KENNETH STRAUSS, PhD
(Conferences / Seminars / Lectures)
EICOSANOIDS IN NEUROTRAUMA, NEUROINFLAMMATION, AND more information...
AGE-RELATED COGNITIVE DECLINE
HOST: Joseph R. Haywood
Neurotrauma afflicts millions annually, and is the major cause of death and disability among young people (16-45 y.o.). Currently there is no medically effective treatment for traumatic brain injury (TBI); clinical trials have failed to improve functional outcomes in victims of TBI. We are studying arachidonic acid (ArA) metabolism after its release from damaged cell membranes to better understand the intrinsic and extrinsic inflammatory responses of the brain after injury. ArA is oxidized by molecular oxygen to a family of compounds known as eicosanoids. Eicosanoid activities are diverse, often acting through 7-transmembrane domain G-protein coupled receptors. Cyclooxygenases (COX1, COX2), lipoxygenases, and epoxygenases catalyze the conversion of ArA to eicosanoids. Over 50 naturally occurring biologically active eicosanoids have been identified in mammals that demonstrate potent vasoactive, inflammatory, neurophysiologic, and gene regulatory functions. However, in many cases eicosanoid activities have not been well defined, particularly in the brain. Some of these molecules, including ArA itself, have specific neural activities that differ from peripheral organ systems. Some of the challenges in studying eicosanoid activities in the brain are their trace levels and local function. With peak levels in the parts per billion range, studies in decades past have focused on hemispheric or global changes, but have not been able to quantify eicosanoids in discrete brain regions. Many of the eicosanoids, particularly the epoxides (EETs) are exceptionally labile and, in the presence of oxygen, are immediately converted to far less active dihydroxy (DiHETE) metabolites. These reactions can be spontaneous, or catalyzed by enzymes including epoxide hydrolases, cyclooxygenases, and prostaglandin dehydrogenases.
To date, we have studied the regulation and function of COX2 in several experiments that show it promotes neuroinflammatory processes and neural cell death. In a rat model of unilateral brain injury, COX2 is dysregulated in the first week after TBI in both the hippocampus (bilaterally) and the injured cerebral cortex. These regions have been associated with several of the functional deficits evident after neurotrauma in humans, e.g., retrograde amnesia, learning and memory problems, and proprioceptive dysfunction. Interestingly, inhibition of COX2 enzyme activity using selective (and less selective) pharmacologic agents improves recovery of function, and reduces inflammation and neural cell loss, as well. Unfortunately, COX2 inhibitors have suffered a setback in clinical utility; unacceptably severe cardiovascular adverse effects have been identified, particularly with long term use.
More recently, our studies have refocused on the metabolism of ArA via other metabolic routes, particularly to epoxyeicosatrienoic acids (EETs) and hydroxyeicosatetraenoic acids (HETEs). To this end, we have developed ultrasensitive chromatographic methods to quantify eicosanoids in small tissue samples, and have begun to characterize the dynamic regulation of the cytochrome P450 epoxygenases that catalyze the synthesis of EETs and HETEs. Recent studies of the injured brain have revealed brain region-specific changes of enzymes that catalyze eicosanoid formation and metabolism, as well as the quantification of brain level changes for over 20 eicosanoids. Currently, novel eicosanoid analogs are being tested in a behavioral pharmacology paradigm towards the development of potentially effective treatments to improve functional recovery after TBI. Moreover, we are testing novel molecular strategies to effect local blockades of induced COX2 activity in the injured brain in an effort to avoid the adverse side-effects of COX2 inhibitors.