Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter

Authors

Adam C. Vana, Uniformed Services University of the Health Sciences
Shihe Li, Uniformed Services University of the Health Sciences
Rachel Ribeiro, Uniformed Services University of the Health SciencesFollow
Flaubert Tchantchou, Uniformed Services University of the Health Sciences
Yumin Zhang, Uniformed Services University of the Health SciencesFollow

Date of this Version

2011

Comments

Published in Experimental Neurology 231 (2011) 45–55; doi:10.1016/j.expneurol.2011.05.014

Abstract

Inhibition of phospholipase A₂ (PLA₂) has recently been found to attenuate the pathogenesis of experimental autoimmune encephalomyelitis (EAE), a commonly used animal model of multiple sclerosis (MS). However, the protective mechanisms that underlie PLA₂ inhibition are still not well understood. In this study, we found that cytosolic PLA₂ (cPLA₂) was highly expressed in infiltrating lymphocytes and macrophages/microglia in mouse spinal cord white matter. Although cPLA₂ is also expressed in spinal cord neurons and oligodendrocytes, there were no differences observed in these cell types between EAE and control animals. Arachidonyl trifluoromethyl ketone (AACOCF3), a cPLA₂ inhibitor, significantly reduced the clinical symptoms and inhibited the body weight loss typically found in EAE mice. AACOCF3 also attenuated the loss of mature, myelin producing, oligodendrocytes, and axonal damage in the spinal cord white matter. Nitrotyrosine immunoreactivity, an indicator of peroxynitrite formation, was dramatically increased in EAE mice and attenuated by treatment with AACOCF3. These protective effects were not evident when AA861, an inhibitor of lipoxygenase, was used. In primary cultures ofmicroglia, lipopolysaccharide (LPS) induced an upregulation of cPLA₂, inducible nitric oxide synthase (iNOS) and components of the NADPH oxidase complex, p47phox and p67phox. AACOCF3 significantly attenuated iNOS induction, nitric oxide production and the generation of reactive oxygen species in reactive microglia. Similar to the decomposition catalyst of peroxynitrite, AACOCF3 also blocked oligodendrocyte toxicity induced by reactive microglia. These results suggest that AACOCF3 may prevent oligodendrocyte loss in EAE by attenuating peroxynitrite formation in the spinal cord white matter.