title: Characterisation of neuroprotective efficacy of modified poly-arginine-9 (R9) peptides using a neuronal glutamic acid excitotoxicity model.
abstract: In a recent study, we highlighted the importance of cationic charge and arginine residues for the neuroprotective properties of poly-arginine and arginine-rich peptides. In this study, using cortical neuronal cultures and an in vitro glutamic acid excitotoxicity model, we examined the neuroprotective efficacy of different modifications to the poly-arginine-9 peptide (R9). We compared an unmodified R9 peptide with R9 peptides containing the following modifications: (i) C-terminal amidation (R9-NH2); (ii) N-terminal acetylation (Ac-R9); (iii) C-terminal amidation with N-terminal acetylation (Ac-R9-NH2); and (iv) C-terminal amidation with D-amino acids (R9D-NH2). The three C-terminal amidated peptides (R9-NH2, Ac-R9-NH2, and R9D-NH2) displayed neuroprotective effects greater than the unmodified R9 peptide, while the N-terminal acetylated peptide (Ac-R9) had reduced efficacy. Using the R9-NH2 peptide, neuroprotection could be induced with a 10 min peptide pre-treatment, 1-6 h before glutamic acid insult, or when added to neuronal cultures up to 45 min post-insult. In addition, all peptides were capable of reducing glutamic acid-mediated neuronal intracellular calcium influx, in a manner that reflected their neuroprotective efficacy. This study further highlights the neuroprotective properties of poly-arginine peptides and provides insight into peptide modifications that affect efficacy.
authors.affiliation: Western Australian Neuroscience Research Institute, A Block, 4th Floor, QEII Medical Centre, Verdun St, Nedlands, WA, 6009, Australia. adam.edwards1@my.nd.edu.au.|School of Health Sciences, The University of Notre Dame Australia, Fremantle, WA, 6160, Australia. adam.edwards1@my.nd.edu.au.|Department of Neurosurgery, Sir Charles Gardiner Hospital, QEII Medical Centre, Nedlands, WA, 6009, Australia. adam.edwards1@my.nd.edu.au.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Edwards
authors.affiliation: Western Australian Neuroscience Research Institute, A Block, 4th Floor, QEII Medical Centre, Verdun St, Nedlands, WA, 6009, Australia.|School of Health Sciences, The University of Notre Dame Australia, Fremantle, WA, 6160, Australia.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Anderton
authors.affiliation: Western Australian Neuroscience Research Institute, A Block, 4th Floor, QEII Medical Centre, Verdun St, Nedlands, WA, 6009, Australia.|Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, 6009, Australia.|Department of Neurosurgery, Sir Charles Gardiner Hospital, QEII Medical Centre, Nedlands, WA, 6009, Australia.
authors.forename: Neville W
authors.initials: NW
authors.lastname: Knuckey
authors.affiliation: Western Australian Neuroscience Research Institute, A Block, 4th Floor, QEII Medical Centre, Verdun St, Nedlands, WA, 6009, Australia.|Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, WA, 6009, Australia.|Department of Neurosurgery, Sir Charles Gardiner Hospital, QEII Medical Centre, Nedlands, WA, 6009, Australia.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Meloni
mesh_terms: D000818:Animals; D020013:Calcium Signaling / Q000187:drug effects; D002540:Cerebral Cortex / Q000378:metabolism* / Q000473:pathology; D018698:Glutamic Acid / Q000633:toxicity*; D009474:Neurons / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*; D051381:Rats
chemical_list: D018696:Neuroprotective Agents; D010455:Peptides; C015462:polyarginine; D018698:Glutamic Acid
keywords: Arginine-rich peptides; Cell-penetrating peptides; Cortical neurons; Glutamate excitotoxicity; Neuroprotection; Poly-arginine peptides