Haem oxygenase-1 induction and activity in astrocytes and possible interactions with nitric oxide.

Haem oxygenase-1 (HO-1) is the inducible form of the enzyme responsible for the breakdown of haem, metabolising it to carbon monoxide (CO), bilirubin and iron. Protective properties have been attributed to HO-1 induction and haem breakdown products. Upregulation of HO-1 has been reported in many neurodegenerative disorders and it has been postulated that this may play an important role in the stress defences of the cell. Inducible nitric oxide (iNOS) activity, nitric oxide production and mitochondrial dysfunction are also reported in neurodegenerative disorders and it has been shown that inducers of iNOS also induce HO-1. Rat astrocytes have been used to examine possible interactions between the iNOS/HO systems by inducing iNOS activity with IFNy/LPS and HO-1 with hemin. It was confirmed that EFNy/LPS mediated NO production caused an upregulated HO-1 expression and an increase in HO activity. Further, it was shown that hemin treatment was able to prevent the previously reported NO mediated irreversible inhibiton of complex IV of the mitochondrial electron transport chain seen when astrocytes are treated with IFNy/LPS. Hemin plus IFNy/LPS treatment was accompanied by an increase in HO activity and an increase in glutathione (GSH) levels and it is postulated that together these confer protection. It may be concluded from this thesis that there are complex interactions between HO and NOS which could contribute to the ability of astrocytes to provide protection to neurones against oxidative and nitrosative stress. This may be relevant to mechanisms by which neurodegeneration occur