Effects of Antiretroviral Drugs on the Glutathione and Glucose Metabolism of Cultured Brain Cells

Abstract

The highly active antiretroviral therapy (HAART) has been successfully used for 30 years to treat the aquired immuno deficiency syndrome (AIDS) and the human immuno deficiency virus (HIV)-associated dementia. However, as minor neurocognitive deficits persist in treated HIV patients potential adverse consequences of antiretroviral drugs on brain cells are currently intensively discussed, but lack sufficient experimental proof. To address such questions, this thesis investigated the acute effects of various antiretroviral drugs from the classes of reverse transcriptase (RT) inhibitors and protease inhibitors on viability, glutathione (GSH) metabolism and glycolytic flux of brain cells, using primary cultures of astrocytes and neurons as model systems. A treatment with protease and RT inhibitors did not acutely damage cultured brain cells. However, the incubation of viable cultured astrocytes or neurons with protease inhibitors, but not with RT inhibitors, strongly stimulated cellular GSH release. The protease inhibitor-induced acceleration of GSH export was completely blocked by an inhibitor of the multidrug resistance protein 1 (Mrp1), suggesting that this exporter mediates the protease inhibitor-induced GSH depletion of brain cells. Protease inhibitors or RT inhibitors did not modulate the glycolytic flux of cultured astrocytes. In contrast, 8-hydroxy efavirenz (8-OH-efv), the primary metabolite of the frequently used RT inhibitor efavirenz, accelerated the glycolysis-derived lactate release from viable cultured astrocytes. However, in contrast to respiratory chain inhibitors, a direct inhibition of mitochondrial respiration by 8-OH-efv appears not to be the mechanism underlying the 8-OH-efv-mediated stimulation of glycolytic flux in astrocytes. As the lifelong treatment of HIV patients with antiretroviral drugs establishes a chronic exposure of brain cells to such compounds or their metabolites, alterations in basic metabolism of brain cells, such as those reported in this thesis, should be considered to contribute to the reported mild neurocognitive impairments of treated HIV patients.