Revealing New Possible Drug Targets for Treating Stroke

The changes in small blood vessels in the brain could be the target for existing or future drugs that treat brain injury or improve stroke recovery, according to a study published in Proceedings of the National Academy of Sciences. Researchers performed a comprehensive survey related to gene activity changes in small blood vessels in the brain following a stroke. Comparing these changes to those that have been recorded in stroke patients, they separated hundreds of genes with significant stroke-driven changes and likely relevance in human strokes.

Stroke is and has long been a leading cause of mortality and long-term disability worldwide. Most strokes are ischemic strokes involving a blood clot in a vessel serving the brain.

The blockage or severe reduction of blood flow reduces oxygen and nutrient delivery to downstream brain cells, killing or injuring them and triggering inflammatory processes that can cause further damage.

These changes in small cerebral blood vessels are thought to contribute further to brain damage post-stroke. Yet these microvascular changes have been technically challenging to record accurately, and thus have not been as well studied as other aspects of stroke—nor do they have any specific treatment.

Stroke-Induced Alterations in Brain Vessels Reveals Promising Therapeutic Candidates

In the new study, researchers comprehensively recorded post-stroke changes in gene activity in the cerebral microvasculature in mice and identified the changes that have also been seen in studies of human stroke patients.

They found 541 genes whose activity was altered similarly in both mice and human brain microvessels post-stroke. Dividing these genes into groups based on their functional roles and disease links, they identified several major clusters.

These included clusters relating to general inflammation, brain inflammation, vascular disease, and the type of vascular dysfunction that would cause cerebral microvessels to become leaky. This leakiness implies a weakening of the “blood-brain barrier,” the cellular lining of cerebral microvessels that protects the brain by keeping most components of circulating blood out of it.

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The analysis also identified the disruption of normal activity in genes controlling the levels of fat-related molecules similar to atherosclerosis and vascular dementia. These new findings will permit the pharmacological targeting of these pathways for stroke treatment.

The study included assessments confirming the “druggability,” or suitability for targeting with small-molecule drugs, of many of the molecules with altered production post-stroke.

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Indeed, some of the identified molecules are already being targeted by candidate drugs to treat other pathological conditions, which could facilitate the repurposing of these drugs for the treatment of stroke and dementia.

Researchers are now following up with preclinical experiments using candidate drugs or genetic methods to reverse some of the specific microvascular changes identified in their study, to investigate if this could be beneficial for stroke patients.



Source-Eurekalert