01:56am Wednesday 13 December 2017

UC Davis researchers find promising new treatment approach for ischemic stroke

(SACRAMENTO, Calif.) —A team of UC Davis scientists has found that administering a small molecule – purmorphamine – in animal models after a stroke results in multiple protective effects, including reducing the size of the stroke, decreasing inflammation and increasing markers for nerve regeneration. The findings, which may offer a new approach to treating ischemic stroke — the disruption of blood flow in the brain from a blood clot — are published online in the journal Cell Death and Disease.

  Wenbin Deng

Wenbin Deng “We have revealed a previously unrecognized role of a developmental pathway that, when stimulated with a small molecule drug, leads to neuroprotection, regeneration and functional recovery following ischemic stroke,” said Wenbin Deng, associate professor in the UC Davis Department of Biochemistry and Molecular Medicine, and principal investigator of the study. “This is an important conceptual advance that could lead to a novel treatment approach. The small molecule compound could pave the way for new medicines in the treatment of many neurological and neurodegenerative diseases.”

The study focused on the humorously named “sonic hedgehog” signaling pathway, which plays a fundamental role in the early development of the central nervous system, regulating the generation and survival of neurons and other brain cells. It is also activated in response to an injury to the nervous system and has been shown to have beneficial effects in animal models of various conditions including stroke, multiple sclerosis, and amyotrophic lateral sclerosis (ALS).

A key component of the sonic hedgehog pathway is the so-called Smoothened protein, a receptor that when stimulated promotes activation of the pathway. Purmorphamine is a small molecule that was developed to be a stimulator (also called an agonist) of the Smoothened protein.

The study analyzed the effects of purmorphamine on a mouse model of stroke. Mice that received the highest dosage of the molecule had a 40-percent reduction of the size of the infarct—the area of dead tissue in the brain resulting from a stroke—compared with controls. Mice given purmorphamine also performed better on tests of motor function following a stroke.

Factors that promote inflammation were also reduced in the area of the infarct in the mice treated with purmorphamine compared with controls. A second treatment of purmorphamine four days after the stroke further reduced inflammation. In addition, indicators of repair—such as the presence of blood vessel-lining cells—were increased in the infarct areas of the mice treated with purmorphamine compared to controls. Treated animals were also found to have reduced blood-brain permeability, an important protective mechanism that keeps harmful molecules from entering the brain.

A concern for this approach is that stimulating a pathway important in early development could also promote cancer growth. However, no evidence of that problem was found in this experimental model. The authors of the study suggest that further studies that explore the possibility of cancer are warranted.

The UC Davis study is important because about 80 percent of strokes are ischemic in nature, occurring when a blood vessel in the brain becomes blocked and deprives the area of oxygen. The other type of stroke, hemorrhagic, occurs with a leak or rupture in a blood vessel, which then causes bleeding to an area of the brain. Currently the only treatment available for ischemic stroke is immediate administration of tissue plasminogen activator, a protein that helps break down blood clots. The therapy is limited by a narrow window of time for therapy to be administered as well as a risk of exacerbating bleeding.   

“We have identified what we anticipate to be an effective and safe new strategy for treating this often devastating event that strikes more than nearly 700,000 Americans every year,” said Deng.

The article is titled, “A Smoothened receptor agonist is neuroprotective and promotes regeneration after ischemic brain injury.”

Other study authors were Olga Chechneva, Daniel Daugherty and RG Krishnamurty of the UC Davis Department of Biochemistry and Molecular Medicine; Florian Mayrhofer and Peter Bannerman of the Shriners Hospitals for Children’s Institute for Pediatric Regenerative Medicine in Sacramento, and David Pleasure, who is affiliated with both institutions. Deng is also associated with Shriners Hospitals for Children’s Institute for Pediatric Regenerative Medicine.

The study was supported by the National Institutes of Health (R01NS061983, R01ES015988) and Shriners Hospitals for Children.

UC Davis Health System is improving lives and transforming health care by providing excellent patient care, conducting groundbreaking research, fostering innovative, interprofessional education, and creating dynamic, productive partnerships with the community. The academic health system includes one of the country’s best medical schools, a 619-bed acute-care teaching hospital, a 1000-member physician’s practice group and the new Betty Irene Moore School of Nursing. It is home to a National Cancer Institute-designated comprehensive cancer center, an international neurodevelopmental institute, a stem cell institute and a comprehensive children’s hospital. Other nationally prominent centers focus on advancing telemedicine, improving vascular care, eliminating health disparities and translating research findings into new treatments for patients. Together, they make UC Davis a hub of innovation that is transforming health for all. For more information, visit healthsystem.ucdavis.edu.

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