Prosurvival NMDA 2A receptor signaling mediates postconditioning neuroprotection in the hippocampus

Abstract

Ischemic postconditioning (Post C), which involves administration of a brief ischemia after the initial ischemic event, has been demonstrated to be strongly neuroprotective against global cerebral ischemia (GCI) and to improve cognitive outcome. To enhance understanding of the underlying mechanisms, the current study examined the role of NMDA receptors in mediating the beneficial effects of Post C (3 min ischemia) administered 2 days after GCI in adult male rats. The results revealed that Post C was strongly neuroprotective against GCI, and that this effect was blocked by administration of the NMDA receptor antagonist MK-801. Further work revealed that the NR2A-type NMDA receptors mediate the Post C beneficial effects as administration of a NR2A-preferring antagonist (NVP-A) blocked Post C neuroprotection and cognitive enhancement, while administration of a NR2B-preferring antagonist (Ro25) was without effect. Post C significantly up-regulated NR2A levels and phosphorylation of NR2A in the hippocampal CA1 region after Post C. Post C also increased Ca(2+) influx and activation/phosphorylation of CamKIIα at Thr(286), effects that were NR2A mediated as they were blocked by NVP-A. Phosphorylation of ERK and CREB was also increased by Post C, as were two downstream CREB-dependent prosurvival factors, brain derived neurotropic factor (BDNF) and Bcl2, effects that were blocked by the NR2A antagonist, NVP-A. Taken as a whole, the current study provides evidence that NR2A-activation and downstream prosurvival signaling is a critical mediator of Post C-induced neuroprotection and cognitive enhancement following GCI.

The differences between GluN2A and GluN2B signaling in the brain

“…Under conditions of moderate activation, such as bicuculline plus 4‐aminopiridine treatment and low‐dose NMDA (15 μM) exposure, the blockage of GluN2A with NVP‐AAM077 could inhibit the increase in CREB activity (Terasaki et al, ; Zhou, Ding, Chen, Yun, & Wang, ). Similar results can be seen under the conditions of pathological activation, such as sublethal OGD in cortical neurons (Terasaki et al, ), ischemia preconditioning in hippocampal slices (M. Chen et al, ), and ischemic postconditioning in the hippocampus (X. Zhang et al, ). The enhancement of GluN2A‐like function via replacing the C‐terminus of GluN2B with the C‐terminus of GluN2A did not alter the basal levels of CREB phosphorylation, but prolonged the duration of CREB phosphorylation induced by NMDA exposure (30 μM) (Martel et al, ).…”

“…GluN2A is a positive regulator of BDNF. NVP‐AAM077, but not ifenprodil, could prevent the increased expression of BDNF under physiological activation, such as under bicuculline exposure in primary hippocampal neurons (Q. Chen et al, ), as well as under pathological activation, such as under sublethal OGD in primary cortical neurons (Terasaki et al, ), and under ischemia preconditioning in hippocampal neurons (M. Chen et al, ; X. Zhang et al, ). The GluN2A‐CaMKIV‐transducer of regulated CREB activity 1 pathway may be a specific signaling pathway for the regulation of BDNF by GluN2A (Xu et al, ).…”

Alpha-7 Nicotinic Receptor Signaling Pathway Participates in the Neurogenesis Induced by ChAT-Positive Neurons in the Subventricular Zone

“…We used the Membrane and Nuclear Protein Extraction Kit (Beyotime, Shanghai, China) according to the manufacturer’s protocol. For the membrane protein extraction, we digested the tissue with solution A and PMSF for 15 min and centrifuged it at 700 g for 10 min to remove the nuclei and unbroken cells [37, 38]. We centrifuged supernatant again at 14,000 g for 30 min to obtain cytosolic proteins.…”

Inhibition of Protein Kinases AKT and ERK1/2 Reduce the Carotid Body Chemoreceptor Response to Hypoxia in Adult Rats

“…Besides, the pathways of protein kinase B (AKT) and extracellular signal-regulated kinases ½ (ERK1/2), are involved in major processes accomplishing a wide variety of neural tasks, including glucose metabolism (Engelman et al 2006 ), cellular apoptosis and survival (Teng et al 2014 ), differentiation (Chan et al 2013 ), neural proliferation and migration (Dey et al 2005 ), neuro-protection (Zhang et al 2014 ), neuro-degeneration (Fang et al 2014 ), and synaptic signaling (Yoshii and Constantine-Paton 2014 . Moreover, AKT and ERK1/2 in brain tissue participate in the modulation of dopaminergic (Beaulieu et al 2006 ), muscarinic (Rosenblum et al 2000 ), adrenergic (Taraviras et al 2002 ), serotonergic (Cowen 2007 ), GABAergic (Balasubramanian et al 2004 ) and adenosinergic (Wiese et al 2007 ) neurotransmission.…”