Brain-derived neurotrophic factor is neuroprotective against human immunodeficiency virus-1 envelope proteins.
Human immunodeficiency virus type 1 (HIV-1)-positive patients in the late phase of infection develop AIDS dementia complex, an array of neurological complications that include extrapyramidal symptoms, cognitive impairments, and psychiatric disturbances. Brains of these patients exhibit brain injury. The HIV-1 envelope glycoprotein 120 (gp120) has been suggested to be a causal agent of neuronal loss; however, several strains of gp120 exist during the infection and the relative neurotoxic potential of each strain is presently unknown. Using cultured cerebellar granule neurons, we determined whether two strains of gp120, gp120IIIB and gp120BaL, which bind to CXCR4 and CCR5 chemokine receptors, respectively, induce cell death. Apoptotic cell death and activated caspase-3 were evident within a few hours in neurons exposed to low nanomolar concentrations of either gp120IIIB or gp120BaL. However, the neurotoxic effect of gp120IIIB was more rapid and occurred at lower concentrations than that of gp120BaL, suggesting that cerebellar granule cells may be more sensitive to apoptotic signals activated by the CXCR4 receptor. The neurotrophin brain-derived neurotrophic factor (BDNF) has been shown to block neuronal apoptosis. Therefore, we examined whether BDNF protects against both strains of gp120. Preexposure of cerebellar granule cells to BDNF prior to both gp120s decreased apoptosis and consequently enhanced their survival. These findings underlie the rationale for exploring the ability of BDNF to reduce HIV-1-mediated neuronal cell death in vivo.
Bachis
Alessia
A
Department of Neuroscience, Georgetown University Medical Center, Research Building, Room EP04, Box 571464, Washington, District of Columbia 20057, USA.
Mocchetti
Italo
I
D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D019208:Brain-Derived Neurotrophic Factor / Q000494:pharmacology*; D016923:Cell Death / Q000187:drug effects; D002531:Cerebellum / Q000166:cytology / Q000187:drug effects; D015699:HIV Envelope Protein gp120 / Q000378:metabolism / Q000633:toxicity*; D006801:Humans; D020287:In Situ Nick-End Labeling; D009474:Neurons / Q000187:drug effects; D018696:Neuroprotective Agents; D009498:Neurotoxins / Q000037:antagonists & inhibitors / Q000633:toxicity; D051381:Rats; D019707:Receptors, Chemokine / Q000037:antagonists & inhibitors; D013778:Tetrazolium Salts; D013844:Thiazoles
D019208:Brain-Derived Neurotrophic Factor; D015699:HIV Envelope Protein gp120; D018696:Neuroprotective Agents; D009498:Neurotoxins; D019707:Receptors, Chemokine; D013778:Tetrazolium Salts; D013844:Thiazoles; C022616:thiazolyl blue