Kynurenic acid protects against the neurochemical and behavioral effects of unilateral quinolinic acid injections into the nucleus basalis of rats

It has recently been demonstrated that kynurenic acid (KYN), an endogenous tryptophan metabolite, provides almost complete protection against the neurotoxic and mnemonic effects of another tryptophan metabolite quinolinic acid (QUIN) on the cell bodies of the nucleus basalis magnocellularis (nbm). The present study further investigated whether unilateral coinjections of KYN and QUIN into the rat nbm antagonized the effects of QUIN alone. Food-deprived rats were pretrained on an eight-arm radial maze, with four arms baited, until choice accuracy stabilized to greater than or equal to 87% correct. Postoperatively, rats were tested on the radial maze for 32 consecutive days. Feeding behavior and locomotor activity were also measured to determine if nonassociative factors accounted for any observed behavioral deficits. QUIN lesions resulted in significantly more working and reference memory errors compared with sham-operated and coinjected animals, which did not differ significantly from each other. There were no reliable group differences in amount of food eaten or locomotor activity. The QUIN group had a reliable decrease in cortical choline acetyltransferase, with no significant changes for the sham and coinjected groups. Results confirm that KYN antagonizes the neurotoxic and mnemonic effects of QUIN alone and suggest that the memory deficits induced by nbm lesions cannot be solely attributed to changes in feeding or locomotor activity.     

Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid

Quinolinic acid, a metabolite of tryptophan, behaves as an excitotoxic amino acid. It has been proposed that quinolinic acid might be implicated in neurodegenerative diseases. The related metabolite, kynurenic acid, has been found to be a powerful antagonist of quinolinic acid. The ability of quinolinic acid, alone or in combination with kynurenic acid, to destroy cholinergic neurons projecting to the cortex was examined by morphological and biochemical criteria. The compounds were injected unilaterally into the nbm of the rat. Neuronal destruction of the basal forebrain occurred with quinolinic acid alone; however, no cell loss was observed when kynurenic and quinolinic acid were co-injected. Quinolinic acid lesions of the nucleus basalis caused significant decreases in cortical choline acetyltransferase, acetylcholinesterase, high affinity choline uptake and ³H-acetylcholine release. These reductions in cortical cholinergic markers were prevented by coinjecting kynurenic with quinolinic acid. A significant decrease in cortical choline acetyltransferase activity was observed three months following quinolinic acid lesions of the nucleus basalis. The results indicate that quinolinic acid can be used as an endogenous neurotoxin to produce lesions of the nbm resulting in impaired cortical cholinergic function similar to that seen in Alzheimer's disease.     

Quinolinic acid neurotoxicity in the nucleus basalis antagonized by kynurenic acid

Quinolinic acid, a metabolite of tryptophan, behaves as an excitotoxic amino acid. It has been proposed that quinolinic acid might be implicated in neurodegenerative diseases. The related metabolite, kynurenic acid, has been found to be a powerful antagonist of quinolinic acid. The ability of quinolinic acid, alone or in combination with kynurenic acid, to destroy cholinergic neurons projecting to the cortex was examined by morphological and biochemical criteria. The compounds were injected unilaterally into the nbm of the rat. Neuronal destruction of the basal forebrain occurred with quinolinic acid alone; however, no cell loss was observed when kynurenic and quinolinic acid were co-injected. Quinolinic acid lesions of the nucleus basalis caused significant decreases in cortical choline acetyltransferase, acetylcholinesterase, high affinity choline uptake and ³H-acetylcholine release. These reductions in cortical cholinergic markers were prevented by coinjecting kynurenic with quinolinic acid. A significant decrease in cortical choline acetyltransferase activity was observed three months following quinolinic acid lesions of the nucleus basalis. The results indicate that quinolinic acid can be used as an endogenous neurotoxin to produce lesions of the nbm resulting in impaired cortical cholinergic function similar to that seen in Alzheimer's disease.     

Functional and neurochemical cortical cholinergic impairment following neurotoxic lesions of the nucleus basalis magnocellularis in the rat

The effect of kainic and quinolinic acid on cortical cholinergic function was examined following injections of these agents into the nucleus basalis magnocellularis (nbm) or into the frontoparietal cortex. The release of cortical ³H-acetylcholine (³H-ACh), high affinity choline uptake (HACU) and acetylcholinesterase was measured 7 days following injections of saline (control), kainic acid (4.7 nmoles) and quinolinic acid (60, 150 and 300 nmoles) into the nbm. These cortical cholinergic parameters were also examined after injections of saline (control), kainic acid (9.4 nmoles) and quinolinic acid (300 nmoles) into the fronto-parietal cortex. The release of ³H-ACh, HACU and AChE was significantly reduced in animals injected with kainic or quinolinic acid into the nbm. Histological examination of stained sections showed a loss of cell bodies in the region of the nbm and the globus pallidus. The size of the lesion produced by quinolinic acid was proportional to the dose injected into the nbm. In animals injected with kainic acid or quinolinic acid into the cerebral cortex, the release of ³H-ACh, HACU and AChE was not significantly reduced when compared with control animals, although histological examination of stained cortical sections showed a marked loss of cortical neurons. Th results show that quinolinic acid, an endogenous neuroexcitant, produces a deficit of cholinergic function similar to that described in the cortical tissue of patients with senile dementia of Alzheimer's type. The toxic effects of quinolinic acid on cortical cholinergic function are due to its action on cholinergic cell bodies in the nbm. The cortical slice preparation from quinolinic acid-treated animals showing impairment of ³H-ACh release, may be useful in assessing the action of drugs designed to improve cholinergic function.     

Functional and neurochemical cortical cholinergic impairment following neurotoxic lesions of the nucleus basalis magnocellularis in the rat

The effect of kainic and quinolinic acid on cortical cholinergic function was examined following injections of these agents into the nucleus basalis magnocellularis (nbm) or into the frontoparietal cortex. The release of cortical ³H-acetylcholine (³H-ACh), high affinity choline uptake (HACU) and acetylcholinesterase was measured 7 days following injections of saline (control), kainic acid (4.7 nmoles) and quinolinic acid (60, 150 and 300 nmoles) into the nbm. These cortical cholinergic parameters were also examined after injections of saline (control), kainic acid (9.4 nmoles) and quinolinic acid (300 nmoles) into the fronto-parietal cortex. The release of ³H-ACh, HACU and AChE was significantly reduced in animals injected with kainic or quinolinic acid into the nbm. Histological examination of stained sections showed a loss of cell bodies in the region of the nbm and the globus pallidus. The size of the lesion produced by quinolinic acid was proportional to the dose injected into the nbm. In animals injected with kainic acid or quinolinic acid into the cerebral cortex, the release of ³H-ACh, HACU and AChE was not significantly reduced when compared with control animals, although histological examination of stained cortical sections showed a marked loss of cortical neurons. Th results show that quinolinic acid, an endogenous neuroexcitant, produces a deficit of cholinergic function similar to that described in the cortical tissue of patients with senile dementia of Alzheimer's type. The toxic effects of quinolinic acid on cortical cholinergic function are due to its action on cholinergic cell bodies in the nbm. The cortical slice preparation from quinolinic acid-treated animals showing impairment of ³H-ACh release, may be useful in assessing the action of drugs designed to improve cholinergic function.     

Kynurenic acid antagonizes hippocampal quinolinic acid neurotoxicity: behavioral and histological evaluation

In the present study, we evaluate the ability of kynurenic acid to protect hippocampal neurons from the neurotoxicity of the N-methyl-D-aspartate (NMDA) agonist quinolinic acid. Bilateral intrahippocampal injection of quinolinic acid (120 nmol) led to severe behavioral disturbances and total loss of hippocampal neurons. Intrahippocampal co-injection of kynurenic acid (360 nmol) completely prevented cell loss and behavioral disturbances. However, the protection was incomplete when kynurenic acid was intraperitoneally injected (500 mg/kg, repeated during 4 days). These above results indicate that kynurenic acid can antagonize the neuronal degeneration mediated by excessive stimulation of NMDA receptors in vivo.     

Targeting the kynurenine pathway as a potential strategy to prevent and treat Alzheimer's disease

Alzheimer’s disease (AD) is a progressive neurodegenerative disorder of the elderly accounting for the vast majority of dementia. Recently, many studies have implicated the role of inflammatory response, especially neuroinflammatory response in the development and progression of AD. However, the underlying mechanism of how inflammatory response induces AD is unknown. Kynurenine pathway is a major route of the amino acid tryptophan catabolism, resulting in the production of nicotine adenine dinucleotide and other neuroactive intermediates: quinolinic acid (QA) and kynurenic acid (KA). QA exerts different toxic effects, including over-activation of N-methyl-d-aspartate (NMDA) receptor and excitotoxicity, synaptic dysfunction and neuronal death. On the other hand, KA is identified as the only endogenous NMDA receptor antagonist and could modulate neurotoxic effects of QA. We hypothesize that an activated kynurenine pathway induced by inflammatory cytokines would generate more neurotoxic metabolites, which could be closely related to the pathogenesis of AD in elderly patients. Moreover, some measures, which facilitate KA synthesis and reduce the formation of QA, may emerge as a new therapeutic strategy against AD.     

Quinolinic acid stimulates luteinizing hormone secretion in female rats: evidence for involvement of N-methyl-D-aspartate-preferring receptors

Summary Pharmacological evidence suggests that endogenous excitatory amino acid neurotransmitters stimulate luteinizing hormone (LH) secretion in neonatal and adult rats. Recent studies have identified quinolinic acid (QUIN), an endogenous brain and peripheral metabolite of tryptophan, as a potent agonist at N-methyl-D-aspartate (NMDA)-preferring excitatory amino acid receptors. The present studies examined whether QUIN alters LH secretion in ovariectomized, estradiol-primed rats and whether such effects are mediated by specific amino acid receptor subtypes. In one experiment, animals received intracisternal injections of either quinolinic acid, N-methyl-DL-aspartate (NMA), aspartate (ASP), quisqualic acid (QA), or monosodium glutamate (GLU) five minutes prior to decapitation. In a second study, animals receiving central QUIN or NMA were treated simultaneously with either 2-amino-7-phosphonoheptanoic acid (APH) or kynurenic acid (KYA), both antagonists of NMDA-preferring receptors, or the quisqualate antagonist, glutamate diethyl ester (GDEE). Serum LH concentrations were measured by radioimmunoassay. Intracisternal administration of either QUIN or NMA resulted in an acute, dose-dependent increase of serum LH concentrations. Coadministration of APH blocked the effects of QUIN and NMA. QUIN stimulation of LH was also blocked by KYA, but not GDEE. Neither GLU nor ASP increased LH release, but QA did produce a small, significant elevation of LH. Light microscopic evaluation of brains showed no morphologic disturbance resulting from administration of these agents. The present results suggest that QUIN, or other endogenous ligands of NMDA-preferring receptors, may participate in the regulation of LH secretion in the adult female rat.This research was supported by National Research Service Award Postdoctoral Fellowship HD-06443 (MDJ); by NIH grant HD-13703 and NIH Research Career Development Award HD-00366 (WRC); by Biomedical Research Support grant GR RR-05423, and by USPHS grant NS-20509 (WOW)     

Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis

Kynurenine 3-mono-oxygenase, one of the key enzymes of the "kynurenine pathway", catalyses the formation of 3-hydroxykynurenine and may direct the neo-synthesis of quinolinic and kynurenic acids. While 3-hydroxykynurenine and quinolinic acid have neurotoxic properties, kynurenic acid antagonizes excitotoxic neuronal death. Here we report that the expression and activity of kynurenine 3-mono-oxygenase significantly increased in the spinal cord of rats with experimental allergic encephalopathy, an experimental model of multiple sclerosis. As a consequence of this increase, the spinal cord content of 3-hydroxykynurenine and quinolinic acid reached neurotoxic levels. We also report that systemic administration of Ro 61-8048, a selective kynurenine 3-mono-oxygenase inhibitor, reduced the increase of both 3-hydroxykynurenine and quinolinic acid, and caused accumulation of kynurenic acid. In the brain and spinal cord of the controls, kynurenine 3-mono-oxygenase immunoreactivity was located in granules (probably mitochondria) present in the cytoplasm of both neurons and astroglial cells. In the spinal cord of rats with experimental allergic encephalopathy, however, cells with a very intense kynurenine 3-mono-oxygenase immunoreactivity, also able to express class II major histocompatibility complex and inducible nitric oxide synthase, were found in perivascular, subependymal and subpial locations. These cells (most probably macrophages) were responsible for the large increase in 3-hydroxykynurenine and quinolinic acid found in the spinal cords of affected animals. The results show that cells of the immune system are responsible for the increased formation of 3-hydroxykynurenine and quinolinic acid, two neurotoxic metabolites that accumulate in the central nervous system of rats with experimental allergic encephalomyelitis. They also demonstrate that selective kynurenine 3-mono-oxygenase inhibitors reduce the neo-synthesis of these toxins.     

Prolonged infusion of quinolinic acid into rat striatum as an excitotoxic model of neurodegenerative disease

The neurotoxic effects of prolonged exposure of rat striatum to quinolinic acid in vivo was evaluated through assays of neurochemical markers for major neuronal populations. Continuous intrastriatal quinolinic acid infusion for 14 days produced a dose-dependent depletion of striatal choline acetyltransferase (ChAT) activity, glutamic acid decarboxylase (GAD) activity, and somatostatin content. ChAT activity was significantly reduced by quinolinic acid at doses of 90, 270, and 540 nmol/day, while GAD activity and somatostatin content were decreased only at doses of 270 and 540 nmol/day. NADPH-diaphorase histochemistry revealed a loss of striatal NADPH-diaphorase neurons as a result of quinolinic acid infusion at a dose of 270 nmol/day. The neurotoxic lesion induced by prolonged quinolinic acid exposure in vivo can be used as a potential model for studying excitotoxic mechanisms in neurodegenerative disease.     

Pharmacology of the corticocaudate excitatory postsynaptic potential in the cat: evidence for its mediation by quisqualate- or kainate-receptors

Caudate neurons were recorded with intracellular electrodes in halothane anaesthetized cats during microiontophoretic application of drugs and simultaneous stimulation of the corticocaudate pathway. Application of 2-amino-7-phosphonoheptanoic acid inhibited excitations induced by the N-methyl-D-aspartic acid receptor agonists N-methyl-D-aspartic acid and quinolinic acid, but not those elicited by quisqualic acid or activation of the cortico-caudate pathway. Selective inhibition of N-methyl-D-aspartic acid induced excitations was also found in vitro in the frog hemisected spinal cord preparation where a pA2-value of 5.5 against N-methyl-D-aspartic acid was determined. The endogenous tryptophan metabolite, kynurenic acid, antagonized excitations induced by N-methyl-D-aspartic, quisqualic, L-glutamic and kainic acid as well as the excitatory postsynaptic potential (EPSP) evoked in caudate cells by stimulation of the corticocaudate pathway, while action potentials elicited by an intracellularly applied depolarizing current were only slightly affected. In vitro experiments with the frog hemisected spinal cord preparation suggested that kynurenic acid might be a competitive antagonist of both N-methyl-D-aspartate and quisqualate receptors, with pA2-values of about 4.8 and 4.0, respectively. From these results it is concluded that the three-receptor concept for excitatory amino acids are proposed by Watkins and colleagues is probably applicable to the cat caudate nucleus and that the cortically evoked monosynaptic EPSP is mediated by a non-N-methyl-D-aspartate quisqualate- or kainate-receptor.     

Effects of immune activation on quinolinic acid and neuroactive kynurenines in the mouse.

Accumulation of quinolinic acid and neuroactive kynurenines derived from tryptophan are of potential significance in human neuropathologic diseases because of their neurotoxic and convulsant properties. Clinical studies have established that sustained elevations of quinolinic acid, L-kynurenine and kynurenic acid within the cerebrospinal fluid occur in patients with a broad spectrum of inflammatory diseases and correlate with markers of immune activation and interferon-gamma activity. The present study describes an animal model that replicates these clinical observations and investigates the role of interferon-gamma as a mediator between immune activation and increased kynurenine pathway metabolism. Marked elevations in quinolinic acid, L-kynurenine and 3-hydroxykynurenine as well as an increased ratio of quinolinic acid: kynurenic acid in brain occurred 24 h after systemic pokeweed mitogen administration to C57BL6 mice. In plasma, L-tryptophan and kynurenic acid levels were reduced by pokeweed mitogen, while the concentrations of L-kynurenine, 3-hydroxykynurenine and quinolinic acid were increased. Interferon-gamma, pokeweed mitogen and lipopolysaccharide induced indoleamine-2,3-dioxygenase, the first enzyme of the kynurenine pathway, and increased both L-kynurenine and quinolinic acid concentrations of brain and systemic tissues, particularly in the lung, gastrointestinal tract and spleen. In contrast, hepatic tryptophan-2,3-dioxygenase activity was either reduced or unaffected. Increases in kynurenine pathway metabolism were sustained in mice given daily injections of interferon-gamma for seven days and subsequent responses to interferon-gamma were further enhanced. In contrast, daily administration of lipopolysaccharide was associated with subsequent attenuated responsiveness (tolerance) to lipopolysaccharide, pokeweed mitogen and interferon-gamma. Systemic administration of a monoclonal antibody to mouse interferon-gamma either attenuated or abolished the responses of kynurenine pathway metabolism to pokeweed mitogen and interferon-gamma. We conclude that acute and chronic increases in quinolinic acid and neuroactive kynurenines follow immune stimulation in mice, and result from indoleamine-2,3-dioxygenase induction. The results demonstrate that interferon-gamma is an important mediator between immune stimulation and indoleamine-2,3-dioxygenase induction. These increases in kynurenine pathway metabolism closely parallel the responses documented in patients with a broad spectrum of inflammatory diseases. Mice treated with immune stimuli are a useful model to investigate the relationships between immune activation and kynurenine pathway metabolism.     

Kynurenines in the CNS: from endogenous obscurity to therapeutic importance

In just under 20 years the kynurenine family of compounds has developed from a group of obscure metabolites of the essential amino acid tryptophan into a source of intensive research, with postulated roles for quinolinic acid in neurodegenerative disorders, most especially the AIDS-dementia complex and Huntington's disease. One of the kynurenines, kynurenic acid, has become a standard tool for use in the identification of glutamate-releasing synapses, and has been used as the parent for several groups of compounds now being developed as drugs for the treatment of epilepsy and stroke. The kynurenines represent a major success in translating a basic discovery into a source of clinical understanding and therapeutic application, with around 3000 papers published on quinolinic acid or kynurenic acid since the discovery of their effects in 1981 and 1982. This review concentrates on some of the recent work most directly relevant to the understanding and applications of kynurenines in medicine.     

Is quinolinic acid an endogenous excitotoxin in alcohol withdrawal?

Levels of tryptophan in brain are increased by the action of chronic ethanol, particularly in the event of compromised hepatic function. This is likely to result in elevated brain levels of the potent excitotoxin quinolinic acid (quinolinate) since levels of this tryptophan metabolite can be elevated considerably by tryptophan loading. Ethanol may also selectively increase the activity of enzymes important in the synthesis of quinolinic acid such as tryptophan oxygenase. It is concluded that ethanol may generate significant levels of the NMDA receptor agonist, quinolinic acid, possibly even toxic levels in localized brain areas, especially during ethanol withdrawal and when associated with acute or chronic hepatotoxicity.     

Memantine increases brain production of kynurenic acid via protein kinase A-dependent mechanism

We describe a novel aspect of action of memantine ex vivo, in the brain cortical slices and in vitro, in mixed glial cultures. The drug potently increased the production of kynurenic acid, an endogenous tryptophan metabolite blocking N-methyl-D-aspartate (NMDA) and nicotinic alpha7 receptors. In cortical slices memantine, an open-channel NMDA blocker (100-150 microM), but not the competitive NMDA receptor antagonist, LY235959 increased the production of kynurenic acid. Neither SCH23390, D1 receptor antagonist (50 microM) nor raclopride, D2 receptor antagonist (10 microM) changed the memantine-induced effects. Propranolol (100 microM) has partially reduced its action. Selective cAMP-dependent protein kinase (PKA) inhibitor, KT5720 (1 microM), but not selective protein kinase C (PKC) inhibitor, NPC15437 (30 microM) totally reversed the action of memantine. In mixed glial cultures, 2-24 h incubation with memantine (2-50 microM) enhanced the production of kynurenic acid. Memantine (up to 0.5 mM) has not affected the activity of kynurenic acid biosynthetic enzymes. The obtained data suggest that memantine enhances the production of kynurenic acid in PKA-mediated way. This effect may partially contribute to the therapeutic actions of memantine and be of a potential clinical importance.     

Kynurenic acid has a dual action on AMPA receptor responses

Glutamate is the predominant excitatory neurotransmitter in the central nervous system. The receptors that bind glutamate, including N-methyl-D-aspartate (NMDA) and alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptor subtypes, are strongly implicated in higher cognitive processes, especially learning and memory. Loss of glutamate receptor function impairs the ability to acquire and retain information in some patients subsequent to stroke or brain injury, and positive allosteric modulators of glutamate receptors can restore learning and memory in some of these patients. Here we demonstrate that kynurenic acid (KYNA), an endogenous tryptophan metabolite, acts upon heterologous AMPA receptors via two distinct mechanisms. Low (nanomolar to micromolar) concentrations of KYNA facilitate AMPA receptor responses, whereas high (millimolar) concentrations of KYNA competitively antagonize glutamate receptors. Low concentrations of KYNA appear to increase current responses through allosteric modulation of desensitization of AMPA receptors. These findings suggest the possibility that low concentrations of endogenous KYNA acting at AMPA receptors may be a positive modulator of excitatory synaptic transmission.     

Depolarization-dependent protein phosphorylation in rat cortical synaptosomes: the effects of calcium, strontium and barium

Infusion of 120 nmol quinolinic acid into several regions of the rat's brain revealed differences in vulnerability to its neurotoxic effects, as judged by light microscopical analysis. The striatum, the pallidal formation and the hippocampus were the most susceptive brain areas whereas the cerebellum, substantia nigra, amygdala, medial septum and hypothalamus proved more resistant.     

Of mice,rats and men: Revisiting the quinolinic acid hypothesis of Huntington's disease

The neurodegenerative disease Huntington's disease (HD) is caused by an expanded polyglutamine (polyQ) tract in the protein huntingtin (htt). Although the gene encoding htt was identified and cloned more than 15 years ago, and in spite of impressive efforts to unravel the mechanism(s) by which mutant htt induces nerve cell death, these studies have so far not led to a good understanding of pathophysiology or an effective therapy. Set against a historical background, we review data supporting the idea that metabolites of the kynurenine pathway (KP) of tryptophan degradation provide a critical link between mutant htt and the pathophysiology of HD. New studies in HD brain and genetic model organisms suggest that the disease may in fact be causally related to early abnormalities in KP metabolism, favoring the formation of two neurotoxic metabolites, 3-hydroxykynurenine and quinolinic acid, over the related neuroprotective agent kynurenic acid. These findings not only link the excitotoxic hypothesis of HD pathology to an impairment of the KP but also define new drug targets and therefore have direct therapeutic implications. Thus, pharmacological normalization of the imbalance in brain KP metabolism may provide clinical benefits, which could be especially effective in early stages of the disease.     

Quinolinate neurotoxicity and glutamatergic structures

Neurotoxic properties of quinolinic acid following intracerebroventricular application were investigated in the hippocampal formation of 12- and 30-day-old rats. Quinolinic acid neurodegenerative potency was found to depend on the survival time, the dose applied and the developmental stage of the animal. Pretreatment with kynurenic acid and ketamine as well as the transection of the perforant path were noted to protect major parts of the hippocampal cell layers from quinolinic acid-induced degenerative effects. The results are interpreted in view of a putative dependence of quinolinic acid neurotoxicity on the presence of established synaptic, in particular glutamatergic, processes which play a major role in the hippocampal formation and mature during the first postnatal weeks. For comparison, we studied local effects of quinolinic acid on superior cervical and dorsal root ganglia in which glutamate inputs obviously do not occur; no signs of neuronal vulnerability were seen.     

Strong association of phenylalanine and tryptophan metabolites with activated cytomegalovirus infection in kidney transplant recipients

Infection-induced inflammation triggers catabolism of proteins and amino acids. Phenylalanine and tryptophan are 2 amino acids related to infections that regulate immune responses. Polyomavirus BK (BKV) and cytomegalovirus (CMV) are important pathogens after kidney transplantation. We investigated the clinical relevance of phenylalanine, tryptophan, and tryptophan metabolites (kynurenine and quinolinic acid) plasma levels in kidney transplant recipients with active CMV (BKV(-)CMV(+), n = 12) or BK virus infection (BKV(+)CMV(-), n = 37). Recipients without active viral infections (CMV(-)BKV(-), n = 28) and CMV(-)BKV(-) healthy individuals (HCs, n = 50) served as controls. In contrast to BKV infection, activated CMV infection is tightly linked to increased phenylalanine and tryptophan metabolite plasma levels (p ≤ 0.002). The association of phenylalanine (cutoff 50 μmol/L) with CMV infection demonstrates high sensitivity (100%) and specificity (94%). By contrast, kynurenine (p = 0.029) and quinolinic acid (p = 0.003) values reflect the severity of CMV infection. In this early proof-of-concept trial, evidence indicates that activated CMV infection is strongly associated with increased phenylalanine as well as kynurenine and quinolinic acid plasma levels. Moreover, tryptophan metabolite levels correlate with disease severity. Measurement of these amino acids is an inexpensive and fast method expected to complete conventional diagnostic assays.