Intrastriatal administration of human immunodeficiency virus-1 glycoprotein 120 reduces glial cell-line derived neurotrophic factor levels and causes apoptosis in the substantia nigra.
Uninfected neurons of the substantia nigra (SN) degenerate in human immunodeficiency virus (HIV)-positive patients through an unknown etiology. The HIV envelope glycoprotein 120 (gp120) causes apoptotic neuronal cell death in the rodent striatum, but its primary neurotoxic mechanism is still under investigation. Previous studies have shown that gp120 causes neurotoxicity in the rat striatum by reducing brain-derived neurotrophic factor (BDNF). Because glial cell line-derived neurotrophic factor (GDNF) and BDNF are neurotrophic factors crucial for the survival of dopaminergic neurons of the SN, we investigated whether gp120 reduces GDNF and BDNF levels concomitantly to induce apoptosis. Rats received a microinjection of gp120 or vehicle into the striatum and were sacrificed at various time intervals. GDNF but not BDNF immunoreactivity was decreased in the SN by 4 days in gp120-treated rats. In these animals, a significant increase in the number of caspase-3- positive neurons, both tyrosine hydroxylase (TH)-positive and -negative, was observed. Analysis of TH immunoreactivity revealed fewer TH-positive neurons and fibers in a medial and lateral portion of cell group A9 of the SN, an area that projects to the striatum, suggesting that gp120 induces retrograde degeneration of nigrostriatal neurons. We propose that dysfunction of the nigrostriatal dopaminergic system associated with HIV may be caused by a reduction of neurotrophic factor expression by gp120.
Nosheny
Rachel L
RL
Department of Neuroscience, Georgetown University Medical Center, Washington DC 20057, USA.
Bachis
Alessia
A
Aden
Sadia A
SA
De Bernardi
Maria A
MA
Mocchetti
Italo
I
D015526:AIDS Dementia Complex / Q000378:metabolism / Q000503:physiopathology; D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D001370:Axonal Transport / Q000502:physiology; D001480:Basal Ganglia Diseases / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D019208:Brain-Derived Neurotrophic Factor / Q000378:metabolism*; D053148:Caspase 3 / Q000378:metabolism; D003342:Corpus Striatum / Q000378:metabolism / Q000503:physiopathology / Q000821:virology; D004195:Disease Models, Animal; D004298:Dopamine / Q000378:metabolism; D015536:Down-Regulation / Q000502:physiology; D051100:Glial Cell Line-Derived Neurotrophic Factor / Q000378:metabolism; D015699:HIV Envelope Protein gp120 / Q000378:metabolism* / Q000633:toxicity; D015497:HIV-1; D008297:Male; D009410:Nerve Degeneration / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013378:Substantia Nigra / Q000378:metabolism / Q000503:physiopathology* / Q000821:virology; D014446:Tyrosine 3-Monooxygenase / Q000378:metabolism
D019208:Brain-Derived Neurotrophic Factor; D051100:Glial Cell Line-Derived Neurotrophic Factor; D015699:HIV Envelope Protein gp120; D014446:Tyrosine 3-Monooxygenase; D053148:Caspase 3; D004298:Dopamine