wei; Yu, Xiu-Ju; Zhu, Jie; Yu, Hong-Min; Han, Dong; Pei, Dong-Sheng; Zhang, Guang-Yi

Source: Epilepsia, Volume 51, Number 3, March 2010 , pp. 391-403(13)

Publisher: Wiley-Blackwell

Abstract:

Summary Purpose: 

Past work has demonstrated that kainic acid (KA)-induced seizures could cause the enhancement of excitation and lead to neuronal death in rat hippocampus. To counteract such an imbalance between excitation and inhibition, we designed experiments by activating the inhibitory γ-aminobutyric acid (GABA) receptor to investigate whether such activation suppresses the excitatory glutamate signaling induced by KA and to elucidate the underlying molecular mechanisms. Methods: 

Muscimol coapplied with baclofen was intraperitoneally administrated to the rats 40 min before KA injection by intracerebroventricular infusion. Subsequently we used a series of methods including immunoprecipitation, immunoblotting, histologic analysis, and immunohistochemistry to analyze the interaction, expression, and phosphorylation of relevant proteins as well as the survival of the CA1/CA3 pyramidal neurons. Results: 

Coadministration of muscimol and baclofen exerted neuroprotection against neuron death induced by KA; inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by KA; and suppressed the activation of MLK3, MKK7, and JNK3. Discussion: 

Taken together, we demonstrate that coactivation of the inhibitory GABA receptors can attenuate the excitatory JNK3 apoptotic signaling pathway via inhibiting the increased assembly of the GluR6-PSD-95-MLK3 signaling module induced by KA. This provides a new insight into the therapeutic approach to epileptic seizure.

Keywords: Kainic acid; GABA; Muscimol; Baclofen; JNK pathway; Neuroprotection

Document Type: Research article

DOI: http://dx.doi.org/10.1111/j.1528-1167.2009.02270.x

Publication date: 2010-03-01

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