role of p450 epoxygenase in control of the cerebral circulation and protection from ischemic brain injury
Nabil Alkayed, M.D., Ph.D. – Principal Investigator

 

Membrane phospholipids in brain cells are highly enriched with polyunsaturated fatty acids, especially arachidonic acid (AA).  In response to cerebral ischemia, AA is released from membrane phospholipids and metabolized to biologically active compounds called eicosanoids.  In this project, we are examining the role of P450 epoxygenase eicosanoids, or epoxyeicosatrienoic acids (EETs), in controlling cerebral circulation and acting as endogenous neuroprotectants during cerebral ischemia.

Under physiological conditions, EETs are formed by astrocytes and link neuronal activity with regional blood flow.  During functional hyperemia, the neurotransmitter glutamate is released during neuronal activation and enhances formation of EETs by astrocytes which, in turn, dilate cerebral blood vessels to match increased neuronal activity.  Again, what is the role of EETs in facilitating this action by the astrocytes?

One approach to finding answers to our questions is to control the amount of soluble epoxide hydrolase (sEH) present in the cells.  This enzyme provides the major pathway by which EETs are broken down and inactivated in the brain.  By restricting the cellular concentration of sEH, then, we can control the level of EETs present and evaluate their neuroprotective effects on tissue damage and functional recovery after an ischemic event.

This research is funded by the National Institutes of Health.