Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Bruno P Meloni; Diego Milani; Adam B Edwards; Ryan S Anderton; Ryan L O'Hare Doig; Melinda Fitzgerald; T Norman Palmer; Neville W Knuckey

doi:10.1016/j.pharmthera.2015.06.002

Neuroprotective peptides fused to arginine-rich cell penetrating peptides: Neuroprotective mechanism likely mediated by peptide endocytic properties

Pharmacol Ther. 2015 Sep:153:36-54. doi: 10.1016/j.pharmthera.2015.06.002. Epub 2015 Jun 3.

Authors

Bruno P Meloni¹, Diego Milani², Adam B Edwards², Ryan S Anderton², Ryan L O'Hare Doig³, Melinda Fitzgerald³, T Norman Palmer⁴, Neville W Knuckey⁵

Affiliations

¹ 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.
² Western Australian Neuroscience Research Institute, Nedlands, Australia; School of Heath Sciences, The University Notre Dame, Fremantle, Western Australia, Australia.
³ 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.
⁴ Centre for Neuromuscular and Neurological Disorders, The University of Western Australia, Nedlands, Australia; Western Australian Neuroscience Research Institute, Nedlands, Australia.
⁵ 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.

PMID: 26048328
DOI: 10.1016/j.pharmthera.2015.06.002

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.

Keywords: Cell penetrating peptides; Endocytosis; Neuroprotection; Poly-arginine peptides; Stroke and cerebral ischaemia; TAT peptide.

Publication types

Research Support, Non-U.S. Gov't
Review

MeSH terms

Animals
Arginine*
Cell-Penetrating Peptides / chemistry
Cell-Penetrating Peptides / pharmacology*
Disease Models, Animal
Endocytosis / drug effects*
Models, Neurological
Neurons / drug effects
Neuroprotective Agents / pharmacology*
Peptides / chemistry
Peptides / pharmacology*

Substances

Cell-Penetrating Peptides
Neuroprotective Agents
Peptides
Arginine