http://www.pnas.org/content/114/14/3750.short
- Edited by Solomon H. Snyder, Johns Hopkins University School of Medicine, Baltimore, MD, and approved February 6, 2017 (received for review September 1, 2016)
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.
Footnotes
- ↵1To whom correspondence may be addressed. Email: l.rash@uq.edu.au or glenn.king@imb.uq.edu.au.
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