Kynurenine pathway inhibition reduces neurotoxicity of HIV-1-infected macrophages

被引:73
作者
Kerr, SJ [1 ]
Armati, PJ
Pemberton, LA
Smythe, G
Tattam, B
Brew, BJ
机构
[1] St Vincents Hosp, Ctr Immunol, Darlinghurst, NSW 2010, Australia
[2] St Vincents Hosp, Dept Neurol, Darlinghurst, NSW 2010, Australia
[3] St Vincents Hosp, Dept HIV Med, Darlinghurst, NSW 2010, Australia
[4] Univ Sydney, Sch Biol Sci, Sydney, NSW 2006, Australia
[5] Univ Sydney, Dept Pharm, Mass Spectrometry Analyt Facil, Sydney, NSW 2006, Australia
[6] Univ New S Wales, Biomed Mass Spectrometry Unit, Kensington, NSW 2033, Australia
关键词
D O I
10.1212/WNL.49.6.1671
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
The AIDS dementia complex (ADC) is a consequence of excessive immune activation driven at least in part by systemic HIV infection and probably brain infection. Quinolinic acid (QUIN) is a neurotoxic tryptophan metabolite produced by macrophages in response to stimulation with cytokines or infection with HIV-1. Consequently it has been implicated in ADC pathogenesis. However, macrophages infected with HIV-1 synthesize numerous neurotoxic substances. Therefore we conducted experiments using human fetal brain tissue to determine the relative importance of QUIN as a neurotoxin in ADC. Human macrophages were infected with HIV-1 in vitro using a viral isolate from a demented patient. 6-Chloro-n-tryptophan, an inhibitor of QUIN biosynthesis, was added to half the macrophage cultures to block formation of QUIN. Supernatants containing QUIN (SQ(pos)) or in which QUIN biosynthesis had been inhibited (SQ(neg)) were then added to human fetal brain aggregate cultures. Toxicity was evaluated using lactate dehydrogenase efflux, trypan blue exclusion, immunohistochemistry, image analysis, and electron microscopy. Each technique showed a reduction of toxicity in SQ(neg)-treated cultures. These studies confirm the significance of QUIN as a neurotoxin in ADC and suggest that neuroprotective strategies may have a place in the treatment of this disease.
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页码:1671 / 1681
页数:11
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