Aging-related changes in the nigral angiotensin system enhances proinflammatory and pro-oxidative markers and 6-OHDA-induced dopaminergic degeneration

An age-related proinflammatory, pro-oxidant state in the nigra may increase the vulnerability of dopaminergic neurons to additional damage. Angiotensin II, via type 1 (AT1) receptors, is one of the most important known inflammation and oxidative stress inducers. However, it is not known if there are age-related changes in the nigral angiotensin system. In aged rats, we observed increased activation of the nicotinamide adenine dinucleotide phosphate-oxidase (NADPH oxidase) complex and increased levels of the proinflammatory cytokines interleukin (IL)-1β and tumor necrosis factor (TNF)-α, which indicate pro-oxidative, proinflammatory state in the nigra. We also observed enhanced 6-hydroxydopamine (6-OHDA)-induced dopaminergic cell death in aged rats. This is associated with increased expression of AT1 receptors and decreased expression of AT2 receptors in aged rats, and is reduced by treatment with the AT1 antagonist candesartan. The present results indicate that brain angiotensin is involved in changes that may increase the risk of Parkinson's disease with aging. Furthermore, the results suggest that manipulation of the brain angiotensin system may constitute an effective neuroprotective strategy against aging-related risk of dopaminergic degeneration.