Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1a

In rodents, but with ANY BRAINS AT ALL in stroke this would be immediately followed up with human testing. Alas, we have NO BRAINS  in stoke leadership so you, your children and grandchildren will be screwed yet on the next stroke.
http://www.pnas.org/content/114/14/3750.short

Irène R. Chassagnon, Claudia A. McCarthy, Yanni K.-Y. Chin, Sandy S. Pineda, Angelo Keramidas, Mehdi Mobli, Vi Pham, T. Michael De Silva, Joseph W. Lynch, Robert E. Widdop, Lachlan D. Rash, and Glenn F. King

PNAS April 4, 2017 114 (14) 3750-3755; published ahead of print March 20, 2017 https://doi.org/10.1073/pnas.1614728114

1. Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 6, 2017 (received for review September 1, 2016)

• Article
• Figures & SI
• Authors & Info
• PDF

Significance

Six million people die each year from stroke, and 5 million survivors are left with a permanent disability. Moreover, the neuronal damage caused by stroke often triggers a progressive decline in cognitive function that doubles the risk of dementia for stroke survivors. Despite this massive global disease burden, there are no approved drugs for treating the neuronal injury caused to the brain by the oxygen deprivation occurring during an ischemic stroke. The precipitous drop in brain pH resulting from stroke activates acid-sensing ion channel 1a. We show that inhibition of these channels using a “double-knot” spider venom peptide massively attenuates brain damage after stroke and improves behavioral outcomes, even when the peptide is administered 8 h after stroke onset.

Abstract

Stroke is the second-leading cause of death worldwide, yet there are no drugs available to protect the brain from stroke-induced neuronal injury. Acid-sensing ion channel 1a (ASIC1a) is the primary acid sensor in mammalian brain and a key mediator of acidosis-induced neuronal damage following cerebral ischemia. Genetic ablation and selective pharmacologic inhibition of ASIC1a reduces neuronal death following ischemic stroke in rodents. Here, we demonstrate that Hi1a, a disulfide-rich spider venom peptide, is highly neuroprotective in a focal model of ischemic stroke. Nuclear magnetic resonance structural studies reveal that Hi1a comprises two homologous inhibitor cystine knot domains separated by a short, structurally well-defined linker. In contrast with known ASIC1a inhibitors, Hi1a incompletely inhibits ASIC1a activation in a pH-independent and slowly reversible manner. Whole-cell, macropatch, and single-channel electrophysiological recordings indicate that Hi1a binds to and stabilizes the closed state of the channel, thereby impeding the transition into a conducting state. Intracerebroventricular administration to rats of a single small dose of Hi1a (2 ng/kg) up to 8 h after stroke induction by occlusion of the middle cerebral artery markedly reduced infarct size, and this correlated with improved neurological and motor function, as well as with preservation of neuronal architecture. Thus, Hi1a is a powerful pharmacological tool for probing the role of ASIC1a in acid-mediated neuronal injury and various neurological disorders, and a promising lead for the development of therapeutics to protect the brain from ischemic injury.

• stroke
• acid-sensing ion channel 1a
• venom peptide
• neuroprotection
• ischemia

Footnotes

• ↵¹To whom correspondence may be addressed. Email: l.rash@uq.edu.au or glenn.king@imb.uq.edu.au.