| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
|
|
|
|||||||
|
|||||||||
RESEARCH COMMUNICATION |
a Laboratory of Neurotoxicology, National Institute of Mental Health, Bethesda, Maryland 20892, USA
b New England Regional Primate Research Center, Harvard Medical School, Southborough, Massachusetts 01772, USA
c Neuropathology Division, Presbyterian-University Hospital, Pittsburgh Pennsylvania 15213, USA
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.—Heyes, M. P., Saito, K., Lackner, A., Wiley, C. A., Achim, C. L., Markey, S. P. Sources of the neurotoxin quinolinic acid in the brain of HIV-1-infected patients and retrovirus-infected macaques. FASEB J. 12, 881–896 (1998)
Key Words: macrophages • astrocytes • indoleamine-2,3-dioxygenase • kynurenine-3-hydroxylase • kynureninase • kynurenine aminotransferase • L-tryptophan • L-kynurenine • kynurenic acid • retrovirus • blood–brain barrier • cytokines • nonhuman primates
This article has been cited by other articles:
|
|
 |
|
  D. Bonneh-Barkay, S. J. Bissel, G. Wang, K. N. Fish, G. C.B. Nicholl, S. W. Darko, R. Medina-Flores, M. Murphey-Corb, P. A. Rajakumar, J. Nyaundi, et al. YKL-40, a Marker of Simian Immunodeficiency Virus Encephalitis, Modulates the Biological Activity of Basic Fibroblast Growth Factor Am. J. Pathol., July 1, 2008; 173(1): 130 - 143. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 G. J. Guillemin, K. M. Cullen, C. K. Lim, G. A. Smythe, B. Garner, V. Kapoor, O. Takikawa, and B. J. Brew Characterization of the Kynurenine Pathway in Human Neurons J. Neurosci., November 21, 2007; 27(47): 12884 - 12892. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 D. G. Walker, J. Link, L.-F. Lue, J. E. Dalsing-Hernandez, and B. E. Boyes Gene expression changes by amyloid {beta} peptide-stimulated human postmortem brain microglia identify activation of multiple inflammatory processes J. Leukoc. Biol., March 1, 2006; 79(3): 596 - 610. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 M. McCrossan, M. Marsden, F. W. Carnie, S. Minnis, B. Hansoti, I. C. Anthony, R. P. Brettle, J. E. Bell, and P. Simmonds An immune control model for viral replication in the CNS during presymptomatic HIV infection Brain, February 1, 2006; 129(2): 503 - 516. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 R. Potula, L. Poluektova, B. Knipe, J. Chrastil, D. Heilman, H. Dou, O. Takikawa, D. H. Munn, H. E. Gendelman, and Y. Persidsky Inhibition of indoleamine 2,3-dioxygenase (IDO) enhances elimination of virus-infected macrophages in an animal model of HIV-1 encephalitis Blood, October 1, 2005; 106(7): 2382 - 2390. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Yu, N. A. Di Prospero, M. T. Sapko, T. Cai, A. Chen, M. Melendez-Ferro, F. Du, W. O. Whetsell Jr., P. Guidetti, R. Schwarcz, et al. Biochemical and Phenotypic Abnormalities in Kynurenine Aminotransferase II-Deficient Mice Mol. Cell. Biol., August 15, 2004; 24(16): 6919 - 6930. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. Valle, R. W. Price, A. Nilsson, M. Heyes, and D. Verotta CSF quinolinic acid levels are determined by local HIV infection: cross-sectional analysis and modelling of dynamics following antiretroviral therapy Brain, May 1, 2004; 127(5): 1047 - 1060. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 E. M. E. Burudi, M. C. G. Marcondes, D. D. Watry, M. Zandonatti, M. A. Taffe, and H. S. Fox Regulation of Indoleamine 2,3-Dioxygenase Expression in Simian Immunodeficiency Virus-Infected Monkey Brains J. Virol., October 25, 2002; 76(23): 12233 - 12241. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 P. Terness, T. M. Bauer, L. Rose, C. Dufter, A. Watzlik, H. Simon, and G. Opelz Inhibition of Allogeneic T Cell Proliferation by Indoleamine 2,3-Dioxygenase-expressing Dendritic Cells: Mediation of Suppression by Tryptophan Metabolites J. Exp. Med., August 19, 2002; 196(4): 447 - 457. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 A. Tanabe, Y. Egashira, S.-I. Fukuoka, K. Shibata, and H. Sanada Expression of Rat Hepatic 2-Amino-3-Carboxymuconate-6-Semialdehyde Decarboxylase Is Affected by a High Protein Diet and by Streptozotocin-Induced Diabetes J. Nutr., June 1, 2002; 132(6): 1153 - 1159. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Jordan-Sciutto, G. Wang, M. Murphey-Corb, and C. A. Wiley Cell Cycle Proteins Exhibit Altered Expression Patterns in Lentiviral-Associated Encephalitis J. Neurosci., March 15, 2002; 22(6): 2185 - 2195. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
S. J. Bissel, G. Wang, M. Ghosh, T. A. Reinhart, S. Capuano III, K. Stefano Cole, M. Murphey-Corb, M. Piatak Jr., J. D. Lifson, and C. A. Wiley Macrophages Relate Presynaptic and Postsynaptic Damage in Simian Immunodeficiency Virus Encephalitis Am. J. Pathol., March 1, 2002; 160(3): 927 - 941. [Abstract] [Full Text] [PDF]
|
|
|
|
 |
|
 S. R. Thomas, H. Salahifar, R. Mashima, N. H. Hunt, D. R. Richardson, and R. Stocker Antioxidants Inhibit Indoleamine 2,3-Dioxygenase in IFN-{{gamma}}-Activated Human Macrophages: Posttranslational Regulation by Pyrrolidine Dithiocarbamate J. Immunol., May 15, 2001; 166(10): 6332 - 6340. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
M. P. Heyes, R. J. Ellis, L. Ryan, M. E. Childers, I. Grant, T. Wolfson, S. Archibald, and T. L. Jernigan Elevated cerebrospinal fluid quinolinic acid levels are associated with region-specific cerebral volume loss in HIV infection Brain, May 1, 2001; 124(5): 1033 - 1042. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
K. L. Jordan-Sciutto, G. Wang, M. Murphy-Corb, and C. A. Wiley Induction of Cell-Cycle Regulators in Simian Immunodeficiency Virus Encephalitis Am. J. Pathol., August 1, 2000; 157(2): 497 - 507. [Abstract] [Full Text] [PDF]
|
|
|
|
|
|
R. S. Grant, H. Naif, S. J. Thuruthyil, N. Nasr, T. Littlejohn, O. Takikawa, and V. Kapoor Induction of Indolamine 2,3-Dioxygenase in Primary Human Macrophages by Human Immunodeficiency Virus Type 1 Is Strain Dependent J. Virol., May 1, 2000; 74(9): 4110 - 4115. [Abstract] [Full Text]
|
|
|
|
 |
|
 J. T. Coyle and R. Schwarcz Mind Glue: Implications of Glial Cell Biology for Psychiatry Arch Gen Psychiatry, January 1, 2000; 57(1): 90 - 93. [Full Text] [PDF]
|
|
| HOME | HELP | FEEDBACK | SUBSCRIPTIONS | ARCHIVE | SEARCH | TABLE OF CONTENTS |
