Glucocorticoids Exacerbate the Deleterious Effects of gp120 in Hippocampal and Cortical Explants

Abstract

Glucocorticoids (GCs), the adrenal steroids secreted during stress, can compromise the ability of hippocampal neurons to survive numerous necrotic insults. We have previously observed that GCs worsen the deleterious effects of gp120, the glycoprotein of the acquired immune deficiency syndrome virus, which can indirectly damage neurons and which is thought to play a role in the neuropathological features of human immunodeficiency virus infection. Specifically, GCs augment gp120-induced calcium mobilization, ATP depletion, decline in mitochondrial potential, and neurotoxicity in fetal monolayer cultures from a number of brain regions. In the present report, we demonstrate a similar gp120/GC synergy in adult hippocampal and cortical explants. We generated explants from rats that were either adrenalectomized, adrenally intact, or intact and treated with corticosterone to produce levels seen in response to major stressors. Metabolic rates in explants were then indirectly assessed with silicon microphysiometry, and cytosolic calcium concentrations were assessed with fura-2 fluorescent microscopy. We observed that basal levels of GCs tonically augment the disruptive effects of gp120 on metabolism in the CA1 cell field of the hippocampus and in the cortex. Moreover, raising GC concentrations into the stress range exacerbated the ability of gp120 to mobilize cytosolic calcium in a number of hippocampal cell fields. Finally, we observed that the synthetic GC prednisone had similarly exacerbating effects on gp120. Thus, GCs can worsen the deleterious effects of gp120 in a system that is more physiologically relevant than the fetal monolayer culture and in a region-specific manner.

Prefrontal cortical volume loss is associated with stress-related deficits in verbal learning and memory in HIV-infected women

“…Early life trauma is associated with HIV and with enduring functional and structural abnormalities in prefrontal cortex as well as memory deficits, due in part to lasting alterations in the hypothalamic-pituitary-adrenal (HPA) axis (Lupien et al, 2007; Lupien et al, 2009); HIV infection may compound these brain vulnerabilities leading to memory dysfunction. Stress may exacerbate the effects of HIV on brain structure; basic science studies show that glucocorticoids exacerbate the negative effects of gp120 protein on function and structure of hippocampal and cortical tissue (Yusim et al , 2000). HIV infection may also serve to deplete cognitive reserve mechanisms (Stern, 2002).…”

Expression of gp120 in mice evokes anxiety behavior: Co-occurrence with increased dendritic spines and brain-derived neurotrophic factor in the amygdala

“…Gp120tg mice exhibit impaired HPA axis and an increase in glucocorticoid levels (Raber et al, 1996). Thus, glucocorticoids, which have been shown to exacerbate the toxic effect of gp120 in the hippocampus (Yusim et al, 2000), could be responsible for the atrophy of neurons in this brain region. Chronic glucocorticoid elevation induces dendritic atrophy in hippocampus (Wood et al, 2004), which in turn reduces negative feedback of ACTH and glucocorticoid secretion prolonging the stress response.…”

Mechanisms of HIV-1 Tat Neurotoxicity via CDK5 Translocation and Hyper-Activation: Role in HIV-Associated Neurocognitive Disorders

“…Mitochondrial alterations and dysfunction are hallmarks of several neurodegenerative disorders, possibly, in part, as a consequence of Tau hyperphosphorylation. HIV proteins Gp120, vpr and Tat have been shown to cause mitochondrial membrane permeablization [MMP] and cell death [140, 141]. Tat, specifically, is linked to alterations in expression of apoptosis-regulating proteins, Bcl-2 and Bax [142], and down regulation of super oxide dismutase [143].…”