Prolonged waking reduces human immunodeficiency virus glycoprotein 120- or tumor necrosis factor alpha-induced apoptosis in the cerebral cortex of rats Corinne J. Montes-Rodrı ´guez a , Silvestre Alavez b,1 , John H. Elder c , Reyes Haro a , Julio Mora ´n b, * , Oscar Prospe ´ro-Garcı ´a a a Grupo de Neurociencias, Departamento de Fisiologı ´a, Facultad de Medicina, Universidad Nacional Auto ´noma de Me ´xico, Me ´xico, D.F., Me ´xico b Departamento de Neurociencias, Instituto de Fisiologı ´a Celular, Universidad Nacional Auto ´noma de Me ´xico, Me ´xico, D.F., Me ´xico c Department of Molecular Biology, The Scripps Research Institute, La Jolla, CA, USA Received 21 October 2003; received in revised form 17 February 2004; accepted 20 February 2004 Abstract The human immunodeficiency virus (HIV) induces neuronal death, presumably by apoptosis. This effect may be triggered by the glycoprotein 120 (HIVgp120) released by HIV when infecting a cell, and mediated by tumor necrosis factor alpha (TNFa), a pro- inflammatory cytokine. Both molecules, HIVgp120 and TNFa, increase sleep when administered acutely in the brain. On the other hand, sleep deprivation increases the levels of several growth factors. In this context, we challenged rats with HIVgp120 or TNFa simultaneously with sleep deprivation. Our results indicate that both HIVgp120 and TNFa increase neuronal death in the rat cerebral cortex, but not hippocampus, and that this effect is completely prevented by total deprivation of sleep. These results suggest that acute total deprivation of sleep protects against the HIVgp120 and TNFa deleterious effects. q 2004 Elsevier Ireland Ltd. All rights reserved. Keywords: Apoptosis; Cytokines; Human immunodeficiency virus; Neuroprotection; Neurotrophic factors; Total deprivation of sleep It has been shown that the human immunodeficiency virus (HIV) invades the brain producing several deleterious effects, including neuronal death. This neuronal death is very likely contributing to the deterioration of cognitive and motor processes that are expressed as neuropsychiatric symptoms in these patients. The HIV mechanism that induces neuronal death remains unclear but it is possible that it occurs as a result of apoptosis [7,8]. The HIV invades microglia but not neurons. As a consequence of this invasion a number of immunological molecules, i.e. cytokines, are released in high amounts that become neurotoxic [7]. Moreover, the glycoprotein 120 (HIVgp120), released by the HIV during the invasive process, seems to amplify this effect by triggering the release of immunological molecules, i.e. tumor necrosis factor alpha (TNFa) [2,6,8]. This statement is based on extensive observations made in several laboratories using in vitro and in vivo models including freely moving animals. In all of these models, HIVgp120 has exhibited a potent neurotoxic action. The reported effects range from neuronal death in cell cultures to behavioral and electrophysiological abnormalities in freely moving rats [18]. The HIVgp120 mechanism of action is not totally clear but most observations involve an increase in Ca 2þ conductance and cytokines release. This observed Ca 2þ influx might be a consequence of NMDA receptor activation, as suggested by experiments showing that NMDA receptor blockers decrease HIVgp120-induced Ca 2þ influx. However, other possible mechanisms responsible for the increase in Ca 2þ conductance could also be involved [8,12]. On the other hand, one of the major effects of HIVgp120 on rat behavior is an increase of delta and rapid-eye-movement sleep after an acute administration [13], as well as a reduction 0304-3940/03/$ - see front matter q 2004 Elsevier Ireland Ltd. All rights reserved. doi:10.1016/j.neulet.2004.02.053 Neuroscience Letters 360 (2004) 133–136 www.elsevier.com/locate/neulet 1 This author contributed to the generation of the data with an effort equal to the first author. * Corresponding author. Departamento de Neurociencias, Lab. BL-302, Instituto de Fisiologı ´a Celular, Universidad Nacional Auto ´noma de Me ´xico, Apdo. Postal 70-253, Me ´xico 04510, D.F., Me ´xico. Tel.: þ 52- 55-5622-5616/5588; fax: þ 52-55-5622-5607. E-mail address: jmoran@ifc.unam.mx (J. Mora ´n).