During a stroke numerous changes are made in gene activity in affected small blood vessels in the brain, however, a new study has shown that these changes are potentially targetable.
Researchers on this study believe that existing or future drugs may be able to be used to mitigate brain injury or improve stroke recovery.
In this study, researchers carried out a comprehensive survey in a preclinical model of gene activity changes in small blood vessels in the brain following stroke.
After comparing these changes to those that have been recorded in stroke patients, they catalogued hundreds of genes with significant stroke-driven changes and likely relevance in human strokes.
Study senior author, Dr. Teresa Sanchez, says: “Our findings provide a knowledge base that improves our understanding of strokes and points to specific molecules and pathways that can now be investigated as potential targets for future stroke treatments.
“It is also increasingly recognised that vascular disease is associated with and contributes to cognitive dysfunction and dementia. This study has identified molecular features associated with vascular dysfunction in the human brain after stroke, a major cause of dementia.”
The blockage or severe reduction of blood flow caused by ischaemic strokes reduces oxygen and nutrient delivery to downstream brain cells, killing or injuring them and triggering inflammatory processes that can cause further damage.
Further brain damage post-stroke is thought to be caused by changes in the small cerebral blood vessels (microvasculature) downstream of the blockage. However, these microvascular changes have been technically challenging to record accurately, meaning they have not been as well studied as other aspects of stroke and they also do not have any specific treatment.
In this study the researchers used the latest optimised methods for studying stroke-affected vessels to surmount these challenges.
They 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.
The research team discovered 541 genes whose activity was altered similarly in both mice and human cerebral microvessels post-stroke. After dividing these genes into groups based on their functional roles and disease links, they were able to identify several major clusters.
These included clusters that related to general inflammation, brain inflammation, vascular disease, and the type of vascular dysfunction that would cause cerebral micro vessels to become leaky. This leak indicates a weakening of the blood-brain barrier.
Dr. Sanchez, says: “We found that, following stroke, some molecules that would weaken the blood-brain barrier were upregulated, while others that should protect the blood-brain barrier were downregulated.
“This is consistent with clinical observations of blood-brain-barrier disruptions following stroke.”
This analysis was also able to identify disruption of normal activity in genes controlling the levels of sphingolipids. These fat-related molecules are heavily involved in regulating blood vessels, and disruptions of their normal workings have been observed in stroke, atherosclerosis and vascular dementia.
The research team were also able to discover that some types of these sphingolipids are highly enriched in cerebral blood flow vessels compared with brain tissue.
Additionally, they identified changes in these sphingolipids in the cerebral microvasculature induced by stroke as well as the changes in key molecules that control the levels of these lipids.
Researchers hope these new findings will permit the pharmacological conditions, which could facilitate the repurposing of these drugs for the treatment of stroke and dementia.
This study also included assessments that confirmed the suitability for targeting its small-molecule drugs, of many of the molecules with altered production post-stroke. Furthermore, some of the molecules identified 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.
