Date of Award

2017

Degree Name

Doctor of Philosophy (College of Health Sciences)

First Supervisor

Assoc/Prof Bruno Meloni

Second Supervisor

Dr Ryan Anderton

Third Supervisor

C/Prof Neville Knuckley

Abstract

Currently, there is no available neuroprotective treatment for reducing acute brain injury following stroke. Recent studies have demonstrated that poly-arginine and arginine-rich peptides (e.g. R18; R = arginine residues) exhibit potent neuroprotective properties in both in vitro and in vivo stroke models, and therefore have the potential to be developed into a neuroprotective treatment for stroke.

Consequently, the aim of this thesis was to further assess the neuroprotective efficacy of several poly-arginine and arginine-rich peptides in permanent and transient middle cerebral artery occlusion (MCAO) stroke models in the rat.

The poly-arginine peptides R12, R15, R18 and the arginine-rich peptide protamine were assessed in a permanent MCAO model when administered intravenously 30 minutes after stroke onset. Treatment with R12, R18 and protamine significantly reduced infarct volume in this model. In a subsequent dose response study (100, 300,1000nmol/kg) with the lead R18 peptide, when administered intravenously 60 minutes after stroke onset using the permanent MCAO model, infarct volume was reduced by 12 - 24%. Surprisingly, the well characterised neuroprotective peptide TAT-NR2B9c, clinically known as NA-1, which was used as a positive control did not exhibit any significant neuroprotection.

When examining R18 efficacy in a milder transient/reperfusion 90-minute MCAO stroke model, the peptide provided significant neuroprotection. R18 decreased infarct volume by 24 and 35% when administered intravenously 60 minutes post-occlusion at the 300 and 1000nmol/kg doses. In comparison, NA-1 decreased infarct volume by 16 and 26% at the same doses. In addition, R18 had a significantly greater beneficial effect in reducing cerebral oedema, when compared to NA-1 treatment.

Following the positive results obtained with R18 when administered 60 minutes after stroke onset, its therapeutic window was further investigated. The effectiveness of R18 was examined when administered intravenously 2-hours after the onset of permanent MCAO or transient MCAO of 180-minutes duration, or when administered intra-arterially immediately after reperfusion following a 120-minute duration of MCAO. R18 did not significantly reduced infarct volume in these studies. However, following permanent MCAO R18 significantly reduced cerebral oedema. NA-1 was also ineffective in the transient MCAO studies.

The findings presented in this thesis have further confirmed the neuroprotective properties of several poly-arginine and arginine-rich peptides. Although additional studies are still required to evaluate R18 as a neuroprotective agent in stroke, the peptide represents a promising lead agent with the findings of this thesis laying the foundation for future pre-clinical and clinical studies.

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