Additive neuroprotection of GABA A and GABA B receptor agonists in cerebral ischemic injury via PI-3K/Akt pathway inhibiting the ASK1-JNK cascade.
Co-activation of GABA A and GABA B receptors results in neuroprotection during in vitro ischemia. However, it is unclear whether this mode of action is responsible for its neuroprotective effects in animal models of ischemia in vivo, and the precise mechanisms are also unknown. This study compared the neuroprotective efficacies of muscimol, a GABA A receptor agonist, and a GABA B receptor agonist baclofen in rat brain ischemia. The additive neuroprotection could be obtained in the hippocampal CA1 pyramidal cells prominently when muscimol and baclofen were co-applied. In particular, our study showed that co-activation of GABA A and GABA B receptors could strongly increase Akt activation and inhibit ASK1 activation by phosphorylation of serine 83 of ASK1. PI-3K inhibitor LY294002 reversed the increasing Akt activation and ASK1 (S83) phosphorylation. Moreover, MKK4/MKK7-JNK signaling activation was inhibited during ischemia/reperfusion (I/R) by co-treatment of muscimol with baclofen. JNK substrate, Bcl-2 and c-jun phosphorylation were also attenuated. Our results indicated that co-activation of GABA A receptor and GABA B receptor exerted neuroprotective effect via PI-3K/Akt pathway, which could inhibit the ASK1-c-Jun N-terminal protein kinase (JNK) cascade.
Xu
Jing
J
Research Center for Biochemistry and Molecular Biology, The Jiangsu Key Laboratory of Brain Disease Bioinformation, Xuzhou Medical College, Jiangsu 221002, PR China.
Li
Chong
C
Yin
Xiao-Hui
XH
Zhang
Guang-Yi
GY
D000704:Analysis of Variance; D000818:Animals; D001418:Baclofen / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000473:pathology / Q000517:prevention & control*; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D004338:Drug Combinations; D004791:Enzyme Inhibitors / Q000494:pharmacology; D018755:GABA Agonists / Q000627:therapeutic use*; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling / Q000379:methods; D048848:MAP Kinase Kinase Kinase 5 / Q000378:metabolism*; D008297:Male; D009118:Muscimol / Q000627:therapeutic use*; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D012694:Serine / Q000378:metabolism; D015398:Signal Transduction / Q000187:drug effects
D004338:Drug Combinations; D004791:Enzyme Inhibitors; D018755:GABA Agonists; D019253:Proto-Oncogene Proteins c-bcl-2; D009118:Muscimol; D012694:Serine; D019869:Phosphatidylinositol 3-Kinases; D048848:MAP Kinase Kinase Kinase 5; D001418:Baclofen