Journal Article

Poly-Arginine and Arginine-Rich Peptides are Neuroprotective in Stroke Models

Edwards, Adam B, Clark, Vince W, Cross, Jane L, Hoffmann, Katrin, Knuckey, Neville W, Anderton, Ryan S, Hopkins, Richard M, Meloni, Bruno P, Brookes, Laura M

2015

Overview

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.

• Publisher: SAGE Publications,Sage Publications Ltd,Nature Publishing Group
• Subject: Animals / Arginine - chemistry / Arginine - therapeutic use / Calcium - metabolism / Cells, Cultured / Disease Models, Animal / Endocytosis - drug effects / Glutamic Acid - metabolism / Heparan Sulfate Proteoglycans - pharmacology / Male / Neurons - drug effects / Neurons - metabolism / Neurons - pathology / Neuroprotective Agents - chemistry / Neuroprotective Agents - therapeutic use / Original / Peptides - chemistry / Peptides - therapeutic use / Rats, Sprague-Dawley / Stroke - drug therapy / Stroke - pathology