Co‐activation of GABA receptors inhibits the JNK3 apoptotic pathway via the disassembly of the GluR6‐PSD95‐MLK3 signaling module in cerebral ischemic‐reperfusion

Abstract

In this study, we investigated whether the increase of inhibitory c-amino butyric acid (GABA) signal suppresses the excitatory glutamate signal induced by cerebral ischemia and the underlying mechanisms. In global cerebral ischemia, focal cerebral ischemia and oxygen-glucose deprivation, application of muscimol and baclofen, agonists of GABA(A) receptor and GABA(B) receptor, exerted neuroprotection. The agonists inhibited the increased assembly of the GluR6-PSD-95-MLK3 module induced by cerebral ischemia and the activation of the MLK3-MKK4/7-JNK3 cascade. Our results suggest that stimulation 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 in cerebral ischemia.

Ferulic acid inhibits nitric oxide-induced apoptosis by enhancing GABAB1 receptor expression in transient focal cerebral ischemia in rats

“…Further validation of this difference was acquired from GABA B1 -nitrotyrosine double staining, which revealed the mutually exclusive expression of GABA B1 and nitrotyrosine. Our work confirms those previous studies [10,33,35,36] and further elucidates that the effect of FA against p38 MAP kinase-mediated apoptosis in the S-FA and R-FA groups is due to the enhancement of GABA B1 receptor expression at 24 h following reperfusion.…”

“…Thus, GABA B receptors play a pivotal role in protecting against glutamate-induced apoptosis in a rat model of transient focal cerebral ischemia [34] . A number of studies have demonstrated a decrease in GABA B receptor expression 24 h after cerebral ischemia and that GABA B agonists could exert neuroprotection against glutamate-induced excitotoxicity via enhancing GABA B receptors [10,33,35,36] . In the present study, we found that FA firstly increased the expression of GABA B1 receptors in the www.nature.com/aps Cheng CY et al Acta Pharmacologica Sinica npg S-FA and R-FA groups at 3 h of reperfusion in spite of reduced nNOS and iNOS expression in the ischemic cortex.…”

“…Cerebral ischemic damage is associated with excessive release of excitatory glutamate, which subsequently upregulates not only the expression of neuronal nitric oxide synthase (nNOS), but also inducible nitric oxide synthase (iNOS) [5,6] . Numerous studies [7][8][9][10] have shown that the glutamate receptor-postsynaptic density-95 (PSD-95)-nNOS complex and iNOS produce an excessive amount of nitric oxide (NO) during cerebral I/R injury; NO immediately reacts with superoxide radicals to form peroxynitrite, which subsequently nitrates protein tyrosine residues, generating nitrotyrosine and leading to oxidative/nitrative stress. Toxic NO-mediated oxidative/nitrative stress during cerebral I/R injury may contribute to the activation of the apoptotic cascade [11] .…”

Cytoprotective Effect of Valeriana officinalis Extract on an In Vitro Experimental Model of Parkinson Disease

“…In vitro, constituents of Valeriana officinalis mediate the release of c-aminobutyric acid and bind the same receptors as benzodiazepines, but with less affinity and milder clinical effects [38]. Recently, Dong-Han et al [39] has suggested that stimulation 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 in cerebral ischemia.…”

Unraveling the neuroprotective mechanisms of PrPCin excitotoxicity

“…92,93 Of the three isoforms of JNK (JNK1, 2 and 3), JNK3 was a good candidate to be a key molecule in the PrP C -dependent transmission of the excitotoxicity provoked by glutamate: (1) JNK3 is predominantly expressed in the CNS; 94 (2) Jnk3 knockout provides neuroprotection against various injuries, 95,96 and most interestingly, resistance to epileptic seizures and hippocampal cell death; 92 and (3) the JNK3 apoptotic signaling pathway is reported to be induced by KA and ischemia. 92,97 With these results in mind, we recently generated a double knockout mutant Prnp/Jnk3, which was insensitive to seizure and hippocampal cell death in response to KA injections. 44 This observation was corroborated in organotypic slices using pharmacological JNK inhibitors.…”