Bidentatide, a Novel Plant Peptide Derived from Achyranthes bidentata Blume: Isolation, Characterization, and Neuroprotection through Inhibition of NR2B-Containing NMDA Receptors.

Fei Ding,Xiaosong Gu,Mengchun Cheng,Yunpeng Bai,Xinmiao Liang,Xiaozhe Zhang,Yulin Wu,Shu Yu,Qiong Cheng

doi:10.3390/ijms22157977

Abstract

Increasing attention is being focused on the use of polypeptide-based N-methyl-d-aspartate (NMDA) receptor antagonists for the treatment of nervous system disorders. In our study on Achyranthes bidentata Blume, we identified an NMDA receptor subtype 2B (NR2B) antagonist that exerts distinct neuroprotective actions. This antagonist is a 33 amino acid peptide, named bidentatide, which contains three disulfide bridges that form a cysteine knot motif. We determined the neuroactive potential of bidentatide by evaluating its in vitro effects against NMDA-mediated excitotoxicity. The results showed that pretreating primary cultured hippocampal neurons with bidentatide prevented NMDA-induced cell death and apoptosis via multiple mechanisms that involved intracellular Ca2+ inhibition, NMDA current inhibition, and apoptosis-related protein expression regulation. These mechanisms were all dependent on bidentatide-induced inhibitory regulation of NR2B-containing NMDA receptors; thus, bidentatide may contribute to the development of neuroprotective agents that would likely possess the high selectivity and safety profiles inherent in peptide drugs.

Highlights

N-methyl-D-aspartic acid (NMDA) receptors, well known as one class of glutamategated ion channels, are critical for regulation of brain function and signal transmission [1]
Bidentatide is a single peptide isolated from Achyranthes bidentata Blume (Figure 1)
We reported that Achyranthes bidentata polypeptides (ABPP) derived from Achyranthes bidentata Blume, a Chinese medicinal herb, can confer selective neuroprotection in diverse in vitro and in vivo models through NMDA-receptor-dependent mechanisms [33,34,35,36,37,38,39,40,41,42]; the ABPP product is a mixture of polypeptides and may be intermingled with a small amount of non-active or adverse constituents, which are bound to have a diminishing impact on the pharmacological efficacy of bidentatide

Summary

Introduction

N-methyl-D-aspartic acid (NMDA) receptors, well known as one class of glutamategated ion channels, are critical for regulation of brain function and signal transmission [1]. They are obligatory heterotetramers composed of 2 glycine-binding GluN1 subunits as an essential part and 2 glutamate-binding GluN2 subunits as a regulatory part. GluN2A/2B-containing NMDA receptors are the major functional isoforms specific to neurons, and show developmental and regional differences in expression levels [7,8]. Overstimulation of NR2B-containing NMDA receptors results in excessive calcium influx and excitotoxicity [10], which may be associated with various neurological diseases and disorders, such as Alzheimer’s disease, stroke, and ischemic damage [6,11,12,13]. NMDA receptors are important targets for drug intervention in nervous system disorders, leading to the development of highly selective antagonists and agonists with differential regulatory functions and fewer side effects

Methods

Results

Discussion

Conclusion