title: Poly-arginine and arginine-rich peptides are neuroprotective in stroke models.
abstract: Using cortical neuronal cultures and glutamic acid excitotoxicity and oxygen-glucose deprivation (OGD) stroke models, we demonstrated that poly-arginine and arginine-rich cell-penetrating peptides (CPPs), are highly neuroprotective, with efficacy increasing with increasing arginine content, have the capacity to reduce glutamic acid-induced neuronal calcium influx and require heparan sulfate preotoglycan-mediated endocytosis to induce a neuroprotective effect. Furthermore, neuroprotection could be induced with immediate peptide treatment or treatment up to 2 to 4 hours before glutamic acid excitotoxicity or OGD, and with poly-arginine-9 (R9) when administered intravenously after stroke onset in a rat model. In contrast, the JNKI-1 peptide when fused to the (non-arginine) kFGF CPP, which does not rely on endocytosis for uptake, was not neuroprotective in the glutamic acid model; the kFGF peptide was also ineffective. Similarly, positively charged poly-lysine-10 (K10) and R9 fused to the negatively charged poly-glutamic acid-9 (E9) peptide (R9/E9) displayed minimal neuroprotection after excitotoxicity. These results indicate that peptide positive charge and arginine residues are critical for neuroprotection, and have led us to hypothesize that peptide-induced endocytic internalization of ion channels is a potential mechanism of action. The findings also question the mode of action of different neuroprotective peptides fused to arginine-rich CPPs.
authors: 1] Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia [2] Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia [3] Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia.
authors: Bruno P
authors: BP
authors: Meloni
authors: 1] Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia [2] Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia [3] Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia.
authors: Laura M
authors: LM
authors: Brookes
authors: 1] Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia [2] Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia [3] Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia.
authors: Vince W
authors: VW
authors: Clark
authors: 1] Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia [2] Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia [3] Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia.
authors: Jane L
authors: JL
authors: Cross
authors: 1] Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia [2] School of Heath Sciences, The University Notre Dame, Fremantle, Western Australia, Australia.
authors: Adam B
authors: AB
authors: Edwards
authors: 1] Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia [2] School of Heath Sciences, The University Notre Dame, Fremantle, Western Australia, Australia.
authors: Ryan S
authors: RS
authors: Anderton
authors: Phylogica Pty. Ltd. Australia and Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, Nedlands, Western Australia, Australia.
authors: Richard M
authors: RM
authors: Hopkins
authors: Phylogica Pty. Ltd. Australia and Telethon Kids Institute, Centre for Child Health Research, The University of Western Australia, Nedlands, Western Australia, Australia.
authors: Katrin
authors: K
authors: Hoffmann
authors: 1] Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Western Australia, Australia [2] Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia [3] Western Australian Neuroscience Research Institute, Nedlands, Western Australia, Australia.
authors: Neville W
authors: NW
authors: Knuckey
mesh_terms: D000818:Animals; D001120:Arginine / Q000737:chemistry / Q000627:therapeutic use*; D002118:Calcium / Q000378:metabolism; D002478:Cells, Cultured; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects; D018698:Glutamic Acid / Q000378:metabolism; D019812:Heparan Sulfate Proteoglycans / Q000494:pharmacology; D008297:Male; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000627:therapeutic use*; D010455:Peptides / Q000737:chemistry / Q000627:therapeutic use*; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy* / Q000473:pathology
chemical_list: D019812:Heparan Sulfate Proteoglycans; D018696:Neuroprotective Agents; D010455:Peptides; C015462:polyarginine; D018698:Glutamic Acid; D001120:Arginine; D002118:Calcium