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DTSTAMP:20110209T170000Z
UID:1296050020854@events.msu.edu
CATEGORIES:Conferences / Seminars / Lectures
DTSTART:20110209T170000Z
DTEND:20110209T180000Z
SUMMARY:KENNETH STRAUSS, PhD
DESCRIPTION:
 EICOSANOIDS IN NEUROTRAUMA, NEUROINFLAMMATION, 
 AND\n
 AGE-RELATED COGNITIVE DECLINE\n
 \n
 HOST: 
 Joseph R. Haywood\n
 \n
 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.\n
 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.\n
 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.\n\n
 Price: free\n
 Sponsor: Dept of Pharmacology & Toxicology\n
 Sponsor's Homepage: http://phmtox.msu.edu\n
 Contact name: Diane Hummel\n
 Contact phone: 353-9616\n
 Contact email: phm@msu.edu\n
 for more info visit the web at:\n 
 http://phmtox.msu.edu/events/pdf/Strauss--Flyer.pdf\n
LOCATION:B448-49 Life Sciences Building
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