A study estimates that a compound appears to improve stroke outcome by reducing the destructive inflammation that can continue months after a stroke. Rats consuming compound 21 following a clot-based stroke, the most common type in humans do not have a smaller stroke size but do have better memory and movement in its aftermath. The study was published in the Journal of Cerebral Blood Flow and Metabolism.
In preclinical studies designed more like clinical trials, relatively young and otherwise healthy rats were given a clot in the middle cerebral artery – a common site for big strokes in humans. They received different doses of compound 21 – known to stimulate the angiotensin type 2 receptor, which is thought to reduce inflammation and improve cell survival for five days, with the first dose given three, six or 24 hours after stroke.
The scientists think the compound inhibits not only terrible things like inflammation and oxidative stress, but also stimulates good ones like brain-derived neurotrophic factor, which is known to help ailing brain cells recover, and production of the blood vessel dilator nitric oxide.
But even the lowest dose of compound 21 given three hours after stroke resulted in significant improvement in these functions although, conversely, no treatment reduced the initial size of the stroke, which is typically determined after about three days. However, in subsequent studies, the scientists found compound 21 dampened inflammation when given even 24 hours after stroke.
The compound works by stimulating the angiotensin type 2 receptor, a cell receptor known to aid blood vessel dilation, minimize cell death, or apoptosis, and reduce inflammation. The type 2 receptor is expressed less in adults than its antithesis, angiotensin type 1 receptor, which typically mediates the more detrimental effects of the renin-angiotensin system, like high blood pressure and inflammation.
In keeping with their desire for translatable findings, the scientists are now working to answer questions like will the results hold in female rats; only male rats were used in the published study to eliminate the stroke protection high estrogen provides. They also are looking at the compound in the face of existing diseases, like hypertension and diabetes, two major stroke risks, as well as increasing age.
Many stroke therapies that looked promising in the laboratory failed in humans, Ergul says, which has led groups like the National Institutes of Health to push for more rigor in study design and reproducibility of results in preclinical trials. This means ensuring that laboratory studies mimic the clinical scenario as closely as possible.
In the case of stroke, they suggest studies should include blinding results, so scientists don't know which animals got which treatment, randomized enrollment of older animals and looking at the impact of tPA on whatever new therapy is being studied. In the case of the MCG studies, even the stroke cause was more translatable: previous lab studies were in models where the event was caused by clamping or putting a balloon in a significant artery in the brain rather than by an actual clot.