Naela Alboloushi
| Naela Alboloushi |
Naela Alboloushi1, Cagla Akay-Espinoza2, Kelly Jordan-Sciutto2
1Endodontics, University of Pennsylvania, School of Dental Medicine; 2Oral Medicine, University of Pennsylvania, School of Dental Medicine
Introduction
The incidence of human immunodeficiency virus (HIV)-associated dementia has been decreasing with the advent of antiretroviral therapy (ART) due to efficient systemic viral control; however, the prevalence remains high, partially due to increase life expectancy. Interestingly, about 50% of the HIV-infected patients have minor cognitive impairment, which led us to hypothesize that antiretroviral drugs (ARVs) induce oxidative stress leading to neuronal dysfunction and damage, contributing to the changing clinical picture seen in HIV-positive individuals.
Methods
We treated primary rat cortical neurons with the commonly prescribed integrase inhibitor dolutegravir (DTG) in therapeutically relevant doses and assessed whether oxidative stress led to neuronal death.
Results
We found that DTG led to neuronal death after 24 hours of treatment, as determined by MAP2 loss and propidium iodide exclusion assay. Our studies also suggest oxidative stress as a potential mechanism, as detected by increased expression levels of HO-1and NQ01. Our data also suggest that pretreatment with CDDO-Im, an NRF2 pathway activator, might inhibit DTG-mediated neuronal death.
Conclusion
DTG induces toxicity in primary rat neurons as determined by the loss of MAP2 after 24 hours of treatment with clinically relevant dosage.Furthermore, neurotoxicity of dolutegravir was blocked by pharmacological augmentation of the endogenous antioxidant heme oxygenase-1 (HO-1), expanding our previous finding that dolutegravir-induced neurotoxicity was mediated by oxidative stress.