Nitrosative Stress Is Associated with Dopaminergic Dysfunction in the HIV-1 Transgenic Rat.

ABSTRACT

Advances in antiretroviral therapy have resulted in significantly decreased HIV-related mortality. HIV-associated neurocognitive disorders, however, continue to be a major problem in infected patients. The neuropathology underlying HIV-associated neurocognitive disorders has not been well characterized, and evidence suggests different contributing mechanisms. One potential mechanism is the induction of oxidative stress. Using the HIV-1 transgenic (Tg) rat model of HIV, we found increased striatal NADPH oxidase-4 and neuronal nitric oxide synthase expression in the adult (7- to 9-month-old) Tg rat compared with control rats but not in the young (1-month-old) Tg rats. This was accompanied by increased 3-nitrotyrosine (3-NT) immunostaining in the adult Tg rats, which worsened significantly in the old Tg rats (18 to 20 months old). There was, however, no concurrent induction of the antioxidant systems because there was no change in the expression of the nuclear factor-erythroid 2-related factor 2 and its downstream targets (thioredoxin and glutathione antioxidant systems). Colocalization of 3-NT staining with neurofilament proteins and evidence of decreased tyrosine hydroxylase and dopamine transporter expression in the old rats support dopaminergic involvement. We conclude that the HIV-1 Tg rat brain shows evidence of nitrosative stress without appropriate oxidation-reduction adaptation, whereas 3-NT modification of striatal neurofilament proteins likely points to the ensuing dopaminergic neuronal loss and dysfunction in the aging HIV-1 Tg rat.