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Arachidonyl Trifluoromethyl Ketone Ameliorates Experimental Autoimmune Encephalomyelitis via Blocking Peroxynitrite Formation in Mouse Spinal Cord White Matter

Arachidonyl Trifluoromethyl Ketone Ameliorates Experimental Autoimmune Encephalomyelitis via Blocking Peroxynitrite Formation in Mouse Spinal Cord White Matter

Adam C Vana, Shihe Li, Rachel Ribeiro, Flaubert Tchantchou, Yumin Zhang

Exp Neurol. 2011 Sep;231(1):45-55.

PMID: 21683698

Abstract:

Inhibition of phospholipase A(2) (PLA(2)) 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 PLA(2) inhibition are still not well understood. In this study, we found that cytosolic PLA(2) (cPLA(2)) was highly expressed in infiltrating lymphocytes and macrophages/microglia in mouse spinal cord white matter. Although cPLA(2) 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 cPLA(2) 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 of microglia, lipopolysaccharide (LPS) induced an upregulation of cPLA(2), 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.

Chemicals Related in the Paper:

Catalog Number	Product Name	Structure	CAS Number	Price
AP149301791	Arachidonyl trifluoromethyl ketone		149301-79-1	Price

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