NADPH Oxidase-4 (Nox4) Mediated Nitration of Striatal Axonal Neurofilaments and a Dysregulation in Redox Adaptation are Associated with Dopaminergic Denervation in the Aging HIV-1 Transgenic Rat

摘要

Due to the success of combined anti-retroviral therapy, HIV-1 infected patients are living longer with a better quality of life. Nonetheless, the prevalence of human immunodeficiency virus associated neurocognitive (HAND) disorder continues to be a widespread problem, and a more rapid progression of neurocognitive impairment caused by ageing in individuals with HIV has been reported. HAND is characterized by an increase in reactive oxygen, and reactive nitrogen species at the cellular level. Motor and behavioral dysfunction are among the common symptoms and it is believed that oxidative and nitrosative stress contribute to mechanistic changes leading to neurocognitive impairment. Our previous imaging, histological, motor and behavioral assessments support a dysregulation in dopaminergic function as the HIV-1 Transgenic Rat (HIV-Tg) ages. The goal of this study is to demonstrate the presence of oxidative and nitrosative stress within the neuroanatomic areas associated with dopaminergic dysfunction in the HIV-1 Tg rat brain. Herein, we report pathology suggestive of pre-synaptic dopaminergic neuronal loss (decreased striatal tyrosine hydroxylase and DAT staining with a decreased NeuN staining in the substantia nigra), increases in striatal Nox4 and neuronal nitric oxide synthase expression with an associated increase in 3-nitrotyrosine (3-NT) modification of striatal axonal neurofilament proteins of aged HIV-1 Tg rats compared to age-matched non-Tg controls. Finally, this increase in free radical mediated neuronal pathology occurred without significant induction of the transcription factor nuclear factor-erythroid 2-related factor 2 (Nrf2) and redox adaptation of the Nrf2 responsive Thioredoxin and Glutathione antioxidant systems. Our findings suggest that in the aging HIV-1 Tg rat, possibly due to chronic exposure to HIV-1 proteins and lack of appropriate redox adaptation, increased nitrosative stress and 3-NT modification of striatal axonal neurofilament proteins is hastened possibly contributing to dopaminergic neuronal structural changes and secondary dopaminergic dysfunction.