Cocaine potentiates astrocyte toxicity mediated by human immunodeficiency virus (HIV-1) protein gp120.
It is becoming widely accepted that psychoactive drugs, often abused by HIV-I infected individuals, can significantly alter the progression of neuropathological changes observed in HIV-associated neurodegenerative diseases (HAND). The underlying mechanisms mediating these effects however, remain poorly understood. In the current study, we explored whether the psychostimulant drug cocaine could exacerbate toxicity mediated by gp120 in rat primary astrocytes. Exposure to both cocaine and gp120 resulted in increased cell toxicity compared to cells treated with either factor alone. The combinatorial toxicity of cocaine and gp120 was accompanied by an increase in caspase-3 activation. In addition, increased apoptosis of astrocytes in the presence of both the agents was associated with a concomitant increase in the production of intracellular reactive oxygen species and loss of mitochondrial membrane potential. Signaling pathways including c-jun N-teminal kinase (JNK), p38, extracellular signal-regulated kinase (ERK)/mitogen-activated protein kinases (MAPK), and nuclear factor (NF-κB) were identified to be major players in cocaine and gp120-mediated apoptosis of astrocytes. Our results demonstrated that cocaine-mediated potentiation of gp120 toxicity involved regulation of oxidative stress, mitochondrial membrane potential and MAPK signaling pathways.
Department of Pharmacology and Experimental Neuroscience, University of Nebraska Medical Center, Omaha, Nebraska, United States of America.
Yanjing
Y
Yang
Honghong
H
Yao
Yaman
Y
Lu
Chao
C
Wang
Shilpa
S
Buch
D000818:Animals; D001253:Astrocytes / Q000187:drug effects* / Q000378:metabolism; D015153:Blotting, Western; D002478:Cells, Cultured; D003042:Cocaine / Q000633:toxicity*; D015699:HIV Envelope Protein gp120 / Q000502:physiology*; D007150:Immunohistochemistry; D051381:Rats; D017207:Rats, Sprague-Dawley; D017382:Reactive Oxygen Species / Q000378:metabolism
D015699:HIV Envelope Protein gp120; D017382:Reactive Oxygen Species; D003042:Cocaine