Ageing-related role of nitric oxide in the brain

Production of nitric oxide (NO) in the cell is catalysed by NO synthase (NOS), which using L-arginine and oxygen as substrates, synthesises NO. Normally cells express neuronal and/or endothelial NOS (nNOS and eNOS, respectively) producing nanomolar NO. Under inflammatory conditions cells express inducible NOS (iNOS), which, once expressed, produces micromolar NO. Since micromolar NO could elicit damage to cells, iNOS expression is time-spatially finely regulated. Recent evidence points out the possible interaction between n/eNOS and iNOS. Under inflammatory conditions interferon-γ, tumour necrosis factor-α and interleukin 1 -β rapidly trigger inhibition of e/nNOS activity with successive drop in the amounts of NO. Since NO normally exerts suppressive action on NF-κB activation, drop in NO may create a favourable conditions for NF-κB activation and successive iNOS exptression. Evidence in the literature indicates that during ageing nNOS activity gradually drops with concomitant increase in iNOS expression in the brain. However, how nNOS activity may influence iNOS expression remains to be elucidated. This review points out the possible functional link between age-dependent decrease in nNOS activity and increase in iNOS expression in the brain. Evidence for the possible scenario that often underestimated continuous infections to the brain, one of the hallmarks of ageing, may trigger apparently spontaneous iNOS expression is presented. Future treatment of aged people based on this scenario is also described.