Roles of Cyclooxygenase-2 in Microglial Activation and Dopaminergic Cell Death

OF DISSERTATION Rattanavijit Vijitruth The Graduate School University of Kentucky 2006 ROLES OF CYCLOOXYGENASE-2 IN MICROGLIAL ACTIVATION AND DOPAMINERGIC CELL DEATH A dissertation submitted in partial fulfillment of the requirement for the degree of Doctor of Philosophy in the College of Medicine at the University of Kentucky By Rattanavijit Vijitruth Lexington, Kentucky Director: Dr. Guoying Bing, Associate Professor of Anatomy and Neurobiology Lexington, Kentucky 2006 Copyright © Rattanavijit Vijitruth 2006 ABSTRACT OF THE DISSERTATION ABSTRACT OF DISSERTATIONOF DISSERTATION ROLES OF CYCLOOXYGENASE-2 IN MICROGLIAL ACTIVATION AND DOPAMINERGIC CELL DEATH Accumulating evidence suggests that inflammation plays an important role in the progression of Parkinson’s disease (PD). Among many inflammatory factors found in the PD brain, cyclooxygenase (COX), especially the inducible isoform, COX-2, is believed to be the critical enzyme in the inflammatory response. Induction of COX-2 is also found in an experimental model of PD produced by administration of 1-methy-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). To investigate whether inhibition of COX-2 by valdecoxib or deficiency in COX-2 could prevent dopaminergic neuronal toxicity and locomotor activity impairment, we injected MPTP into valdecoxib-treated C57BL/6N mice and COX-2 deficient mice, respectively. Both automated total distance and vertical activity measurements of the open-field test were significantly reduced in the vehicle-treated mice at two weeks post-MPTP injection. In contrast, valdecoxib treatment significantly attenuated these deficits. Similarly, COX-2 deficiency attenuated MPTP-induced loss of coordination on a rotarod assay. Valdecoxib or deficiency of COX-2 reduced microglial activation while preventing loss of tyrosine hydroxylase (TH)-positive neurons in the substantia nigra pars compacta (SNpc). The total number of activated microglia in the SNpc had a strong positive correlation with the level of COX-2 and dopaminergic neurodegeneration. The results of this study indicate that reducing the activity of COX-2 can mitigate the progressive loss of dopaminergic neurons as well as the motor deficits caused by MPTP neurotoxicity, possibly by suppressing the activation of microglia in the SNpc.