Heme oxygenase-1 and NADPH cytochrome P450 reductase expression in experimental allergic encephalomyelitis: An expanded view of the stress response

Oxidative stress is implicated in the pathogenesis of experimental allergic encephalomyelitis (EAE), a model for multiple sclerosis, Heme oxygenase-` (HO-1) is a heat shock protein induced by oxidative stress. HO-1 metabolize s the pro-oxidant heme to the antioxidant biliverdin and CO. HO-1 requires electrons, donated by NADPH cytochrome P450 reductase thenceforth, reductas e), for catalytic activity. EAE was induced with a peptide of proteolipid p rotein in SJL mice, and the expression of HO-1 and reductase in the hindbra in was analyzed. HO-1 protein levels were significantly increased in EAE an imals compared with control mice. HO-1 expression was present in ameboid ma crophages, reactive microglia, and astrocytes in white matter tracks. Bergm ann glia and ameboid macrophages also were occasionally stained in the mole cular layer of the cerebellum. Unlike HO-1, reductase protein levels decrea sed with disease severity. HO-1 and reductase were associated with each oth er in endoplasmic reticulum micelles, suggesting that the decrease in reduc tase does not interfere with its association with HO-1. In cells that expre ss HO-1, the association of reductase with HO-1 should competitively inhibi t the interaction of reductase with cytochrome P450 isozymes and thereby li mit free radical production as the latter two enzymes act cooperatively to produce superoxide. The increase in HO-1 together with the decrease in redu ctase may be part of a common defense mechanism attempting to minimize tiss ue damage in several neurological conditions.