Chimeric Peptide Tat-HA-NR2B9c Improves Regenerative Repair after Transient Global Ischemia.

Hai-Hui Zhou,Hai-Xia Zhang,Wei-Hong Ge,Li Zhang,Jin-Ping Zhang

doi:10.3389/fneur.2017.00509

Hai-Hui Zhou, Hai-Xia Zhang + Show 3 more

Open Access

https://doi.org/10.3389/fneur.2017.00509

Copy DOI

Abstract

Transient global ischemia (TGI) is a major public health problem, and it heightens the need of effective treatments. The present study was undertaken to investigate whether recombinant polypeptide Tat-HA-NR2B9c improves spatial learning and memory deficits in rats after TGI. Rats were subjected to 20-min ischemia induced by four-vessel occlusion (4-VO) method and daily injected with Tat-HA-NR2B9c (1.12 mg/kg) for 1 week. Tat-HA-NR2B9c increased CREB activity, upregulated B-cell lymphoma-2 (Bcl-2) expression after treated for 24 h. There was a significant increase in dendrite spine density in hippocampal CA1 region and BrdU-positive cells and BrdU/NeuN-positive cells in the dentate gyrus after Tat-HA-NR2B9c treatment, compared with ischemia group at postischemic day 28. Inhibition of the CREB activation by recombinant lentivirus, LV-CREB133-GFP, abolished the upregulation effects of Tat-HA-NR2B9c on Bcl-2 expression. Moreover, Tat-HA-NR2B9c improved the impaired spatial learning and memory ability in Morris water maze. These results suggest that Tat-HA-NR2B9c substantially ameliorated the TGI-induced loss of dendrite spine in hippocampal CA1, increased neurogenesis in dentate gyrus, and significantly improved cognitive abilities by the CREB pathway in rats after transient global cerebral ischemia. It may be served as a treatment for TGI.

Highlights

Transient global ischemia (TGI) occurs when blood flow stops or reduced after cardiac and respiratory arrest, and leads to neural dysfunction and neuron necrosis in hippocampus, especially the CA1 pyramidal neurons [1]
To examine whether Tat-hemagglutinin epitope-tag (HA)-NR2B9c benefits TGI outcome, we subjected rats to 4-VO and treated them with Tat-HA-NR2B9c (1.12 mg/kg i.v.) for 7 days starting at reperfusion
We investigated whether Tat-HA-NR2B9c increased neurogenesis in dentate gyrus and reduced the apoptosis of pyramidal neurons in hippocampus CA1 region

Summary

Introduction

Transient global ischemia (TGI) occurs when blood flow stops or reduced after cardiac and respiratory arrest, and leads to neural dysfunction and neuron necrosis in hippocampus, especially the CA1 pyramidal neurons [1]. Delayed neuronal death often happens on 3–4 days after the onset of ischemic injury [2, 3], and many of the newborn hippocampal neurons die within a few weeks [4]. Excessive release of glutamate causes rise to ion channel receptor activation and in turn recruits intracellular multiprotein signaling complexes by the postsynaptic density (PSD) [5, 6]. A prominent organizing protein is PSD-95, which binds both N-Methyl-d-aspartate receptors (NMDARs) and neuronal nitric oxide synthase (nNOS) at excitatory synapses [7, 8]. Targeting PSD-95 protein, represents an alternative therapeutic strategy for TGI. We prepared a recombinant chimeric peptide Tat-HA-NR2B9c, which contains last nine amino acids of the carboxyl tail of GluN2B, an influenza virus hemagglutinin epitope-tag (HA)

Methods

Results

Conclusion