Dimethyl Fumarate, an Approved Multiple Sclerosis Treatment, Reduces Brain Oxidative Stress in SIV-Infected Rhesus Macaques: Potential Therapeutic Repurposing for HIV Neuroprotection

Abstract

Dimethyl fumarate (DMF), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, induces antioxidant enzymes, in part through transcriptional upregulation. We hypothesized that DMF administration to simian immunodeficiency virus (SIV)-infected rhesus macaques would induce antioxidant enzyme expression and reduce oxidative injury and inflammation throughout the brain. Nine SIV-infected, CD8+-T-lymphocyte-depleted rhesus macaques were studied. Five received oral DMF prior to the SIV infection and through to the necropsy day. Protein expression was analyzed in 11 brain regions, as well as the thymus, liver, and spleen, using Western blot and immunohistochemistry for antioxidant, inflammatory, and neuronal proteins. Additionally, oxidative stress was determined in brain sections using immunohistochemistry (8-OHdG, 3NT) and optical redox imaging of oxidized flavoproteins containing flavin adenine dinucleotide (Fp) and reduced nicotinamide adenine dinucleotide (NADH). The DMF treatment was associated with no changes in virus replication; higher expressions of the antioxidant enzymes NQO1, GPX1, and HO-1 in the brain and PRDX1 and HO-2 in the spleen; lower levels of 8-OHdG and 3NT; a lower optical redox ratio. The DMF treatment was also associated with increased expressions of cell-adhesion molecules (VCAM-1, ICAM-1) and no changes in HLA-DR, CD68, GFAP, NFL, or synaptic proteins. The concordantly increased brain antioxidant enzyme expressions and reduced oxidative stress in DMF-treated SIV-infected macaques suggest that DMF could limit oxidative stress throughout the brain through effective induction of the endogenous antioxidant response. We propose that DMF could potentially induce neuroprotective brain responses in persons living with HIV.

Discovery of Therapeutics Targeting Oxidative Stress in Autosomal Recessive Cerebellar Ataxia: A Systematic Review

“…Dimethyl fumarate (DMF) is a methyl ester synthesized through the esterification of fumaric acid. Recently, DMF has been shown to exert neuroprotective and immunomodulatory effects associated with endogenous antioxidant mechanisms and mitigation of oxidative stress in in vivo models [147,148].…”

The Role of Tricarboxylic Acid Cycle Metabolites in Viral Infections

“…DMF has been approved for the treatment of multiple sclerosis and might also protect against systemic and central nervous system complications in HIV infection ( Gill and Kolson, 2013 ). In a study on rhesus macaques infected with simian immunodeficiency virus, treatment with DMF limited the oxidative stress throughout the brain ( Garcia-Mesa et al, 2021 ). Olagnier et al demonstrated that DMF inhibits SARS-CoV-2 replication and the expression of associated inflammatory genes, thus proposing that DMF could be repurposed as a small molecule inhibitor of SARS-CoV-2 replication and inflammation-associated pathology in COVID-19 patients ( Olagnier et al, 2020 ; Timpani and Rybalka, 2021 ) ( Figure 2 ).…”

Advances in SIV/SHIV Non-Human Primate Models of NeuroAIDS

“…Thus, protective therapies that aim at suppressing these pathologic pathways would be desirable. In a recent study the ability of dimethyl fumarate (DMF), an antioxidant/anti-inflammatory drug approved for the treatment of multiple sclerosis, has been examined in a rhesus macaque SIV infection model [ 113 , 114 ]. In various animal models, activation of nuclear factor erythroid 2–related factor 2 (Nrf2)/ARE pathway by DMF in the brain is associated with reduced neurodegeneration, and may promote axonal regeneration and block neurotoxicity [ 115 , 116 ].…”

“…In various animal models, activation of nuclear factor erythroid 2–related factor 2 (Nrf2)/ARE pathway by DMF in the brain is associated with reduced neurodegeneration, and may promote axonal regeneration and block neurotoxicity [ 115 , 116 ]. In a CD8+ T lymphocyte depletion model of SIV neuro-pathogenesis, rhesus macaques received oral DMF prior to SIV infection and through to the necropsy day [ 114 ]. Global brain responses to DMF treatment, such as higher brain expression of antioxidant enzymes, lower DNA and protein oxidation, and a more reduced redox state is observed in SIV-infected treated animals as compared to the untreated.…”

“…Global brain responses to DMF treatment, such as higher brain expression of antioxidant enzymes, lower DNA and protein oxidation, and a more reduced redox state is observed in SIV-infected treated animals as compared to the untreated. This suggests a direct link between enzyme induction and reduced oxidative stress and injury, thus evidencing DMF as a robust antioxidant for the brain [ 114 ]. These observations indicate the importance of the macaque SIV infection model, and the potential neuroprotective therapeutic benefit of DMF treatment in persons living with HIV.…”