CRMP2-derived peptide ST2-104 (R9-CBD3) protects SH-SY5Y neuroblastoma cells against AŒ≤25-35-induced neurotoxicity by inhibiting the pCRMP2/NMDAR2B signaling pathway
Authors: Yuan Yao
Rajesh Khanna
Li Sun
Yang Hu
Jinghong Ren
Yingshi Ji
Qi Li
Yang Chen
Journal: Chemico-Biological Interactions (2019)
Discipline: PHARMACOLOGY & TOXICOLOGY
Keywords: Alzheimer's disease; Ca(2+); NMDAR2B; Neuroprotection; ST2-104
Affiliations: Department of Pharmacology, College of Basic Medical Sciences, Jilin University, Changchun, Jilin, 130021, PR China., Department of Pharmacology, College of Medicine, University of Arizona, Tucson, AZ, 85724, USA., Department of Neurology and Neuroscience Center, The First Hospital, Jilin University, Changchun, Jilin, 130021, PR China. Electronic address: .

Abstract:  Collapsin response mediator protein 2 (CRMP2),by regulating voltage-gated calcium channel activity, is a crucial regulator of neuronal excitability. Hyperphosphorylation of CRMP2 has been reported in brains of Alzheimer's disease (AD) patients and other neurodegenerative diseases. CRMP2 acting on N-methyl-d-aspartate receptors (NMDARs) may contribute to AD pathology. A short peptide from CRMP2, designated the Ca2+ channel-binding domain 3 (CBD3) peptide, has recently emerged as a Ca2+ channel blocker that exerts neuroprotective effects in traumatic brain injury and cerebral ischemia by disrupting pCRMP2/NMDAR interaction to inhibit calcium influx. ST2-104, a nona-arginine (R9)-conjugated CBD3 peptide derived from CRMP2, exerts a beneficial effect on neuropathic pain; however, the effect of ST2-104 on AD and its mechanism of action have not been studied. In this study we investigated the effects of ST2-104 on SH-SY5Y neuroblastoma cells stimulated by AŒ≤25-35. To induce neurotoxicity, SH-SY5Y cells were incubated with AŒ≤25-35, the shortest toxic fragment of AŒ≤. CRMP2 expression was manipulated by knockdown or overexpression of CRMP2 before ST2-104 treatment to further explore if the pCRMP2/NMDAR2B signaling pathway is involved in the action of the ST2-104 peptide. The results show that ST2-104 significantly enhanced cell viability, inhibited cell apoptosis, decreased LDH release, suppressed the expression of the pCRMP2 protein, disrupted pCRMP2/NMDAR2B interaction, inhibited AŒ≤25-35-induced NMDAR currents, and decreased intracellular Ca2+ levels. The effects of ST2-104 was abolished by overexpression of CRMP2 and intensified by knockdown of CRMP2 in SH-SY5Y cells. Taken together, our results support ST2-104 as a possible biologic therapeutic in the face of AŒ≤25-35-induced injury via the inhibition of the pCRMP2/NMDAR2B signaling pathway. 

Retracted: No

PubPeer comments:
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