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Open AccessArticle

Poly-arginine-18 (R18) Confers Neuroprotection through Glutamate Receptor Modulation, Intracellular Calcium Reduction, and Preservation of Mitochondrial Function

1
Perron Institute for Neurological and Translational Science, Nedlands, WA 6009, Australia
2
Institute for Health Research, School of Heath Sciences and Institute for Health Research, The University Notre Dame, Fremantle, WA 6160, Australia
3
Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Perth, WA 6009, Australia
4
Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, WA 6008, Australia
*
Author to whom correspondence should be addressed.
Academic Editors: Kamelija Zarkovic and Neven Zarkovic
Molecules 2020, 25(13), 2977; https://doi.org/10.3390/molecules25132977
Received: 22 May 2020 / Revised: 23 June 2020 / Accepted: 26 June 2020 / Published: 29 June 2020
(This article belongs to the Collection Molecular Medicine)
Recent studies have highlighted that a novel class of neuroprotective peptide, known as cationic arginine-rich peptides (CARPs), have intrinsic neuroprotective properties and are particularly effective anti-excitotoxic agents. As such, the present study investigated the mechanisms underlying the anti-excitotoxic properties of CARPs, using poly-arginine-18 (R18; 18-mer of arginine) as a representative peptide. Cortical neuronal cultures subjected to glutamic acid excitotoxicity were used to assess the effects of R18 on ionotropic glutamate receptor (iGluR)-mediated intracellular calcium influx, and its ability to reduce neuronal injury from raised intracellular calcium levels after inhibition of endoplasmic reticulum calcium uptake by thapsigargin. The results indicate that R18 significantly reduces calcium influx by suppressing iGluR overactivation, and results in preservation of mitochondrial membrane potential (ΔΨm) and ATP production, and reduced ROS generation. R18 also protected cortical neurons against thapsigargin-induced neurotoxicity, which indicates that the peptide helps maintain neuronal survival when intracellular calcium levels are elevated. Taken together, these findings provide important insight into the mechanisms of action of R18, supporting its potential application as a neuroprotective therapeutic for acute and chronic neurological disorders. View Full-Text
Keywords: poly-arginine-18 (R18); cationic arginine-rich peptides (CARPs); neuroprotection; ROS; mitochondrial membrane potential (ΔΨm); ionotropic glutamate receptors poly-arginine-18 (R18); cationic arginine-rich peptides (CARPs); neuroprotection; ROS; mitochondrial membrane potential (ΔΨm); ionotropic glutamate receptors
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MDPI and ACS Style

MacDougall, G.; Anderton, R.S.; Trimble, A.; Mastaglia, F.L.; Knuckey, N.W.; Meloni, B.P. Poly-arginine-18 (R18) Confers Neuroprotection through Glutamate Receptor Modulation, Intracellular Calcium Reduction, and Preservation of Mitochondrial Function. Molecules 2020, 25, 2977.

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