Regional distribution of heme oxygenase, HSP70, and glutathione in brain: relevance for endogenous oxidant/antioxidant balance and stress tolerance.

It is generally recognized that lipid peroxides play an important role in the pathogenesis of several diseases and that sulfhydryl groups are critically involved in cellular defense against endogenous or exogenous oxidants. Recent evidence indicates that lipid peroxides directly participate in induction of cytoprotective proteins, such as heat shock proteins (Hsps), which play a central role in the cellular mechanisms of stress tolerance. Heme oxygenase (HO) is a stress protein that has been implicated in defense mechanisms against agents that may induce oxidative injury, such as endotoxins, cytokines and heme and its induction represents a common feature in a number of neurodegenerative diseases. In the present report we studied regional distribution of heme oxygenase (HO) activity and protein expression, together with that of Hps70, in brain of C57BL6 mice. Endogenous lipid peroxidation was investigated on the basis of the analysis of ultra weak chemiluminescence, hydro peroxides and lipid soluble fluorescent products, and compared to the regional distribution of thiols, antioxidant enzymes and trace metals. Our results show that levels of HO activity and expression of inducible Hsp70 and the ratio of GSH/GSSG in the different brain regions examined were positively correlated with the content of peroxides. Substantia Nigra was the brain area exhibiting the highest levels of HO-2, constitutive and inducible Hsp70, GSSG, peroxides, iron, and calcium, in contrast with the lowest content in GSH, GSH/GSSG ratio and glutathione reductase activity, compared to the other cerebral regions examined. Among these, cortex showed the lowest levels of HO-2, Hsp70, GSSG and peroxides that were associated with the highest levels of GSH and GSH/GSSG ratio. These data support the hypothesis that the glutathione redox state and basal peroxides can directly participate in the signaling pathways of heat shock protein expression and hence of stress tolerance.