In response to injury and neurodegenerative disease, endogenous CNS glial cells produce pro-inflammatory cytokines such as IL-1ß, TNF-alpha, and IL-6 that have the potential to exacerbate brain damage. For example, polymorphisms in the IL-1 locus are linked to Alzheimer’s disease and blockade of IL-1 attenuates damage in models of stroke. To better understand the actions of these cytokines in the CNS, we are characterizing molecular and cellular responses to IL-1ß using in vitro and in vivo approaches. A major related effort focuses on CNS expression of cyclooxygenase, the enzyme responsible for prostaglandin production. Multiple lines of evidence indicate that inhibitors of cyclooxygenase, such as ibuprofen, may be beneficial in the prevention of Alzheimer's disease. Two isoforms of this enzyme exist: cyclooxygenase-1 is expressed by microglia in vivo and regulated by NGF in PC12 cell differentiation; whereas cyclooxygenase-2 is expressed by glia treated with pro-inflammatory cytokines as well as by neurons following synaptic stimulation. Research is underway to characterize the normal and pathological roles of glial and neuronal cyclooxygenases and the prostaglandins they produce. Studies are carried out at several levels, including cellular and molecular biological aspects of gene regulation in tissue culture, pharmacologic and transgenic manipulation of mice, and analysis of human brain tissue. Specific model systems currently under investigation include Alzheimer’s Disease, Amyotrophic Lateral Sclerosis, and CNS Radiation Injury.

Journal Articles

Moore, A. H., J. A. Olschowka, Williams, J. P., Okunieff, P., and M. K. O’Banion.  2005.  Regulation of prostaglandin E2 synthesis after brain irradiation.  Int. J. Rad. Oncol. Biol. Phys.  62:267-272.

Heneka, M. T., M. Sastre, L. Dumitrescu-Ozimek, A. Hanke, I. Dewachter, C. Kuiperi, K. O’Banion, T. Klockgether, F. Van Leuven, and G. E. Landreth.  2005.  Acute treatment with the PPARg agonist pioglitazone and ibuprofen reduces glial inflammation and Ab1-42 levels in APPV717I transgenic mice.  Brain 128:1442-1453.

Reviews

Hoozemans, J. J. M. and M. K. O’Banion. 2005.  The role of COX-1 and COX-2 in Alzheimer’s disease pathology and the therapeutic potential of nonsteroidal anti-inflammatory drugs.  Curr. Drug Targets CNS and Neurol Disord.  4:307-315.

Abstracts

O’Banion, M. K., S. D. Hurley, J. P. Williams, and J. A. Olschowka.  2005.  HZE radiation effects on neuroinflammation: role of COX-2.  Bioastronautics Investigator’s Workshop, Galveston, TX, January 10-12.

Hurley, S. D, M. J. Moravan, A. Want, M. K. O’Banion, J. A. Olschowka.  2005.  Aging’s adverse relationship with traumatic brain injury outcome: does neuroinflammation play a role? 23rd Annual National Neurotrauma Society Symposium, Washington, DC, November 9-11.  J. Neurotrauma 22:1206.

Joseph, S. A., E. Lynd-Balta, M. K. O’Banion, J. Padowski, and R. M. Rappold.  2005.  Identification of a seizure circuit by cyclooxygenase upregulation in the kainate model. Society for Neuroscience Annual Meeting, Washington, DC, November 8-12. Soc. Neurosci. Abstr. 432.22.

Maida, M. E., A. H. Moore, S. D. Hurley, J. M. Daeschner, and M. K. O’Banion.  2005.  Cytosolic prostaglandin E2 synthase (cPGES) is decreased in discrete cortical regions in psychiatric disease. Society for Neuroscience Annual Meeting, Washington, DC, November 8-12. Soc. Neurosci. Abstr. 445.11.

S. S. Shaftel, J. A. Olschowka, S. Kyrkanides, and M. K. O’Banion.  2005.  Temporally and spatially controlled IL-1b production in the adult mouse brain leads to glial activation, chemokine upregulation, and inflammatory cell recruitment. Society for Neuroscience Annual Meeting, Washington, DC, November 8-12. Soc. Neurosci. Abstr. 907.1.