Neuroprotective Effects of Preconditioning Ischemia on Ischemic Brain Injury through Down-regulating Activation of JNK1/2 via N-Methyl-D-aspartate Receptor-mediated Akt1 Activation

Abstract

Our previous studies have demonstrated that the JNK signaling pathway plays an important role in ischemic brain injury and is mediated via glutamate receptor 6. Others studies have shown that N-methyl-D-aspartate (NMDA) receptor is involved in the neuroprotection of ischemic preconditioning. Here we examined whether ischemic preconditioning down-regulates activation of the mixed lineage kinase-JNK signaling pathway via NMDA receptor-mediated Akt1 activation. In our present results, ischemic preconditioning could not only inhibit activations of mixed lineage kinase 3, JNK1/2, and c-Jun but also enhanced activation of Akt1. In addition, both NMDA (an agonist of NMDA receptor) and preconditioning showed neuroprotective effects. In contrast, ketamine, an antagonist of NMDA receptor, prevented the above effects of preconditioning. Further studies indicated that LY294002, an inhibitor of phosphoinositide 3-kinase that is an upstream signaling protein of Akt1, could block neuroprotection of preconditioning, and KN62, an inhibitor of calmodulin-dependent protein kinase, also achieved the same effects as LY294002. Therefore, both phosphoinositide 3-kinase and calmodulin-dependent protein kinase are involved in the activation of Akt1 in ischemic tolerance. Taken together, our results indicate that preconditioning can inhibit activation of JNK signaling pathway via NMDA receptor-mediated Akt1 activation and induce neuroprotection in hippocampal CA1 region.Glutamate is the most prevalent excitatory neurotransmitter in the central nervous system. Based on studies of pharmacology, electrophysiology, and molecular biology, the ionotropic receptors are further divided into NMDA, 1 ␣-amino-3-hydroxy-5-methyl-isoxsazole-4-propionic acid, and kainate receptors (1, 2). The ionotropic glutamate receptor NMDA subtype is a kind of prominent ligand-gated ionic channel in excitatory synapses that is involved in ischemic neuronal cell damage events. Functional NMDA receptor (NR) is composed of three types of subunits: NR1, NR2 (2A-2D), and NR3 (3A/3B) (3-5). NR1 is a principal subunit for NMDA receptor channel activity, and NR2 subunits determine the specificity of receptor function (1).

Differential Roles of NMDA Receptor Subtypes in Ischemic Neuronal Cell Death and Ischemic Tolerance

“…36 Previous studies demonstrate that the NMDA receptordependent cellular signaling pathway is crucial in the protective effect of ischemia tolerance and that de novo protein synthesis is also required in this process. [37][38][39] Our results demonstrated that blocking NR2A completely abolished the neuroprotective effect induced by ischemic preconditioning. However, blocking NR2B further enhanced the neuroprotective effect.…”

The Correlation Between Ketamine and Posttraumatic Stress Disorder in Burned Service Members

“…16 -18 With ketamine exposure, the NMDA receptor is not activated and does not initiate downstream signaling. Ketamine alters Ca 2ϩ , 16 cAMP, 19 protein kinase C, 20 and mitogen activated protein kinase 21 signaling.…”

Elevated Synaptic Activity Preconditions Neurons against an in Vitro Model of Ischemia

“…A key role for activation of the NMDA type of glutamate receptor during preconditioning by ischemia or OGD is well established (3)(4)(5)(6)(7)(8)(9)(10), although agreement is not complete (11,12). Moreover, transient non-lethal exposure to high dose glutamate or NMDA is sufficient on its own to also induce potent cross-tolerance to ischemia (13) or to OGD (1,6,14). To date, preconditioning achieved either by transient ischemia OGD or NMDA can require bringing neurons to the "brink of death" (1,14,15), a trait shared with some other preconditioning paradigms (2).…”