title: Neuronal bioenergetics and acute mitochondrial dysfunction: a clue to understanding the central nervous system side effects of efavirenz.
abstract: BACKGROUND
  Neurological pathogenesis is associated with mitochondrial dysfunction and differences in neuronal/glial handling of oxygen and glucose. The main side effects attributed to efavirenz involve the CNS, but the underlying mechanisms are unclear.
  
  
  METHODS
  Human cell lines and rat primary cultures of neurons and astrocytes were treated with clinically relevant efavirenz concentration.
  
  
  RESULTS
  Efavirenz alters mitochondrial respiration, enhances reactive oxygen species generation, undermines mitochondrial membrane potential, and reduces adenosine triphosphate (ATP) levels in a concentration-dependent fashion in both neurons and glial cells. However, it activates adenosine monophosphate-activated protein kinase only in glial cells, upregulating glycolysis and increasing intracellular ATP levels, which do not occur in neurons. To reproduce the conditions that often exist in human immunodeficiency virus-related neuroinflammatory disorders, the effects of efavirenz were evaluated in the presence of exogenous nitric oxide, an inflammatory mediator and mitochondrial inhibitor. The combination potentiated the effects on mitochondrial parameters in both neurons and glial cells, but ATP generation and lactate production were enhanced only in glial cells.
  
  
  CONCLUSIONS
  Efavirenz affects the bioenergetics of neurons through a mechanism involving acute mitochondrial inhibition, an action exacerbated in neuroinflammatory conditions. A similar scenario of glial cells survival and degeneration of neurons with signs of mitochondrial dysfunction and oxidative stress has been associated with neurocognitive disorders.
authors.affiliation: Departamento de Farmacología, Facultad de Medicina FISABIO-Hospital Universitario Dr. Peset.
authors.forename: Haryes A
authors.initials: HA
authors.lastname: Funes
authors.affiliation: CIBERehd, Valencia Facultad de Ciencias de la Salud, Universidad Jaime I, Castellón de la Plana, Spain.
authors.forename: Nadezda
authors.initials: N
authors.lastname: Apostolova
authors.affiliation: Departamento de Farmacología, Facultad de Medicina FISABIO-Hospital Universitario Dr. Peset.
authors.forename: Fernando
authors.initials: F
authors.lastname: Alegre
authors.affiliation: Departamento de Farmacología, Facultad de Medicina FISABIO-Hospital Universitario Dr. Peset.
authors.forename: Ana
authors.initials: A
authors.lastname: Blas-Garcia
authors.affiliation: Departamento de Farmacología, Facultad de Medicina Fundación General, Universidad de Valencia CIBERehd, Valencia.
authors.forename: Angeles
authors.initials: A
authors.lastname: Alvarez
authors.affiliation: Departamento de Farmacología, Facultad de Medicina CIBERehd, Valencia.
authors.forename: Miguel
authors.initials: M
authors.lastname: Marti-Cabrera
authors.affiliation: Departamento de Farmacología, Facultad de Medicina FISABIO-Hospital Universitario Dr. Peset CIBERehd, Valencia.
authors.forename: Juan V
authors.initials: JV
authors.lastname: Esplugues
mesh_terms: D000480:Alkynes; D000818:Animals; D001253:Astrocytes / Q000187:drug effects; D048588:Benzoxazines / Q000009:adverse effects* / Q000494:pharmacology; D045744:Cell Line, Tumor; D019069:Cell Respiration / Q000187:drug effects; D002470:Cell Survival / Q000187:drug effects; D003521:Cyclopropanes; D004305:Dose-Response Relationship, Drug; D004734:Energy Metabolism / Q000187:drug effects*; D006801:Humans; D053078:Membrane Potential, Mitochondrial / Q000187:drug effects; D008928:Mitochondria / Q000187:drug effects*; D009457:Neuroglia / Q000187:drug effects; D009474:Neurons / Q000187:drug effects*; D010101:Oxygen Consumption / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D018894:Reverse Transcriptase Inhibitors / Q000009:adverse effects* / Q000494:pharmacology; D013481:Superoxides / Q000378:metabolism
chemical_list: D000480:Alkynes; D048588:Benzoxazines; D003521:Cyclopropanes; D018894:Reverse Transcriptase Inhibitors; D013481:Superoxides; C098320:efavirenz
keywords: HIV; HIV-associated neurocognitive disorders; central nervous system; efavirenz; mitochondria; neurotoxicity; nitric oxide