• A stroke occurs when a bleed or blockage stops or reduces blood flow to part of the brain.
• Although some people make a full recovery, many stroke survivors have lasting effects and are at risk of further strokes.
• Changes in small blood vessels beyond the blockage are thought to contribute to post-stroke brain damage.
• A new study has found numerous changes in gene activity in affected small blood vessels in the brain, that may provide targets for drug therapy to improve recovery from stroke.

A stroke occurs when an artery in the brain becomes blocked or bursts. The brain cells beyond the blockage or bleed are deprived of oxygen and nutrients, so are damaged or die.

Scientists have been trying to find ways to minimize the damage following a stroke and speed up recovery.

Now, a study led by scientists from Weill Cornell Medicine has found changes in gene activity in small blood vessels following a stroke. The findings suggest that these changes could be targeted with existing or future drugs to mitigate brain injury or improve stroke recovery.

The study is published in PNAS.

Lead author, Dr. Teresa Sanchez, assistant professor of pathology and laboratory medicine at Weill Cornell Medicine, told Medical News Today:

“Our study has improved our understanding of the pathophysiology of stroke by providing a knowledge platform of the molecular alterations in the cerebral microvasculature, which is critical to develop novel therapeutic strategies for this devastating condition.”

“The findings open a new avenue in stroke research. Most of the current focus has been on the acute effects of stroke and acute treatments. The chronic effects of stroke, especially on chronic cognitive dysfunction, have been far more neglected. This work shines a light on the potential in this area.”

— Dr. Steve Allder, consultant neurologist at Re:Cognition Health, who was not involved in the study, speaking to Medical News Today

Stroke symptoms

Most strokes are ischemic strokes, where a blood clot blocks a vessel leading to the brain, preventing oxygen and nutrients from reaching brain cells.

Immediate symptoms may include:

• confusion and speech problems
• headache, possibly with altered consciousness or vomiting
• numbness or an inability to move parts of the body, particularly on one side
• vision problems
• dizziness, lack of coordination, and difficulty walking.

Rapid diagnosis and treatment are vital to minimize long-term effects. However, many stroke survivors have lasting physical and emotional effects.

According to the Centers for Disease Control and Prevention (CDC), more than 795,000 people have a stroke each year in the United States, and stroke is a leading cause of long-term disability.

Much of that disability is thought to be caused by long-term effects on the small blood vessels in the brain.

Long-term damage from a stroke

Although about 10% of people make an almost full recovery from a stroke, survivors are often left with a range of symptoms, including:

• Paralysis and/or weakness on one side of the body.
• Problems with thinking, memory and speech.
• Trouble with chewing and swallowing.
• Problems with bladder and bowel control.
• Depression.

Many of these symptoms are caused by inflammation and long-term changes in the small blood vessels in the brain, which lead to restricted blood flow to brain cells and leakage through the blood-brain barrier.

This new study recorded post-stroke changes in gene activity in the cerebral microvasculature in mice. It also identified similar changes in human stroke patients.

“This study essentially identified potential molecular changes that occur in brain microvascular following ischemic stroke. By comparing the messenger RNA profile of model mice to humans who have suffered strokes, scientists have a better understanding of which exact genes and proteins may be affected in the blood-brain barrier following ischemic strokes.”

— Dr. Adi Iyer, neurosurgeon and neurointerventional surgeon, of Pacific Neuroscience Institute at Providence Saint John’s Health Center in Santa Monica, California

Changes in gene activity after a stroke

Having found 541 genes whose activity was altered similarly in both mice and people following stroke, the researchers identified several clusters of genes with different roles.

“Our work has also elucidated the shared transcript alterations between human and mouse stroke and identified common changes in pathways associated with vascular/endothelial dysfunction, sphingolipid metabolism and signaling.”

— Dr. Teresa Sanchez

They identified genes involved in general inflammation, brain inflammation, vascular disease, and the type of vascular dysfunction that makes cerebral microvessels leaky. These leaky vessels then weaken the blood-brain barrier that regulates the movement of substances between the blood and brain cells.

The researchers found that, after stroke, the activity of molecules that control the blood-brain barrier was changed.

“Stroke induces robust alterations in genes governing the blood-brain barrier and endothelial activation, i.e. upregulation of genes leading to blood-brain barrier leakage and downregulation of genes protecting the blood-brain barrier,” Dr. Sanchez explained.

They also discovered that the activity of genes controlling the levels of sphingolipids — fat molecules that are involved in a complex range of biological processes, including inflammation — was disrupted following stroke.

Potential treatment pathways

The researchers suggest that some of these molecular changes could be new targets for drug therapy. They highlight the increased levels of sphingolipids in cerebral microvasculature, suggesting that targeting these might have therapeutic potential following stroke.

MNT asked Dr. Sanchez whether she thought therapies might aim to prevent these changes, or repair the damage done.

“Both, since endothelial dysfunction is a major cause of stroke and, at the same time, stroke-induced cerebral ischemia causes additional injury to the endothelium, which further compromises cerebral blood flow and exacerbates brain injury,” she explained.

Dr. Allder believes the findings may lead to developments in other neurological disorders:

“I can imagine it may open treatments post-stroke, but I also imagine it will create possibilities for new treatments such as dementia and post-brain injuries, especially repetitive brain injuries.”

More research needed

So, the findings may well point towards new pathways for treatment, but Dr. Iyer cautioned that further research is needed:

“The main limitation of this study is that mouse models of the genome/transcriptions don’t always translate to humans. However, this study elucidates a previously unstudied cellular signaling pathway that is undoubtedly ripe for future investigation.”

Dr. Sanchez and her team 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.

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