Kynurenic Acid Metabolism in Various Types of Brain Pathology in HIV-1 Infected Patients

Kynurenic acid, an intermediate metabolite of L-kynurenine, is a competitive antagonist of inotropic excitatory amino acid (EAA) receptors as well as a non competitive antagonist of 7 alpha nicotine cholinergic receptors and its involvement in memory deficit and cognition impairment has been suggested. Alterations of kynurenic acid metabolism in the brain after HIV-1 (human immunodeficiency virus type-1) infection have been demonstrated. The present study evaluates the biosynthetic machinery of kynurenic acid e.g. the content of L-kynurenine and kynurenic acid, as well as the activity of enzymes synthesizing kynurenic acid, kynurenine aminotransferase I (KAT I) and kynurenine aminotransferase II (KAT II) in the frontal cortex and cerebellum of HIV-1 infected patients in relation to different types of pathology classified as follows: HIV in brain (HIV); opportunistic infection (OPP); infarction of brain (INF); malignant lymphoma of brain (LY); and glial dystrophy (GD) and of control (CO) subjects. Of all investigated pathologies the most frequent was OPP (65%), followed by HIV (26%), LY, INF, and GD (each 22%, respectively). Further, 68% of HIV-1 patients had bronchopneumonia, the highest incidence of which, at 60%, was seen in the OPP and LY group. Kynurenic acid was increased significantly in the frontal cortex of LY (392% of CO, P < 0.001), HIV (231% of CO, P < 0.01) and GD (193% of CO, P < 0.05), as well as in the cerebellum of GD (261% of CO, P < 0.01). A significant increase of L-kynurenine was observed in the frontal cortex of LY (385% of CO, P < 0.001) and INF (206% of CO, P < 0.01), and in the cerebellum of GD, LY, OPP and HIV (between 177% and 147% of CO). The KAT I activity increased significantly in the frontal cortex of all pathological subgroups, ie OPP = 420% > INF > LY > HIV > GD = 192% of CO. In the cerebellum, too, all pathological subgroups showed marked increase of KAT I activity (OPP = 320% > LY, HIV > GD > INF = 176% of CO). On contrary, the activity of KAT II was moderately, but significantly, higher in the frontal cortex of INF and OPP; in the cerebellum of HIV, OPP and LY it was comparable to the control, while mildly reduced in INF and GD. Interestingly, normal subjects with the diagnosis of bronchopneumonia were characterized by high kynurenic acid metabolism in the brain, too. Correlation analyses between kynurenine parameters revealed association between high ratio KAT I/KAT II and increased kynurenic acid level and lower L-kynurenine in the frontal cortex and cerebellum of HIV and LY subgroups. The present study revealed a different pattern of alteration of kynurenic acid metabolism in frontal cortex and cerebellum among investigated pathological subgroups of HIV-1 infected patients. Interestingly, a marked enhancement of kynurenic acid metabolism in the brain has been found with occurrence of bronchopneumonia. This finding indicates a notable association between impaired conditions of oxygen availability and enhancement of kynurenic acid formation in the human brain. These observation(s) might have an impact on the understanding of pathological processes in the brain after HIV-1 infection involving the development of neuropsychiatric and neurological symptoms, including memory and cognition impairment.

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Kynurenic acid metabolism in the brain of HIV-1 infected patients

Journal of Neural Transmission ◽

10.1007/s007020070026 ◽

2000 ◽

Vol 107 (10) ◽

pp. 1127-1138 ◽

Cited By ~ 26

Author(s):

H. Baran ◽

J. A. Hainfellner ◽

B. Kepplinger ◽

P. R. Mazal ◽

H. Schmid ◽

...

Keyword(s):

Kynurenic Acid ◽

Acid Metabolism ◽

The Brain ◽

Hiv 1

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Role of Tryptophan-kynurenine Pathway in Depression: Psychopathological Aspect

European Psychiatry ◽

10.1016/s0924-9338(09)70521-8 ◽

2009 ◽

Vol 24 (S1) ◽

pp. 1-1

Author(s):

A.-M. Myint

Keyword(s):

Kynurenic Acid ◽

Excitatory Amino Acid ◽

Kynurenine Pathway ◽

Response To Treatment ◽

Excitatory Amino Acid Receptors ◽

Amino Acid Receptors ◽

Tryptophan Catabolism ◽

Ifn Γ ◽

The Brain

It was reported that cytokines such as IFN-γ reduce the synthesis of 5-HT by stimulating the activity of indoleamine 2,3 dioxygenase (IDO) enzyme which degrades tryptophan to kynurenine. Kynurenine is further metabolized to kynurenic acid (KYNA), 3-hydroxykynurenine (3OHK) and quinolinic acid (QA) by kynurenine aminotransferase (KAT), kynurenine 3-monooxygenase (KMO) and kynureninase. Both KMO and kynureninase are also shown to be activated by IFNγ. The 3OHK is neurotoxic apoptotic while QA is the excitotoxic N-methyl-D-aspartate (NMDA) receptor agonist. Conversely KYNA is an antagonist of all three ionotropic excitatory amino acid receptors and considered neuroprotective. In the brain, tryptophan catabolism occurs in the astrocytes and. The astrocytes are shown to produce mainly KYNA whereas microglia and macrophages produced mainly 3OHK and QA. The astrocytes have been demonstrated to metabolise the QA produced by the neighbouring microglia.Tryptophan breakdown has been found to be increased but KYNA, the neuroprotective metabolite is decreased in both blood and cerebrospinal fluid of the patients with major depression compared to healthy controls. Moreover, the ratio between KYNA and 3OHK showed significant correlation with response to treatment. These findings lead to the hypothesis an imbalance neuroprotection-neurodegener-ation in terms of kynurenine metabolites and their immunological and biochemical interactions in the brain might further induce the apoptosis of the neuroprotective astrocytes and the vulnerability to stress is thereby enhanced.

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Inflammation, Glutamate, and Glia in Depression: A Literature Review

CNS Spectrums ◽

10.1017/s1092852900016734 ◽

2008 ◽

Vol 13 (6) ◽

pp. 501-510 ◽

Cited By ~ 188

Author(s):

Leah McNally ◽

Zubin Bhagwagar ◽

Jonas Hannestad

Keyword(s):

Glutamate Receptor ◽

Inflammatory Mediators ◽

Microglial Activation ◽

Acid Metabolism ◽

Excitatory Amino Acid ◽

Receptor Activation ◽

Interferon Α ◽

Neurotoxic Effects ◽

Chronic Activation ◽

The Brain

ABSTRACTMultiple lines of evidence suggest that inflammation and glutamate dysfunction contribute to the pathophysiology of depression. In this review we provide an overview of how these two systems may interact. Excess levels of inflammatory mediators occur in a subgroup of depressed patients. Studies of acute experimental activation of the immune system with endotoxin and of chronic activation during interferon-α treatment show that inflammation can cause depression. Peripheral inflammation leads to microglial activation which could interfere with excitatory amino acid metabolism leading to inappropriate glutamate receptor activation. Loss of astroglia, a feature of depression, upsets the balance of anti- and pro-inflammatory mediators and further impairs the removal of excitatory amino acids. Microglia activated by excess inflammation, astroglial loss, and inappropriate glutamate receptor activation ultimately disrupt the delicate balance of neuroprotective versus neurotoxic effects in the brain, potentially leading to depression.

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Faculty Opinions recommendation of What the brain stem tells the frontal cortex. I. Oculomotor signals sent from superior colliculus to frontal eye field via mediodorsal thalamus.

Faculty Opinions – Post-Publication Peer Review of the Biomedical Literature ◽

10.3410/f.1016466.200751 ◽

2003 ◽

Author(s):

Klaus-Peter Hoffmann

Keyword(s):

Superior Colliculus ◽

Frontal Cortex ◽

Brain Stem ◽

Frontal Eye Field ◽

Mediodorsal Thalamus ◽

Eye Field ◽

The Brain

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II. Excitatory amino acid receptors in the brain-gut axis

AJP Gastrointestinal and Liver Physiology ◽

10.1152/ajpgi.2001.280.6.g1055 ◽

2001 ◽

Vol 280 (6) ◽

pp. G1055-G1060 ◽

Cited By ~ 54

Author(s):

Pamela J. Hornby

Keyword(s):

Metabotropic Glutamate Receptors ◽

Excitatory Amino Acid ◽

Motor Pattern ◽

Pattern Generation ◽

Gut Contents ◽

Dorsal Vagal Complex ◽

Gastric Accommodation ◽

Metabotropic Glutamate ◽

Therapeutic Benefits ◽

The Brain

In the last decade, there has been a dramatic increase in academic and pharmaceutical interest in central integration of vago-vagal reflexes controlling the gastrointestinal tract. Associated with this, there have been substantial efforts to determine the receptor-mediated events in the dorsal vagal complex that underlie the physiological responses to distension or variations in the composition of the gut contents. Strong evidence supports the idea that glutamate is a transmitter in afferent vagal fibers conveying information from the gut to the brain, and the implications of this are discussed in this themes article. Furthermore, both ionotropic and metabotropic glutamate receptors mediate pre- and postsynaptic control of glutamate transmission related to several reflexes, including swallowing motor pattern generation, gastric accommodation, and emesis. The emphasis of this themes article is on the potential therapeutic benefits afforded by modulation of these receptors at the site of the dorsal vagal complex.

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Increased Concentrations of the Neurotoxin 3-Hydroxykynurenine in the Frontal Cortex of HIV-1-Positive Patients

Journal of Neurochemistry ◽

10.1046/j.1471-4159.1995.64020932.x ◽

2002 ◽

Vol 64 (2) ◽

pp. 932-935 ◽

Cited By ~ 63

Author(s):

A. M. Sardar ◽

J. E. Bell ◽

G. P. Reynolds

Keyword(s):

Frontal Cortex ◽

Hiv 1

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The Brain of an Outstanding Scientist-Inventor: Structural Organization of Area 10 of the Frontal Cortex

Bulletin of Experimental Biology and Medicine ◽

10.1007/s10517-021-05344-8 ◽

2021 ◽

Author(s):

I. N. Bogolepova ◽

L. I. Malofeeva ◽

P. A. Agapov

Keyword(s):

Frontal Cortex ◽

Structural Organization ◽

Outstanding Scientist ◽

The Brain

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Autoradiographic Examination of Behaviorally Induced Changes in the Protein and Nucleic Acid Metabolism of the Brain

Macromolecules and Behavior ◽

10.1007/978-1-4684-6042-1_14 ◽

1972 ◽

pp. 305-334 ◽

Cited By ~ 2

Author(s):

Joseph Altman

Keyword(s):

Nucleic Acid ◽

Acid Metabolism ◽

Nucleic Acid Metabolism ◽

Induced Changes ◽

The Brain

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Neural Mechanisms of Negative Symptoms

The British Journal of Psychiatry ◽

10.1192/s0007125000291599 ◽

1989 ◽

Vol 155 (S7) ◽

pp. 93-98 ◽

Cited By ~ 40

Author(s):

Nancy C. Andreasen

Keyword(s):

Frontal Cortex ◽

Negative Symptoms ◽

Neural Mechanism ◽

Brain Regions ◽

Brain Dysfunction ◽

Neural Mechanisms ◽

Dementia Praecox ◽

Intellectual Abilities ◽

The Brain ◽

Psychic Mechanisms

When Kraepelin originally defined and described dementia praecox, he assumed that it was due to some type of neural mechanism. He hypothesised that abnormalities could occur in a variety of brain regions, including the prefrontal, auditory, and language regions of the cortex. Many members of his department, including Alzheimer and Nissl, were actively involved in the search for the neuropathological lesions that would characterise schizophrenia. Although Kraepelin did not use the term ‘negative symptoms', he describes them comprehensively and states explicitly that he believes the symptoms of schizophrenia can be explained in terms of brain dysfunction:“If it should be confirmed that the disease attacks by preference the frontal areas of the brain, the central convolutions and central lobes, this distribution would in a certain measure agree with our present views about the site of the psychic mechanisms which are principally injured by the disease. On various grounds, it is easy to believe that the frontal cortex, which is specially well developed in man, stands in closer relation to his higher intellectual abilities, and these are the faculties which in our patients invariably suffer profound loss in contrast to memory and acquired ability.” Kraepelin (1919, p. 219)

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