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. HIVassociated 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-montheold) Tg rat compared with control rats but not in the young (1-montheold) 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 factoreerythroid 2erelated 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.

Redistribution of brain glucose metabolism in people with HIV after antiretroviral therapy initiation

“…This predilection has been shown in brain autopsies of HIV-infected patients, with HIVassociated brain lesions identified mainly in the putamen and thalamus [36], as well as a higher concentration of HIV p24 positive cells in the basal ganglia [37]. We have also previously shown subcortical dopaminergic loss (both presynaptic and postsynaptic) in an animal model of HIV infection [38][39][40][41], which was associated with Gp120 levels and oxidative stress [39] dopamine levels and CNS vacuolization, SIVencephalitic lesions and enhanced CNS viral replication during early infection [42,43]. This could be due to the role of dopamine in increasing the susceptibility of primary human macrophages to HIV entry through stimulation of both D1-like and D2-like receptors [44] via an alternative signalling pathway [45].…”

Identification of Increased Blood Brain Barrier Permeability in the Substantia Nigra of the HIV-1 Transgenic Rat

“…Our first report noted the symptomology related to Basal Ganglia dysfunction [6]. Subsequently, further studies provided clarification to changes of the dopaminergic system [7]. Further we note this rat model possesses a CXCR4 receptor capable of binding to GP-120.…”

Evaluation and Validation of Commercially Available Dopamine Transporter Antibodies

“…Of the numerous papers using various DAT antibodies for WB and/or immunohistology discussed and cited here (Loder and Melikian, 2003;Sorkina et al, 2003;Torres et al, 2003a;Sorkina et al, 2006;Miranda et al, 2007;Boudanova et al, 2008a, b;Lyck et al, 2008;Eriksen et al, 2009;Vina-Vilaseca and Sorkin, 2010;Cone et al, 2013;McIntosh et al, 2013;Ruocco et al, 2014;Gou et al, 2015;Sarkar et al, 2015;Sconce et al, 2015;Garea-Rodríguez et al, 2016;Hood et al, 2016;Churchill et al, 2017;Y. Zhang et al, 2017;Colon-Perez et al, 2018;Jovanovic et al, 2018;Perdikaris et al, 2018;Li et al, 2019;Rosas-Hernandez et al, 2019;Shah et al, 2019;Harraz et al, 2021;Niu et al, 2021;W. Zhang et al, 2021;Cuevas et al, 2022), only a handful used a DAT-KO sample as a comparator to determine specificity for DAT (Leo et al, 2018;Yang et al, 2019).…”