UNMASKING SPIDER'S VENOM: A SAVIOUR FOR BRAIN STROKE

A ‘toxin’ isn’t necessarily toxic to us – there are more than 100,000 species of spiders, yet only a handful of them are dangerous to humans – Glenn King

INTRODUCTION:

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. Even though ischemic strokes cause a lot of brain damage worldwide, there are no medicines approved for treating this damage caused by oxygen deprivation

During a stroke, most damage occurs due to a lack of blood flow, and there are two main areas of damage: the core and penumbral zones. The core is severely affected and experiences irreversible cell death, while the penumbra, which can be almost half of the damaged area, can be saved with the right treatment for a limited time.

As the brain lacks oxygen during a stroke, it switches to a less efficient energy production method, causing acid levels to rise. Acid-sensing ion channel 1a (ASIC1a) in the brain is very sensitive to this acid increase and plays a crucial role in stroke-induced damage.

       

PSALMOTOXIN 1:

Researchers found a powerful inhibitor called psalmotoxin 1 (PcTx1) that can block ASIC1a effectively. When administered after a stroke in animal experiments, it significantly reduced brain damage and improved outcomes, even when given up to 8 hours after the stroke. This discovery offers hope for better stroke treatments.

SECRET WEAPON:

In the venom of the Australian funnel-web spider, a new peptide known as Hi1a was found by researchers. This peptide resembles the toxin PcTx1, but it is larger and has two parts that are similar to PcTx1 linked together. Hi1a, which they produced in the lab, effectively blocked ASIC1a channels in the brain that are linked to damage from strokes.

In both rat and human cells, Hi1a inhibited ASIC1a, but it had little effect on other comparable channels. Another significant difference between PcTx1 and Hi1a is how long their effects persisted after the toxin was eliminated. It hasn't been observed with other drugs that affect these channels, so this is unusual.

Unlike another toxin called PcTx1, which causes these channels to be less sensitive to acidity and promotes a change towards more alkaline conditions, Hi1a has a different effect. It doesn't depend much on pH levels and cannot be easily overcome.

In experiments with human cells, Hi1a significantly reduces the activity of ASIC1a channels and slows down their activation. However, it doesn't affect the deactivation or desensitization of these channels. Single-channel recordings show that Hi1a delays the time it takes for the channels to become active in response to acidity, but it doesn't alter the flow of ions through the channels.

In summary, Hi1a works differently from PcTx1 by delaying the activation of ASIC1a channels, suggesting that it stabilizes the closed state of the channels. This is in contrast to PcTx1, which stabilizes a different state of these channels. Hi1a, a spider venom peptide, has shown promising neuroprotective effects in both laboratory and animal studies related to stroke. When tested on brain cell cultures under oxidative stress, both Hi1a and PcTx1 increased cell survival in a dose-dependent manner. Notably, Hi1a provided even better protection at the highest concentration tested. In a rat model of stroke, Hi1a was administered after the stroke had occurred. Remarkably, even a small dose of Hi1a significantly reduced the size of the brain damage in both the penumbral and core regions, which is usually resistant to treatment. This protection was reflected in preserved neuronal structures and improved neurological and motor function in treated animals. Importantly, Hi1a's neuroprotective effects are not due to its ability to dilate blood vessels, as it did not affect the constricting properties of isolated cerebral arteries. This suggests that Hi1a's action is specifically related to protecting brain tissue rather than influencing blood flow.

REFERENCE:

Chassagnon IR, McCarthy CA, Chin YK-Y, Pineda SS, Keramidas A, Mobli M, et al. Potent neuroprotection after stroke afforded by a double-knot spider-venom peptide that inhibits acid-sensing ion channel 1A. Proceedings of the National Academy of Sciences. 2017;114(14):3750–5. doi:10.1073/pnas.1614728114