Sandra Hewett’s research is driven
by the effects of stroke on her family

Photo: Al Ferreira

Sandra Hewett, associate professor of neuroscience at the UConn Health Center, is researching ways to minimize the damage from ischemic stroke.

The complex nature of a stroke was brought to worldwide attention earlier this year when news organizations followed the health of Israeli prime minister Ariel Sharon after he suffered a stroke.

The kind of stroke Sharon suffered — a hemorrhagic stroke, which causes bleeding into the brain — is relatively rare.

A far more frequently occurring medical emergency is an ischemic stroke that leaves many survivors with serious disabilities.

The only FDA-approved drug treatment for ischemic stroke is the clot-buster TPA, which must be administered within three hours of an ischemic stroke to unblock the clot. More than 700,000 Americans will suffer a stroke this year alone.

Sandra Hewett, whose grandfather died and whose mother was disabled following a stroke, is an associate professor of neuroscience at the UConn Health Center, researching ways to minimize damage from ischemic strokes.

She has been conducting stroke research since her days as a postdoctoral fellow at Washington University School of Medicine in St. Louis, nearly 15 years.

Hewett and her husband and colleague, assistant professor of neuroscience James Hewett, share a laboratory at the UConn Health Center and often collaborate on projects.  

When a stroke occurs, the flow of blood to a particular area of the brain is disrupted. Brain cells affected by the blockage die because the blood supply is their sole source of oxygen and nutrients.

“It happens very rapidly, and brain cells literally excite themselves to death,” Hewett explains.

The early stages of stroke trigger the release and accumulation of glutamate, an amino acid that normally serves as a neurotransmitter but in high concentration sets off another series of chemical reactions that can lead to the death or dysfunction of cells.  

Although there is little hope for survival of cells in the core of the stroke, damage may progress into the adjacent area, known as the penumbra.

The penumbra contains cells that have been partially damaged but may still be restored.

“In the last 10 years, it has been recognized that inflammation occurs in the penumbra after stroke,” says Hewett, who has a doctorate in pharmacology.

“We are currently working on understanding the secondary inflammatory changes occurring in the penumbra and how that leads to the progression of cellular injury. Once we identify the pathways and determine what’s most important, we can identify a therapeutic strategy to block inflammation and preserve the penumbra.”

Using a model she calls “stroke in a dish,” Hewett and her assistants mix together nerve cells, known as neurons, and star-like nerve tissue, called astrocytes, dissected from the brains of mice.

They simulate stroke conditions by removing oxygen and glucose from this tissue culture for varying periods of time. As neurons die, astrocytes become activated resulting in the inflammation that contributes to the progression of neuronal injury.

Hewett’s research is focusing on how inflammatory enzymes known to be present in the stroke’s penumbra contribute to the degeneration of brain tissue after a stroke.

Working in collaboration with New Jersey based Onconova Therapeutics, she has tested a number of their proprietary compounds — designated as COX-2 inhibitors — to offer anti-inflammatory protection.

“If you inhibit inflammation you can decrease stroke-mediated brain injury,” Hewett says.

“What we’re trying to do is find out when the inflammatory enzyme becomes activated and how it causes cell death.”

“It’s very exciting,” Hewett says.

“I’ve always wanted my work to be clinically relevant, to make a difference in the world,” adding she hopes her discoveries will prompt Onconova or other pharmaceutical companies to develop more clinical trials.

“We’ve made progress, but we won’t have an answer or a cure tomorrow.”

She says one of the challenges of stroke research is that it is difficult to design clinical trials because there is so much individual human variation in post-stroke neurological damage.

That translates into a process that is time-consuming and expensive, which has caused many pharmaceutical companies to discontinue stroke research, Hewett says.

To hasten the journey from lab bench to bedside, the National Institutes of Health (NIH) is providing grants to academic researchers to help defray research costs for clinical trials.

“Sandra simply bubbles over with enthusiasm about science, whether doing her own lab work, teaching students one-on-one, or in a larger lecture setting,” says Richard Mains, professor and head of the department of neuroscience at the UConn Health Center.

“Her work on stroke models has a very obvious clinical-human impact. In addition, she serves as the current director of the Neuroscience Graduate Program, a role well suited to her enthusiasm, scientific breadth and people skills.”

Hewett has turned down offers to work for pharmaceutical companies, preferring to conduct her own research and help teach UConn medical students — whom she calls “the next generation” of scientists — about the molecular mechanisms and treatments of stroke.  

— Karen Singer ’73 (CLAS)