- 01Studies found Xaranetide potently inhibits NMDA currents linked to brain-cell damage.
- 02Its effect was partly reversible, potentially preserving normal brain signalling.
- 03Results strengthen the scientific rationale for the investigational neuroprotectant.
Argenica Therapeutics (ASX: AGN) has announced results of pharmacology studies that strengthen the evidence for investigational neuroprotective peptide drug Xaranetide’s multi-target mechanism of action in acute brain injuries.
Conducted at research organisations ApconiX in the UK and B’SYS GmbH in Switzerland, the in vitro studies evaluated the inhibitory potential, kinetics, mechanism, and voltage dependence of Xaranetide on N-methyl-D-aspartate (NMDA) receptor currents.
The results showed the drug can potently inhibit in two subunits of NMDA, which allow damaging amounts of calcium into brain cells when excessively activated following large ischaemic stroke or other serious neurological conditions.
Argenica believes they strengthen the scientific rationale for xaranetide as a novel treatment to protect vulnerable brain tissue following injury.
Glutamate Build-Up
Poor collateral blood supply following traumatic brain events can cause glutamate to accumulate and excessively activate NMDA channels.
Inhibition developed more rapidly once the peptide concentration was increased, demonstrating that the NMDA channel responds to high levels of glutamate and changes in electrical voltage across the cell membrane.
Xaranetide’s NMDA-blocking effect showed partial reversibility in laboratory testing, with channel activity recovering after drug removal and a change in membrane voltage.
Reversibility is considered to be critical, as NMDA receptors also support normal brain signalling, learning, and plasticity (the ability of connections between brain cells to adapt).
This means an acute neuroprotectant should limit harmful receptor activity without persistently suppressing these essential functions.
Damaging Biological Processes
Acute ischaemic stroke and traumatic brain injuries trigger a cascade of damaging biological processes that can begin within minutes and continue over hours to days.
Glutamate can accumulate and excessively activate receptors on neurons, particularly NMDAs, allowing calcium to enter and build up within the cells.
The resulting calcium overload can potentially damage mitochondria and activate processes that lead to neuronal death (excitotoxicity).
As NMDA receptors are known to be major mediators of excitotoxicity, with other receptors and ion channels also contributing to brain cell injury, reducing excessive NMDA receptor activity with a peptide such as Xaranetide may interrupt this injury cascade before further damage occurs.
The Stroke Treatment Academic Industry Roundtable (STAIR) international expert forum has previously recommended prioritising therapies that act on multiple injury pathways and proposed that this approach could improve the likelihood of successful brain protection.
Compelling Body of Evidence
Argenica chief executive officer Dr Liz Dallimore said the data from pharmacology studies continued to build on the compelling body of evidence being accumulated on Xaranetide as a novel therapy for brain injury.
“The proposed mechanism targets NMDA channels once they open, potentially limiting damaging calcium entry,” she said.
“Further, studies show a multi-target activity targeting other channels implicated in stroke, being the ASIC1a and CaV2.2 channels.”
“This could be particularly relevant in more severe strokes where still-living tissue is under substantial stress resulting in channel opening and offers a possible explanation for our exploratory Phase 2 signals.”
“Activity against multiple channels strengthens the rationale for addressing several contributors to brain injury with one therapy.”
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