Arachidonyl trifluoromethyl ketone ameliorates experimental autoimmune encephalomyelitis via blocking peroxynitrite formation in mouse spinal cord white matter.
نویسندگان
چکیده
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.
منابع مشابه
Distinct role of nitric oxide and peroxynitrite in mediating oligodendrocyte toxicity in culture and in experimental autoimmune encephalomyelitis.
Nitric oxide has been implicated in the pathogenesis of multiple sclerosis. However, it is still unclear whether nitric oxide plays a protective role or is deleterious. We have previously shown that peroxynitrite, a reaction product of nitric oxide and superoxide, is toxic to mature oligodendrocytes (OLs). The toxicity is mediated by intracellular zinc release, phosphorylation of extracellular ...
متن کاملTherapeutic potential of a novel cannabinoid agent CB52 in the mouse model of experimental autoimmune encephalomyelitis.
Multiple Sclerosis (MS) is a demyelinating disease which causes inflammation, demyelination, and axonal injury. Currently, there is no cure for the disease. The endocannabinoid system has recently emerged as a promising therapeutic target for MS. The protective mechanisms of cannabinoids are thought to be mediated by the activation of the cannabinoid type 1 (CB1) and type 2 (CB2) receptors expr...
متن کاملCinnamon Ameliorates Experimental Allergic Encephalomyelitis in Mice via Regulatory T Cells: Implications for Multiple Sclerosis Therapy
Upregulation and/or maintenance of regulatory T cells (Tregs) during an autoimmune insult may have therapeutic efficacy in autoimmune diseases. Although several immunomodulatory drugs and molecules are available, most present significant side effects over long-term use. Cinnamon is a commonly used natural spice and flavoring material used for centuries throughout the world. Here, we have explor...
متن کاملExperimental autoimmune encephalomyelitis in the rat spinal cord: lesion detection with high-resolution MR microscopy at 17.6 T.
BACKGROUND AND PURPOSE Experimental autoimmune encephalomyelitis (EAE) is an inflammatory demyelinating disorder of the CNS and an animal model of multiple sclerosis. We used high-field MR microscopy at 17.6 T to image spinal cord inflammatory lesions in the acute stage of chronic relapsing rat EAE. We sought to compare lesions detected on MR imaging with histopathologic findings and to quantif...
متن کاملEffects of progesterone in the spinal cord of a mouse model of multiple sclerosis.
The spinal cord is a target of progesterone (PROG), as demonstrated by the expression of intracellular and membrane PROG receptors and by its myelinating and neuroprotective effects in trauma and neurodegeneration. Here we studied PROG effects in mice with experimental autoimmune encephalomyelitis (EAE), a model of multiple sclerosis characterized by demyelination and immune cell infiltration i...
متن کاملذخیره در منابع من
با ذخیره ی این منبع در منابع من، دسترسی به آن را برای استفاده های بعدی آسان تر کنید
عنوان ژورنال:
- Experimental neurology
دوره 231 1 شماره
صفحات -
تاریخ انتشار 2011