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J Infect Dis. 2014 Nov 1;210(9):1385-95. doi: 10.1093/infdis/jiu273. Epub 2014 May 9.

Neuronal bioenergetics and acute mitochondrial dysfunction: a clue to understanding the central nervous system side effects of efavirenz.

Author information

1
Departamento de Farmacología, Facultad de Medicina FISABIO-Hospital Universitario Dr. Peset.
2
CIBERehd, Valencia Facultad de Ciencias de la Salud, Universidad Jaime I, Castellón de la Plana, Spain.
3
Departamento de Farmacología, Facultad de Medicina Fundación General, Universidad de Valencia CIBERehd, Valencia.
4
Departamento de Farmacología, Facultad de Medicina CIBERehd, Valencia.
5
Departamento de Farmacología, Facultad de Medicina FISABIO-Hospital Universitario Dr. Peset CIBERehd, Valencia.

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.

KEYWORDS:

HIV; HIV-associated neurocognitive disorders; central nervous system; efavirenz; mitochondria; neurotoxicity; nitric oxide

PMID:
24813473
DOI:
10.1093/infdis/jiu273
[Indexed for MEDLINE]

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