Oxidative stress and toxicity induced by the nucleoside reverse transcriptase inhibitor (NRTI)—2′,3′-dideoxycytidine (ddC): Relevance to HIV-dementia

Abstract

Human immunodeficiency virus dementia (HIVD) is the most common form of dementia occurring among young adults. In HIVD, neuronal cell loss occurs in the absence of neuronal infection. With the advent of highly active anti-retroviral therapy (HAART), the incidence of HIVD has drastically reduced, though prevalence of milder forms of HIVD continues to rise. Though these agents have been used successfully in suppressing viral production, they have also been associated with a number of side effects. Here we examine the possible role of NRTIs, in particular 2′, 3′-dideoxycytidine (ddC), in the neuropathology of HIVD. Synaptosomes and isolated mitochondria treated and incubated for 6 h with CSF-achievable concentrations of ddC, i.e., 6-11ng/ml, were found to show a significant increase in oxidative stress with 40 nM ddC as measured by protein carbonyls and 3-nitrotyrosine (3NT), effects that were not observed in the more tolerable NRTI; 3TC. Protection against protein oxidation induced by ddC was observed when brain mitochondria were isolated from gerbils 1 h after injection i.p with the brain accessible antioxidant and glutathione mimetic, tricyclodecan-9-yl-xanthogenate (D609). In addition, there is a significant reduction in the levels of anti-apoptotic protein Bcl-2 and a significant increase in cytochrome-c release and also a significant increase in the expression of pro-apoptotic protein caspase-3 after mitochondria were treated with 40 nM ddC. The results reported here show that ddC at 40 nM can induce oxidative stress, cause the release of cytochrome c, and in addition, reduce the levels of anti-apoptotic proteins, increase the levels of pro-apoptotic proteins, thereby increasing the possibility for induction of apoptosis. These findings are consistent with the notion of a possible role of the NRTIs, and in particular, ddC, in the mechanisms involved in HIVD.

Antiretroviral Treatment is Associated with Increased Attentional Load-Dependent Brain Activation in HIV Patients

“…However, other 1 H-MRS studies found either no change or even improvement in NAA or NAA/creatine in patients treated with ARVs (Chang et al 1999Tarasow et al 2004;Vion-Dury et al 1995), although most studies did not distinguish those treated with NRTIs from those on non-NRTIs. A preclinical study also found that ddC, but not 3TC, at CSF-achievable concentrations, induced oxidative stress and increased proteins associated with induction of apoptosis (Opii et al 2006). Therefore, whether NRTIs may contribute to brain injury that could exacerbate HIV dementia or cognitive impairment remains controversial.…”

Oxidative Stress and β-Amyloid Protein in Alzheimer’s Disease

“…D609 mimics glutathione (GSH) and has a free thiol group, which upon oxidation forms a disulfide. The resulting dixanthate is a substrate for glutathione reductase, regenerating D609 (Joshi et al 2005;Opii et al 2007).…”

Antiviral effects of three novel derivatives of adefovir on the replication of hepatitis B virus

“…Evidentially, the levels of HepG2 cell proliferation and viability, and their mitochondrial DNA contents in the compound-treated cells were similar to that of untreated controls. Long-term treatments with antiviral nucleotide analogs are associated with severe mitochondrial toxicity due to the incorporation of nucleotide analogs or the termination of DNA replication (Dusheiko and Antonakopoulos, 2008;Gordon, 1996;Opii et al, 2007;Prince, 1996). The very low cytotoxicity of those novel derivatives of adefovir, together with their high anti-HBV activities, suggests that they may be relatively safe for long-term treatments of HBV infection.…”