Toward development of a dynamic supramolecular peptide therapy for acute ischemic stroke

TL;DR

This study explores a new peptide therapy that can cross the blood-brain barrier and reduce brain damage after stroke.

Contribution

A dynamic supramolecular peptide therapy is shown to reduce infarct size in a pre-clinical stroke model.

Findings

IKVAV-PA crosses the blood-brain barrier and accumulates in the ischemic hemisphere.

Treatment with IKVAV-PA significantly reduces brain infarct volume compared to saline.

IKVAV-PA shows good biocompatibility in systemic organs after stroke.

Abstract

Acute ischemic stroke (AIS) treatment relies on early restoration of blood flow; however, ischemia/reperfusion (I/R) may lead to secondary brain injury. Supramolecular peptide assemblies in which many molecules move collectively by design can activate key cellular pathways by displaying bioactive molecules on their surfaces. In this study, we hypothesized that a highly dynamic assembly formed by a peptide amphiphile (PA) that displays the laminin-mimetic sequence IKVAV (IKVAV-PA), known to promote neuron survival, could be delivered systemically, reach the ischemic brain, and exert therapeutic effects following AIS. C57BL/6 heterozygous CX3CR1GFP mice underwent 60-min of transient middle cerebral artery occlusion and were administered IKVAV-PA or saline (control) immediately after reperfusion. IKVAV-PA presence and distribution was evaluated by intracranial intravital and wide-field imaging. Cresyl violet staining was performed to quantitate final brain infarct volume at 7 days post stroke. IKVAV-PA formed scaffolds that contain both nanoscale filaments in equilibrium with small micellar aggregates, which is a signature of enhanced epitope dynamicity. Systemically administered IKVAV-PA crossed the blood-brain barrier and was primarily detected within the ischemic hemisphere. Cresyl violet staining demonstrated IKVAV-PA treatment significantly reduced infarct size when compared to saline treated animals. Histological screening of systemic organs suggested good biocompatibility of IKVAV-PAs at 7 days post stroke. We demonstrated the therapeutic potential of systemically delivering IKVAV-PA in a pre-clinical model of ischemic stroke. This work lays the foundation for further studies utilizing supramolecular PA assemblies as an adjunct therapy to reperfusion therapies in order to enhance long-term tissue-level neural regeneration post stroke.

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