Research on strokes
Stroke is one of the leading causes of death and long term disability in the United States, but unfortunately there are no safe and effective treatments available to prevent the brain damage associated with the "brain attack". A collaboration between Biology faculty members Joseph Burdo and Charles Hoffman aims to identify novel bioactive compounds that may protect against the devastating effects of this disease. Stroke is one of the leading causes of death and long term disability in the United States, but unfortunately there are no safe and effective treatments available to prevent the brain damage associated with the "brain attack". A collaboration between Biology faculty members Joseph Burdo and Charles Hoffman aims to identify novel bioactive compounds that may protect against the devastating effects of this disease.
Aging is one of the most important risk factors for ischemic stroke, which is the leading cause of severe disability and the third leading cause of death in the United States. During an ischemic stroke, blood flow is decreased to affected areas of the brain due to a blood vessel that has either burst or become occluded. This decrease in blood flow leads to a decline of glucose and oxygen availability to neurons, which are the principal signaling cells of the brain. Since neurons are the most metabolically demanding cells in the body, they are exquisitely sensitive to the absence of these fuels, and irreversible damage or neuronal death quickly results when glucose and oxygen are not available. Despite these well-known facts, there are no drugs available to protect neurons against the devastating effects of stroke.
In collaboration with Dr. Hoffman our lab has investigated the neuroprotective effects of a novel phosphodiesterase inhibitor (PDE-I) named BC27 in a cell culture model of stroke. We have shown that BC27 inhibits the PDE4 enzyme, one of the eleven different types of PDE enzymes present within cells. PDE4 inhibition has been investigated as a treatment for many neurological conditions, including depression, spinal cord injury and psychosis, as well as a treatment to increase memory function. While it is known that the molecular pathways downstream of PDE4 affect neuronal health and survival, very little research has been performed investigating the effect of PDE4 inhibitors on prevention of stroke-mediated brain damage.
We have found that BC27 (but not Rolipram, the classical PDE4 inhibitor) significantly protects immortalized mouse hippocampal neurons against glutamate toxicity in cell culture. Glutamate is a neurotransmitter released in toxic quantities by many neurons in vivo when they are exposed to the glucose and oxygen deprivation effects of stroke. This large amount of glutamate release overstimulates nearby neurons and leads to a wave of cell death spreading away from the initial stroke infarct. Unlike Rolipram, which blocks the active site of the PDE4 enzyme, BC27 is thought to bind an allosteric or modulatory site on the PDE4 enzyme, which results in high efficacy while potentially avoiding the severe gastrointestinal and nausea side effects of Rolipram that have prevented its FDA approval for some of the neurological conditions described above.
While the cell culture model described above is useful for understanding some aspects of the cellular pathways altered by stroke, we also need to know how the intact brain environment is altered during this process. Treating rat brain slices with altered levels of glucose and oxygen is a useful and well-accepted method of stroke modeling. Since the slices are hundreds of microns thick and are bathed in artificial cerebrospinal fluid, the cellular architecture and connections are preserved and the cells continue to function relatively normally for weeks after brain sectioning. As such, this research method is much more powerful than working with individual cells in culture, while being less expensive, complicated and difficult for students to learn than are whole animal stroke studies.
With support from the Boston College Institute on Aging (IOA), we will now be able to extend our investigation of the neuroprotective properties of BC27 from our cell culture studies to the rat brain slice model using oxygen and glucose deprivation as a stroke simulator. My students and I are very thankful for the IOA support for this promising project.