University of Nebraska Medical Center researcher Yuri Persidsky, M.D., Ph.D., recently received renewal of an important grant that will allow him to continue his work on understanding the mechanisms of blood brain barrier injury caused by neuron-inflammation and HIV brain infection.
Dr. Persidsky hopes to use the five-year, $2.3 million grant from the National Institute of Mental Health (a division of the National Institutes of Health) to evaluate the anti-inflammatory effects of a protein in the body called glycogen synthase kinase-3 beta (GSK-3B).
The grant will seek to determine if inhibiting the normal function of GSK-3B in patients with HIV infection will prevent damage to the brain and the protective coating around the brain called the blood brain barrier.
Stopping GSK-3B activity is believed to play a key role in the pathogenesis of such neurodegenerative disorders as Alzheimer’s disease, bipolar disorder and Huntington’s disease.
“Lithium, a GSK-3B inhibitor, has been used for many years to treat bipolar disorder and is being explored for its neuroprotective abilities in Alzheimer’s disease. A recent small clinical trail showed that lithium improved cognition in people with HIV,” Dr. Persidsky said. “However, GSK-3B inhibitors have never been assessed for their potential anti-inflammatory effects in the brain or protection of the blood brain barrier.”
The blood brain barrier is composed of highly specialized endothelial cells that control penetration of harmful substances and inflammatory cells trying to get into the brain. Injury to the blood brain barrier is one of the leading causes of neuronal demise in HIV infection of the brain.
"The work proposed by Yuri Persidsky to explore GSK-3B inhibitors as anti-inflammatory agents in the brain is fascinating,” said Kenneth Williams, Ph.D., associate professor of medicine, Harvard Medical School. “The possibility that lithium may protect the blood brain barrier from damage has broad implications to neuroinflammatory diseases, including HIV and multiple sclerosis."
Previous work done with GSK-3B by Dr. Persidsky’s lab has shown that pro-inflammatory molecules secreted by HIV infected macrophages (or white blood cells) in the brain can cause blood brain barrier disruption.
Another cause of damage is related to migration of HIV infected monocytes (an earlier version of a macrophage) into the brain.
Accumulation of these cells in the brain is thought to result in neuronal demise and cognitive impairment.
“Now we have evidence that GSK-3B inhibitors will block migration of infected monocytes, tighten the endothelial barrier and suppress production of toxic compounds by HIV infected macrophages thus protecting the blood brain barrier and ultimately brain tissue,” Dr. Persidsky said.
Another interesting aspect of the grant is that it will be done using mice, whose brains will be scanned via MRI.
Michael Boska, Ph.D., vice-chair of the Department of Radiology at UNMC, developed the technique to do the scans on the mice.
“This will allow us to measure the effectiveness of GSK-3B inhibition in live animals,” Dr. Persidsky said.