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Ibuprofen Fails to Prevent Brain Pathology in a Model of Neuropsychiatric Lupus
DAVID A. BALLOK, XIAOXING MA, JUDAH A. DENBURG, LARRY ARSENAULT, and BORIS SAKIC ABSTRACT. Objective. Neurologic and psychiatric manifestations are severe complications of systemic lupus erythematosus (SLE). As commonly seen in patients, spontaneous development of lupus-like disease in MRL-lpr mice is accompanied by brain atrophy and behavioral dysfunction. We examined inflammatory and ultrastructural aspects of central nervous system (CNS) involvement using a nonselective cyclooxygenase-2 (COX-2) inhibitor and measuring effects on behavior, microglial activation, and neuronal morphology. Methods. Ibuprofen (IBU) was provided in a rodent chow (375 ppm) for animals 5–19 weeks of age. Exploration of a novel environment and performance in the forced swim test assessed effects on behavior. Immunohistochemistry, fluoro-Jade B (FJB) staining, and flow cytometry were employed in neuropathological analysis. Transmission electron microscopy was used to examine ultrastructural morphology of cortical, hippocampal, hypothalamic, nigral, and cerebellar cells. Results. Chronic IBU treatment failed to normalize immune status, behavior, and brain mass in lupus-prone MRL-lpr mice. It also did not reduce density of CD3+ lymphocytes in the choroid plexus, or FJB+ neurons in the hypothalamus. Activated F4/80+ microglia increased with age, but IBU treatment was not effective in reducing their numbers. Although numerous dark cells were seen in functionally critical brain regions (e.g., paraventricular nucleus and subgranular zone), ultrastructural morphologies of classical apoptosis or necrosis were not detected. Conclusion. The COX-dependent pathway does not seem to be critical in the etiology of CNS disease in this model of neuropsychiatric lupus. Reduced brain mass, increased microglial activation, and condensation of cytoplasm point to a metabolic perturbation (e.g., excitotoxic damage) that compromises function and survival of central neurons during lupus-like disease. (J Rheumatol 2006;33:2199-213) Key Indexing Terms:
AUTOIMMUNITY From the Department of Psychiatry and Behavioral Neurosciences, Department of Medicine, Department of Pathology and Molecular Medicine, and The Brain-Body Institute (St. Joseph's Healthcare), McMaster University, Hamilton, Ontario, Canada. Supported by doctoral research award grant MOP 38065 from the Canadian Institutes of Health Research to D. Ballok, and grant 1R21 AR49163-01 from the National Institutes of Health to B. Sakic. Mr. Sakic is a recipient of the Father Sean O'Sullivan Research Centre career development award. D.A. Ballok, PhD; X. Ma, MSc, Department of Psychiatry and Behavioral Neurosciences; J.A. Denburg, MD, FRCP, Department of Medicine; L. Arsenault, PhD, Department of Pathology and Molecular Medicine; B. Sakic, PhD, Department of Psychiatry and Behavioral Neurosciences, The Brain-Body Institute (St. Joseph's Healthcare). Address reprint requests to B. Sakic, Department of Psychiatry and Behavioral Neuroscience, HSC Room 4N81, McMaster University, 1200 Main Street West, Hamilton, Ontario L8N 3Z5, Canada. E-mail: sakic@mcmaster.ca Accepted for publication June 23, 2006.
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