title: Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties.
abstract: Several recent studies have demonstrated that TAT and other arginine-rich cell penetrating peptides (CPPs) have intrinsic neuroprotective properties in their own right. Examples, we have demonstrated that in addition to TAT, poly-arginine peptides (R8 to R18; containing 8-18 arginine residues) as well as some other arginine-rich peptides are neuroprotective in vitro (in neurons exposed to glutamic acid excitotoxicity and oxygen glucose deprivation) and in the case of R9 in vivo (after permanent middle cerebral artery occlusion in the rat). Based on several lines of evidence, we propose that this neuroprotection is related to the peptide's endocytosis-inducing properties, with peptide charge and arginine residues being critical factors. Specifically, we propose that during peptide endocytosis neuronal cell surface structures such as ion channels and transporters are internalised, thereby reducing calcium influx associated with excitotoxicity and other receptor-mediated neurodamaging signalling pathways. We also hypothesise that a peptide cargo can act synergistically with TAT and other arginine-rich CPPs due to potentiation of the CPPs endocytic traits rather than by the cargo-peptide acting directly on its supposedly intended intracellular target. In this review, we systematically consider a number of studies that have used CPPs to deliver neuroprotective peptides to the central nervous system (CNS) following stroke and other neurological disorders. Consequently, we critically review evidence that supports our hypothesis that neuroprotection is mediated by carrier peptide endocytosis. In conclusion, we believe that there are strong grounds to regard arginine-rich peptides as a new class of neuroprotective molecules for the treatment of a range of neurological disorders.
authors.affiliation: Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia; Western Australian Neuroscience Research Institute, Nedlands, Australia. Electronic address: bruno.meloni@wanri.uwa.edu.au.
authors.forename: Bruno P
authors.initials: BP
authors.lastname: Meloni
authors.affiliation: Western Australian Neuroscience Research Institute, Nedlands, Australia; School of Heath Sciences, The University Notre Dame, Fremantle, Western Australia, Australia.
authors.forename: Diego
authors.initials: D
authors.lastname: Milani
authors.affiliation: Western Australian Neuroscience Research Institute, Nedlands, Australia; School of Heath Sciences, The University Notre Dame, Fremantle, Western Australia, Australia.
authors.forename: Adam B
authors.initials: AB
authors.lastname: Edwards
authors.affiliation: Western Australian Neuroscience Research Institute, Nedlands, Australia; School of Heath Sciences, The University Notre Dame, Fremantle, Western Australia, Australia.
authors.forename: Ryan S
authors.initials: RS
authors.lastname: Anderton
authors.affiliation: Experimental and Regenerative Neurosciences, Western Australia, Australia; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Nedlands, Australia; School of Animal Biology, The University of Western Australia, Nedlands, Australia.
authors.forename: Ryan L
authors.initials: RL
authors.lastname: O'Hare Doig
authors.affiliation: Experimental and Regenerative Neurosciences, Western Australia, Australia; School of Anatomy, Physiology and Human Biology, The University of Western Australia, Nedlands, Australia; School of Animal Biology, The University of Western Australia, Nedlands, Australia.
authors.forename: Melinda
authors.initials: M
authors.lastname: Fitzgerald
authors.affiliation: Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Western Australian Neuroscience Research Institute, Nedlands, Australia.
authors.forename: T Norman
authors.initials: TN
authors.lastname: Palmer
authors.affiliation: Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Department of Neurosurgery, Sir Charles Gairdner Hospital, QEII Medical Centre, Nedlands, Western Australia, Australia; Western Australian Neuroscience Research Institute, Nedlands, Australia.
authors.forename: Neville W
authors.initials: NW
authors.lastname: Knuckey
mesh_terms: D000818:Animals; D001120:Arginine; D057846:Cell-Penetrating Peptides / Q000737:chemistry / Q000494:pharmacology*; D004195:Disease Models, Animal; D004705:Endocytosis / Q000187:drug effects*; D008959:Models, Neurological; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents / Q000494:pharmacology*; D010455:Peptides / Q000737:chemistry / Q000494:pharmacology*
chemical_list: D057846:Cell-Penetrating Peptides; D018696:Neuroprotective Agents; D010455:Peptides; D001120:Arginine
keywords: Cell penetrating peptides; Endocytosis; Neuroprotection; Poly-arginine peptides; Stroke and cerebral ischaemia; TAT peptide