Ibuprofen fails to prevent brain pathology in a model of neuropsychiatric lupus.
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.


CONCLUSIONS
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.
Ballok
David A
DA
Department of Psychiatry and Behavioral Neurosciences, McMaster University, 1200 Main Street West, Hamilton, Ontario, Canada.
Ma
Xiaoxing
X
Denburg
Judah A
JA
Arsenault
Larry
L
Sakic
Boris
B
D000818:Animals; D001284:Atrophy; D001921:Brain / Q000276:immunology / Q000473:pathology*; D051546:Cyclooxygenase 2 / Q000378:metabolism; D016861:Cyclooxygenase Inhibitors / Q000494:pharmacology / Q000627:therapeutic use*; D004195:Disease Models, Animal; D007052:Ibuprofen / Q000494:pharmacology / Q000627:therapeutic use*; D007150:Immunohistochemistry; D007249:Inflammation; D020945:Lupus Vasculitis, Central Nervous System / Q000188:drug therapy* / Q000503:physiopathology; D008297:Male; D051379:Mice; D019463:Mice, Inbred MRL lpr; D017628:Microglia / Q000473:pathology*; D008854:Microscopy, Electron
D016861:Cyclooxygenase Inhibitors; D051546:Cyclooxygenase 2; D007052:Ibuprofen