Peroxisome proliferator-activated receptors (PPAR) are members of a nuclear hormone receptor superfamily that includes receptors for steroids, retinoids, and thyroid hormone, all of which are known to affect the immune response. Previous studies dealing with PPAR-γ expression in the immune system have been limited. Recently, PPAR-γ was identified in monocyte/macrophage cells. In this study we examined the role of PPAR-γ in experimental autoimmune encephalomyelitis (EAE), an animal model for the human disease multiple sclerosis. The hypothesis we are testing is whether PPAR-γ plays an important role in EAE pathogenesis and whether PPAR-γ ligands can inhibit the clinical expression of EAE. Initial studies have shown that the presence of the PPAR-γ ligand 15-deoxy-Δ12,14-PGJ2 (15d-PGJ2) inhibits the proliferation of Ag-specific T cells from the spleen of myelin basic protein Ac1–11 TCR-transgenic mice. 15d-PGJ2 suppressed IFN-γ, ΙL-10, and IL-4 production by both Con A- and myelin basic protein Ac1–11 peptide-stimulated lymphocytes as determined by ELISA and ELISPOT assay. Culture of encephalitogenic T cells with 15d-PGJ2 in the presence of Ag reduced the ability of these cells to adoptively transfer EAE. Examination of the target organ, the CNS, during the course of EAE revealed expression of PPAR-γ in the spinal cord inflammatory infiltrate. Administration of 15d-PGJ2 before and at the onset of clinical signs of EAE significantly reduced the severity of disease. These results suggest that PPAR-γ ligands may be a novel therapeutic agent for diseases such as multiple sclerosis.

No abstract

Doxorubicin is the most commonly prescribed chemotherapeutic agent. Doxorubicin causes an increase in free radical production in the myocardium and cardiac muscle dysfunction. Patients receiving chemotherapy also experience weakness and fatigue leading us to hypothesize doxorubicin (1) increases muscle‐derived oxidants and (2) depresses diaphragm and limb muscle force in mice. Doxorubicin treatment (20μM, 1hr) in vitro increased oxidant activity in diaphragm muscle as measured using DCF fluorescence (n=3, p<0.04). We injected C57B6 male mice intraperitoneally with doxorubicin (20 mg/kg), a cumulative dose commonly used in cardiotoxicity studies. Diaphragm and extensor digitorum longus (EDL) were excised three days post injection, compared to controls, doxorubicin lowered maximal force in diaphragm by 62.2 ± 7.1% (mean ± SE; n=5, p<0.01) and EDL by 28.7 ± 7.9% (n=3, p<0.03). Doxorubicin depressed diaphragm twitch characteristics, including peak force (−37.7 ± 12.5%; n=5, p<0.01) and time to peak force (Doxorubicin 0.15 ± 0.02 N s−1, Control 0.29 ± 0.02 N s−1). At the end of the fatigue trial, force was lower in doxorubicin treated mice 26.9 ± 12.2% of control values. The stability of the muscle in vitro was not altered. Our data shows that doxorubicin causes skeletal muscle weakness and predisposes muscle to fatigue, which may be due to an increase in muscle‐derived oxidants.Supported by: HL 59878 (MBR)