Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques

Melvyn P. Heyes, Kuniaki Saito, Andrew Lackner, Clayton A. Wiley, Cristian L. Achim, Sanford P. Markey

研究成果: Article

126 引用 (Scopus)

抄録

This study investigated the sources of quinolinic acid, a neurotoxic tryptophan-kynurenine pathway metabolite, in the brain and blood of HIV- infected patients and retrovirus-infected macaques. In brain, quinolinic acid concentrations in HIV-infected patients were elevated by > 300-fold to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma. Because nonretrovirus-induced encephalitis confounds the interpretation of human postmortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations and determine the relationships of quinolinic acid to encephalitits and systemic responses. The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses. CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus- induced encephalitis. In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis vs. those without. Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almost all quinolinic acid (>98%) was synthesized locally within the brain. These results demonstrate a role for induction of indoleamine-2,3-dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood. Strategies to reduce QUIN production, targeted at intracerebral sites, are potential approaches to therapy.

元の言語English
ページ(範囲)881-896
ページ数16
ジャーナルFASEB Journal
12
発行部数10
出版物ステータスPublished - 08-07-1998
外部発表Yes

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Quinolinic Acid
Neurotoxins
Macaca
Retroviridae
HIV-1
Brain
Encephalitis
Cerebrospinal fluid
Kynurenine
Cerebrospinal Fluid
Blood
HIV
Indoleamine-Pyrrole 2,3,-Dioxygenase
Meninges
Metabolites
Macaca mulatta
Tryptophan
Tissue

All Science Journal Classification (ASJC) codes

  • Biotechnology
  • Biochemistry
  • Molecular Biology
  • Genetics

これを引用

Heyes, M. P., Saito, K., Lackner, A., Wiley, C. A., Achim, C. L., & Markey, S. P. (1998). Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. FASEB Journal, 12(10), 881-896.
Heyes, Melvyn P. ; Saito, Kuniaki ; Lackner, Andrew ; Wiley, Clayton A. ; Achim, Cristian L. ; Markey, Sanford P. / Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. :: FASEB Journal. 1998 ; 巻 12, 番号 10. pp. 881-896.
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abstract = "This study investigated the sources of quinolinic acid, a neurotoxic tryptophan-kynurenine pathway metabolite, in the brain and blood of HIV- infected patients and retrovirus-infected macaques. In brain, quinolinic acid concentrations in HIV-infected patients were elevated by > 300-fold to concentrations that exceeded cerebrospinal fluid (CSF) by 8.9-fold. There were no significant correlations between elevated serum quinolinic acid levels with those in CSF and brain parenchyma. Because nonretrovirus-induced encephalitis confounds the interpretation of human postmortem data, rhesus macaques infected with retrovirus were used to examine the mechanisms of increased quinolinic acid accumulations and determine the relationships of quinolinic acid to encephalitits and systemic responses. The largest kynurenine pathway responses in brain were associated with encephalitis and were independent of systemic responses. CSF quinolinic acid levels were also elevated in all infected macaques, but particularly those with retrovirus- induced encephalitis. In contrast to the brain changes, there was no difference in any systemic measure between macaques with encephalitis vs. those without. Direct measures of the amount of quinolinic acid in brain derived from blood in a macaque with encephalitis showed that almost all quinolinic acid (>98{\%}) was synthesized locally within the brain. These results demonstrate a role for induction of indoleamine-2,3-dioxygenase in accelerating the local formation of quinolinic acid within the brain tissue, particularly in areas of encephalitis, rather than entry of quinolinic acid into the brain from the meninges or blood. Strategies to reduce QUIN production, targeted at intracerebral sites, are potential approaches to therapy.",
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Heyes, MP, Saito, K, Lackner, A, Wiley, CA, Achim, CL & Markey, SP 1998, 'Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques', FASEB Journal, 巻. 12, 番号 10, pp. 881-896.

Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. / Heyes, Melvyn P.; Saito, Kuniaki; Lackner, Andrew; Wiley, Clayton A.; Achim, Cristian L.; Markey, Sanford P.

:: FASEB Journal, 巻 12, 番号 10, 08.07.1998, p. 881-896.

研究成果: Article

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