Abstract
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.
Highlights
Glutamate excitotoxicity is a critical neurodamaging event responsible for neuronal death in acute forms of brain injury, such as stroke, traumatic brain injury (TBI) and hypoxic-ischaemic encephalopathy (HIE), as well as chronic neurodegenerative disorders such as Alzheimer’s disease (AD) [1,2], Huntington’s disease (HD) [3,4], Parkinson’s disease (PD) [5,6], and amyotrophic lateralMolecules 2020, 25, 2977; doi:10.3390/molecules25132977 www.mdpi.com/journal/moleculesMolecules 2020, 25, 2977 sclerosis (ALS) [7,8]
We explored the ability of R18 to attenuate excessive calcium influx and excitotoxic neuronal death induced by a variety of ionotropic glutamate receptor agonists, namely glutamate, NMDA, kainic acid (KA), and amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA)
Given that mitochondria are a critical modulator of intracellular calcium levels during neuronal excitotoxicity and are responsible for a significant share of the ensuing oxidative stress and energy collapse, we examined whether R18 could preserve mitochondrial bioenergetics, in particular via the maintenance of the mitochondrial membrane potential (∆Ψm) and ATP production, and through limiting reactive oxygen species (ROS) generation
Summary
Glutamate excitotoxicity is a critical neurodamaging event responsible for neuronal death in acute forms of brain injury, such as stroke, traumatic brain injury (TBI) and hypoxic-ischaemic encephalopathy (HIE), as well as chronic neurodegenerative disorders such as Alzheimer’s disease (AD) [1,2], Huntington’s disease (HD) [3,4], Parkinson’s disease (PD) [5,6], and amyotrophic lateralMolecules 2020, 25, 2977; doi:10.3390/molecules25132977 www.mdpi.com/journal/moleculesMolecules 2020, 25, 2977 sclerosis (ALS) [7,8]. The excessive release of the excitatory neurotransmitter glutamate from pre-synaptic neurons can trigger the overactivation of ionotropic glutamate receptors (iGluRs), such as. The overactivation of iGluRs causes excessive neuronal calcium uptake and triggers a range of harmful intracellular biochemical cascades, culminating in cell death [9]. Excessive intracellular calcium levels can cause a toxic influx of calcium into mitochondria, loss of the mitochondrial membrane potential (∆Ψm) across the inner mitochondrial membrane, and inhibition of the electron transport chain (ETC) and oxidative phosphorylation, leading to reduced ATP synthesis. While several key cell death pathways are involved in neuronal NMDA and non-NMDA receptor-mediated excitotoxicity, mitochondrial dysfunction is considered a critical event [12,13,14,15,16,17]
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