HIV Non-Nucleoside Reverse Transcriptase Inhibitor Efavirenz Reduces Neural Stem Cell Proliferation in Vitro and in Vivo

• Published in: Cell transplantation Vol. 25; no. 11; pp. 1967 - 1977
• Main Authors: Jin, Jingji, Grimmig, Bethany, Izzo, James, Brown, Lecia A. M., Hudson, Charles, Smith, Adam J., Tan, Jun, Bickford, Paula C., Giunta, Brian
• Format: Journal Article
• Language: English
• Published: Los Angeles, CA SAGE Publications 01.11.2016; Sage Publications Ltd; SAGE Publishing
• Subjects: Adenosine Triphosphate - metabolism; Animals; Antiretroviral drugs; Antiretroviral therapy; Apoptosis; Apoptosis - drug effects; ATP; Bax protein; bcl-2-Associated X Protein - metabolism; Benzoxazines - administration & dosage; Benzoxazines - toxicity; Brain injury; Caspase 3 - metabolism; Caspase-3; Cell migration; Cell proliferation; Cell Proliferation - drug effects; Cells, Cultured; Cognition; Cognitive ability; Efavirenz; Female; Immunocytochemistry; Immunohistochemistry; Injections, Intraperitoneal; Kinases; L-Lactate dehydrogenase; Lactic acid; Lateral Ventricles - drug effects; Lateral Ventricles - metabolism; MAP kinase; Membrane potential; Membrane Potential, Mitochondrial - drug effects; Mice; Mice, Inbred C57BL; Mitochondria; Nestin; Neural stem cells; Neural Stem Cells - cytology; Neural Stem Cells - drug effects; Neural Stem Cells - metabolism; Non-nucleoside reverse transcriptase inhibitors; Oxidative stress; p38 Mitogen-Activated Protein Kinases - metabolism; Phosphorylation - drug effects; Protein kinase; Rats; Reverse Transcriptase Inhibitors - administration & dosage; Reverse Transcriptase Inhibitors - toxicity; RNA-directed DNA polymerase; Oxidative stress; Neural stem cells (NSCs); Efavirenz (EFV)
• ISSN: 0963-6897; 1555-3892
• DOI: 10.3727/096368916X691457

The prevalence of HIV-associated neurocognitive disorders (HAND) remains high despite combination antiretroviral therapy (cART). There is evidence that neural stem cells (NSCs) can migrate to sites of brain injury such as those caused by inflammation and oxidative stress, which are pathological features of HAND. Thus, reductions in NSCs may contribute to HAND pathogenesis. Since the HIV non-nucleoside reverse transcriptase inhibitor efavirenz (EFV) has previously been associated with cognitive deficits and promotion of oxidative stress pathways, we examined its effect on NSCs in vitro as well as in C57BL/6J mice. Here we report that EFV induced a decrease in NSC proliferation in vitro as indicated by MTT assay, as well as BrdU and nestin immunocytochemistry. In addition, EFV decreased intracellular NSC adenosine triphosphate (ATP) stores and NSC mitochondrial membrane potential (MMP). Further, we found that EFV promoted increased lactate dehydrogenase (LDH) release, activation of p38 mitogen-activated protein kinase (MAPK), and increased Bax expression in cultured NSCs. Moreover, EFV reduced the quantity of proliferating NSCs in the subventricular zone (SVZ) of C57BL/6J mice as suggested by BrdU, and increased apoptosis as measured by active caspase-3 immunohistochemistry. If these in vitro and in vivo models translate to the clinical syndrome, then a pharmacological or cell-based therapy aimed at opposing EFV-mediated reductions in NSC proliferation may be beneficial to prevent or treat HAND in patients receiving EFV.