1 INTRODUCTION

Tryptophan, an essential neutral amino acid, is a pivotal constituent of proteins and a source of numerous, biologically significant compounds. Only a small quantity of compound (1–2%) undergoes incorporation into peptides or proteins, whereas the remaining 98–99% follows two major metabolic routes. These include (a) the methoxyindole pathway yielding 5-hydroxytryptamine (5-HT; serotonin), and (b) the kynurenine pathway (KP) generating metabolites collectively called kynurenines (Figure 1). The KP converts 95% of tryptophan and ultimately leads to the formation of nicotinamide adenine dinucleotide (NAD+), with a number of neuroactive kynurenines en route.1, 2 The discoveries of last decades strongly support the concept of viewing the disturbed KP as an important link in the cycle of events leading to the development of brain pathologies. Various kynurenines are of substantial biological importance due to their ability to modify neurotransmission and to alter the immune response.3, 4

Scheme of kynurenine pathway

The family of KP metabolites comprises compounds acting in a divergent way and considered to be either neuroprotective or neurotoxic.5 The synthesis of specific compounds is tightly regulated and may considerably vary under physiological and pathological conditions.5 Kynurenic acid (KYNA), the main neuroprotective compound of the path, was discovered in the 19th century as a constituent of canine urine and initially regarded merely as a by-product of tryptophan degradation.6 The molecular structure of KYNA was unraveled at the beginning of the 20th century,7 yet the particular steps of the KP leading to KYNA formation were determined much later. Discoveries of the 1980s revealed the ability of KYNA to block the excitatory amino acid receptors under in vitro and in vivo conditions.8, 9 Soon, abnormalities in cerebral KYNA synthesis have been implicated in the pathogenesis of neurodegeneration.10 Intensified research during last four decades revolutionized our knowledge about KYNA and brought valuable data supporting the significant role of KYNA as an exceptional tryptophan metabolite in the mammalian brain.11 This review aimed to discuss the involvement of altered KYNA metabolism in the development of neurodegenerative diseases, as well as the future of pharmacological manipulations aimed to boost brain KYNA as potential therapeutic agents.

The KP is functional in the brain and in the periphery.12 The first step of tryptophan metabolism is catalyzed by the step-limiting enzymes, indoleamine 2,3-dioxygenases (IDO-1 and 2) and tryptophan 2,3-dioxygenase (TDO), yielding N-formyl-kynurenine (Figure 1). N-formyl-kynurenine is further converted to a direct precursor of KYNA, L-kynurenine, by formamidase. In the periphery, the constitutive expression of IDO-1 is restricted and was described mostly within endothelial, pancreatic, placental, or antigen-presenting cells. Interestingly, IDO-1 manifests pronounced susceptibility to the induction by proinflammatory molecules, such as interferon-γ, tumor necrosis factor α (TNF-α), interleukin-6 (IL-6), or IL-10, in a variety of cells.13, 14

IDO-2 and TDO show higher tissue specificity, mainly restricted to liver, and much lower expression level.15 The enzymatic activity of TDO can be induced by estrogens, glucocorticoids, and tryptophan itself.2 In the brain, striatal neurons and astrocytes express high levels of IDO-1 mRNA.16 TDO protein and its mRNA are also detectable in neurons and astrocytes.17-19

The major central pool of KYNA is formed locally, from its precursor, L-kynurenine.20, 21 L-kynurenine, on the contrary, originates mostly from peripheral sources (60–70%), whereas the remaining 30–40% is produced in situ.21 L-kynurenine can be also converted along another arm of the KP to neurotoxic 3-hydroxykynurenine (3-HK), QUIN, and further down to NAD.22 The fate of L-kynurenine degradation and its availability for the synthesis of KYNA is determined by a number of factors, including tissue and cell type. Central KYNA production occurs mostly in astrocytes and endothelial cells and to a much lesser extent within neurons.23-26 In contrast, neurotoxic QUIN is generated in the human brain mainly by the microglial cells and macrophages.27

The principal route of KYNA synthesis is based on an irreversible transamination of L-kynurenine catalyzed by kynurenine transaminases (KATs).28 KYNA is produced by various tissues and organs, including liver, kidneys, intestines, or endothelium.29, 30 In the brain, KATs are expressed mainly in astrocytes and to a lesser degree in neuronal cells, for example, in hippocampus, substantia nigra, or striatum.24, 25, 31-33 KATs are characterized by a different level of specific activity in various brain regions.34, 35

In humans and rodents, four isoforms of KATs, using L-kynurenine as a donor for amino group, were characterized and include KAT I (glutamine transaminase K/cysteine conjugate beta-lyase 1), KAT II (α-aminoadipate aminotransferase), KAT III (glutamine transaminase L/cysteine conjugate beta-lyase 2), and KAT IV (the mitochondrial aspartate aminotransferase/glutamic-oxaloacetic transaminase 2).36 Each KAT enzyme has an optimal pH range and a distinct substrate profile, despite sharing a number of amino acid and α-keto acid substrates.37-39 KATs manifest relatively low affinity for L-kynurenine (Km approx. 1 mM). Under physiological conditions, KAT II is considered a major biosynthetic enzyme responsible for KYNA formation.40

A targeted deletion of KAT II in mice leads to an early and transitory decrease in brain KAT activity and KYNA levels with commensurate behavioral and neuropathological changes.41 In KAT II–deficient mice, striatal KYNA level was transiently reduced around the 2nd week of age and the degree of neuronal loss following the local administration of QUIN was strongly enhanced.42 Later on, however, KYNA levels were normalized, possibly as a result of compensatory changes.41, 42

Indirectly, the activity of kynurenine monooxygenase (KMO), synthesizing 3-HK and displaying a much lower Km value for L-kynurenine, also impacts the synthesis of KYNA. Inhibition of KMO activity increases the pool of L-kynurenine available for KATs. This, in turn, may easily shift the KP and direct it to the neuroprotective branch; conversely, an enhanced activity of KMO stimulates metabolism of tryptophan along the neurotoxic arm of the pathway.43

As shown under in vitro and in vivo conditions, the composition of the extracellular milieu, the availability of oxygen and glucose, or level of ammonia and amino acids may influence the synthesis of KYNA.44-47 Notably, neurotoxic compounds such as mitochondrial toxins or pyrethroid pesticides inhibit, whereas a number of therapeutic agents, including beta-adrenoceptor agonists, nitric oxide donors, memantine, antidepressants, or some antiepileptics, stimulate KYNA production in the brain 48-53.

1.1 Other sources of brain KYNA

Apart from the canonical KAT-related synthesis, alternative mechanisms were implicated in the synthesis of KYNA.54, 55 Indole-3-pyruvic acid, the keto-analog of tryptophan, increases KYNA content in various organs, including brain.56 Indole-3-pyruvic acid is effectively converted to KYNA in a non-enzymatic reaction requiring ample presence of oxygen. Reactive oxygen species (ROS) target the enol form of indole-3-pyruvic acid, which undergoes pyrrole ring cleavage and subsequently forms KYNA.57, 58 L-L-kynurenine may also yield KYNA when incubated in the presence of H2O2, with or without peroxidases.55 It is a pH-dependent process, with the highest conversion of L-kynurenine occurring at the pH between 7.4 and 8.0.55 The contribution of alternative routes to the overall KYNA production still remains unclear. However, in the altered redox environment and when the antioxidant system is defective, as often is the case in neurodegenerative disorders, their significance may increase. Indeed, the lack of correlation between KATs activities and KYNA levels was reported in lead intoxication, Down syndrome, and disturbances of thyroid hormone levels.59-62

Furthermore, although peripherally synthesized KYNA poorly passes through the blood-brain barrier, certain conditions may facilitate its penetration into the brain. Systemic administration of KYNA prior to the cerebral ischemia potently increased its brain concentrations,63 possibly as a result of passive diffusion.21 In addition, KYNA was identified as a high-affinity substrate for organic anion transporters, OAT1 and OAT3.64, 65 Experimental use of probenecid, a non-selective inhibitor of Oat1, was shown to increase the brain level of KYNA.66, 67 Interestingly, thyroid hormones may enhance the removal of KYNA and modulate its brain level via diverse mechanisms, including the action of Oat.59

Finally, apart from the de novo synthesis by the mammalian tissues, KYNA can be generated in the digestive system by microbiota and exogenously delivered with food products.68, 69

1.2 Neurotoxic branch of kynurenine pathway

Three major neurotoxic metabolites of the KP include 3-HK, QUIN, and 3-hydroxyanthranilic acid (3-HANA). 3-HK is an immediate product of L-kynurenine conversion carried out by KMO. Metabolism of 3-HK by kynureninase yields 3-HANA, which, in two enzymatic steps, can be further converted to QUIN. The toxicity of 3-HK has been attributed mainly to the formation of free radicals and an induction of apoptotic neuronal death.70, 71

The results of numerous research clearly indicate that QUIN is capable of acting as an endogenous excitotoxin. QUIN-evoked neuronal loss is mostly associated with an excessive stimulation of NR2A and NR2B subunits of N-methyl-D-aspartate (NMDA) receptor at agonist-binding site. In the brain, physiological concentrations of QUIN are in nM range (~50–100 nM) and are approx. 20 times lower than in the periphery.72 At low concentrations, QUIN induces proliferation of the stem cells and is an intermediate metabolite along the pathway yielding NAD+in human brain cells.73, 74 At high, close to millimolar concentrations, QUIN induces selective, axon-sparing neuronal loss under various experimental conditions. The susceptibility of neurons to the QUIN-induced damage depends on the brain area, with cortical, striatal, and hippocampal neurons being the most sensitive.3 It was debated whether endogenous levels of QUIN are sufficient to cause neurotoxicity, yet, in the view of accumulated data, the compound undoubtedly may evoke neuronal death. In human brain, QUIN levels increase during inflammation or cerebral insults up to the micromolar values.75 Locally, QUIN concentration may be much higher.3 Notably, even low concentrations of QUIN may induce neuronal loss, providing that the exposure is prolonged. In organotypic corticostriatal, but not in caudate nucleus, cultures, exposed to low (100 nM) concentration of QUIN for up to 7 weeks, a clear focal neurodegeneration was developed.76

QUIN was also demonstrated to enhance the glutamate release, to inhibit glutamate reuptake, and to stimulate lipid peroxidation.77 Such local rise evokes depolarization of the postsynaptic membrane sufficient to remove the Mg2+ block of NMDA receptor–linked ion channel. Moreover, QUIN may impair the function of blood-brain barrier, induce nitric oxide production, and cause hyperphosphorylation of cytoskeletal intermediate filament proteins in astrocytes and neurons.73, 78-80 In the view of accumulated data, QUIN produces neurotoxicity through a link of events initiated by the excessive stimulation of the NMDA receptor, Ca2+ influx, energy deficit, and oxidative stress.

The proper balance between neurotoxic kynurenines and neuroprotective KYNA can be viewed, in fact, as the interplay between astrocytes, microglia, and neurons. Under physiological conditions, the astrocytic KP serves as a source of neuroprotective KYNA, whereas neuronal KP produces NAD+ improving cellular energy status. In diseased brain, the inflammatory signals stimulate the KP within macrophages, microglia, and dendritic cells to produce large quantities of QUIN. Astrocytes remove QUIN from synaptic cleft and catabolize it to NAD+; however, the enzyme responsible for catabolism is easily saturated. Thus, when the overall balance of the pathway is shifted toward QUIN and other neurotoxic kynurenines, with an absolute/relative deficiency of KYNA, neurodegenerative changes can follow.

2 BIOLOGICAL KYNA TARGETS IN THE BRAIN

The level of KYNA in the central nervous system (CNS) depends on the species, studied region, and the ontogenetic stage of development.81 In human brain, KYNA occurs in low micromolar range (approx. 0.1–1.5 μM), which is 20–50 times higher than in rodent CNS (0.001–0.05 μM).34, 82-85 The content of KYNA was reported to be the lowest in cerebellum and medulla (0.1–0.3 pmol/mg), intermediate in cortical areas and substantia nigra (0.2–0.6 pmol/mg), and the highest in putamen and globus pallidus (0.7–1.4 pmol/mg).34, 82 In human CSF, KYNA concentration is low (0.001–0.01 μM), yet it steadily increases with age.81, 86, 87 In other species, the brain content of KYNA also rises with age.88 Over 50-fold increase in brain KYNA between 1st week and 18th month of age was reported in rats.89 Others demonstrated a threefold increase between the 3rd and 24th months of age.90

KYNA is quickly liberated from the cell and is not a subject of enzymatic degradation or reuptake processes.11, 91 Extracellular KYNA interacts with a number of biological targets (Figure 2). KYNA was initially recognized as a broad-spectrum antagonist of ionotropic excitatory amino acid receptors. KYNA displays the highest affinity for the co-agonist glycine site of NMDA receptor complex (IC50 ~8–15 μM in the absence of glycine; ~50–200 μM in the presence of 10 μM glycine.92, 93 KYNA, in a competitive manner, blocks also agonist-binding sites of NMDA, kainic acid, and alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors, yet with lower affinity (IC50 of 100–500 μM).3, 94 Despite the discrepancy between physiologically occurring levels of KYNA and the levels needed to interfere with glutamatergic receptors, it is well established that KYNA synthesis may increase locally due to various factors and easily reach the concentration sufficient to interact with NMDA receptors.95

Targets of kynurenic acid. NMDA—N-methyl-D-aspartate; KA—kainic acid; AMPA—alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid; AHR—aryl hydrocarbon receptor; GPR35—G protein–coupled orphan receptor 35; ROS—reactive oxygen species

Neuroprotective and anticonvulsant properties of KYNA are broadly documented under in vivo and in vitro conditions.94-97 Notably, KYNA attenuates the morphological and behavioral consequences of experimental administration of its kynureninergic alter ego—excitotoxic QUIN.

As KYNA may impact the extracellular levels of glutamate, acetylcholine, GABA, and dopamine, neuromodulation is an important aspect of its role.98-101 In striatal preparations, low nanomolar concentrations of KYNA reduced glutamate release in caudate nucleus and impaired the neurotransmitter release.102 Experimental studies in vivo confirmed that fluctuations of KYNA level may alter glutamine, acetylcholine, and dopamine release.98, 99, 101

KYNA has also been identified as a ligand of formerly orphan G protein–coupled receptor, GPR35,103 broadly expressed in various immune cells. Apart from the regulation of immune response, KYNA-GPR35 interaction may inhibit Ca2+ channels in sympathetic neurons and reduce synaptic activity in hippocampal neurons.104, 105 Therefore, KYNA capability to activate GPR35 might represent another way to reduce the excitatory transmission.105, 106 KYNA is also targeting xenobiotic receptor, the aryl hydrocarbon receptor (AHR).107 KYNA-related AHR stimulation increases the interleukin-6 expression, which is often associated with promoting carcinogenesis and tumor outgrowth.107, 108 Moreover, KYNA displays the scavenging ability toward ROS. In the homogenates of rat brains, KYNA decreased the production of free radicals and lipid peroxidation.109 It has been postulated that KYNA targets also α7-nicotinic acetylcholine receptors (α7nAChR); however, this mechanism is still being controversial.110-112

The inflammation emerged as one of the key factors contributing to the neuronal loss and compromised regeneration and thus was implicated in the pathogenesis of neurodegenerative disorders. An important link between proinflammatory status and the activation of KP is well substantiated.11, 86 Importantly, the metabolites of KP may act as pro- and antiinflammatory compounds. Genomic interventions aimed to eliminate IDO, TDO, or KMO were shown to alleviate the course of chronic inflammation, reduce viral replication, or change the expression of proinflammatory molecules.113 On the contrary, a number of kynurenines, including KYNA, emerged as antiinflammatory compounds.11, 113 KYNA was demonstrated to attenuate inflammation by several ways including the reduction in TNF expression, diminished interleukin-4 and α-defensin secretion, or inhibition of Th17 cell differentiation, at least in part through activation of GPR35.11 The interplay between immune activation and the KP activity results in a delicate balance, which may easily be shifted either to or away from neuroprotective KYNA (Figure 3).

Role of kynurenic acid in neurodegeneration. The interplay between astrocytes, microglia, and neurons in terms of the quantities of produced KYNA and other kynurenines can be altered by various genetically determined and postnatal factors, including inflammation. Deficiency of KYNA may enhance the GLU-mediated neurotransmission, reduce antioxidant capacity, and shift the kynurenine pathway toward neurotoxic metabolites, with ensuing neuronal loss

However, an excessive blockade of glutamate-mediated neurotransmission may impair cognition and memory processes.114-118 Thus, manipulations of the endogenous KYNA level may exert dual, conflicting effects—beneficial neuroprotection and unfavorable cognitive dysfunction. Considering the chronic nature of neurodegenerative disorders, neuroprotection seems to be essential, as it may slow the progress of disease. Maintaining adequate levels of brain KYNA seems vital to obtain neuroprotection without cognitive adverse effects. The optimal therapeutic intervention would include a region-selective increase in KYNA; however, such pharmacological tools are not available yet.

3 KYNA ALTERATIONS IN NEURODEGENERATIVE DISEASES 3.1 Huntington's disease

Huntington's disease (HD) is an autosomal dominant neurodegenerative disease. Clinically, it is characterized by a gradual deterioration of voluntary movements, appearance of chorea, cognitive decline, and complex psychiatric symptoms.119 Symptoms begin slowly, usually in the fourth decade of life, and lead ultimately to death within 15–20 years. The genetic background of disease is linked with an expansion of CAG trinucleotide repeats within exon 1 on chromosome 4, following a single mutation within the IT15 gene encoding huntingtin.120 Neurodegeneration affects primarily cerebral cortex and striatum, but as disease progresses, neuronal loss develops in multiple areas of the brain. Apart from the accumulation of huntingtin, the precise mechanisms leading to neurodegeneration and subsequent clinical symptoms are not fully elucidated. Aberrations in function of glial cells, inflammation, mitochondrial dysfunction, or oxidative stress were all implicated in the pathogenesis of HD.121-123

The potential role of aberrant tryptophan metabolism in the pathogenesis of neurodegenerative disorders has been postulated by Schwarcz and co-workers who discovered that intrastriatal application of excitotoxic KP metabolite, QUIN, results in neuropathological and behavioral alterations closely mimicking HD.124 Further support to this concept was provided by numerous research data, including studies on the experimental KYNA deficiency caused by the pharmacological tools, aminooxyacetic acid (AOAA), and 3-nitropropionic acid (3-NPA).96, 125, 126 AOAA, a non-selective aminotransferase inhibitor, potently diminishes synthesis of KYNA in vitro, with very low, micromolar IC50 values. When administered intrastriatally, AOAA produces a pattern of neurodegenerative and behavioral changes modeling HD and astonishingly resembling the outcome of intrastriatal application of QUIN.96 The axon-sparing excitotoxic neuronal loss is age-dependent, is susceptible to blockade with KYNA itself, and could be prevented by the ablation of corticostriatal glutamatergic input.96

Similarly, 3-NPA was shown to impair the synthesis of KYNA in rat cortical slices and to inhibit the activity of KAT I and KAT II.126 In vivo, 3-NPA decreased the number of KAT I immunopositive glial cells in the striatum (−3.57-fold) and temporal cortex (-twofold) of rats.127 Behavioral consequences of 3-NPA application in rodents are influenced by the mode of treatment. Acute application of 3-NPA evokes seizures, whereas chronic administration of low doses of 3-NPA results in a progressive locomotor deterioration and selective striatal degeneration resembling changes characteristic for HD.128-130 Susceptibility to the effects of 3-NPA increases with age; furthermore, 3-NPA and mutated huntingtin seem to share certain mechanisms of toxicity.131

Alterations in the metabolism of KP have also been demonstrated in genetic animal models of HD. In FVB/N mice with a mutation in the huntingtin gene, more than 10-fold increase of 3-HK level in the striatum and cortex was accompanied by a slight increase in KYNA levels and a considerable, 5.7-fold, increase in the 3-HK/KYNA ratio.132 A study in R6/2 mice, modeling HD, also demonstrated the increased activity of KMO (1.65-fold change in vmax value between 8-week-old wild-type and R6/2 animals) and decreased activity of kynureninase (−1.5- to −1.67-fold), resulting in an excessive enzymatic conversion of tryptophan to 3-HK.133

Data from human studies are in line with the experimental research, despite a clear limitation of postmortem analyses. Brain changes in KYNA content seem to be region-selective. Neostriatal KYNA level was reported as either decreased or unaltered, whereas cortical KYNA levels seem to increase, especially during the late stage of disease.34, 83, 134-136 Furthermore, an increase in frontocortical QUIN and 3-HK (both c. 2.5-fold) levels and a decrease in the KYNA/QUIN ratio (over −2.5-fold in neostriatum and over -twofold in frontal cortex) were detectable at stage 1 of HD. Qualitatively similar changes were observed in mice transgenic for the full-length mutant huntingtin.132, 137 In the advanced stages of HD, a reduction (−1.6-fold) in KYNA CSF levels was observed.136 In the periphery, the baseline L-kynurenine levels were higher in HD and the difference remained obvious despite tryptophan depletion or loading.138 Serum KYNA level in HD was not altered in comparison with control; however, the KYNA/L-kynurenine ratio was lower.138 In a cohort of patients at different stages of HD, the greatest increase in the L-kynurenine/tryptophan ratio and their overall concentrations was observed among patients possessing more CAG repeats or in those in the later stages of HD.139 These observations suggest that changes in the activity of KP, possibly leading to the excessive activity of the neurotoxic arm of the pathway, may have an impact on the development of HD.

In a prospective single-site controlled cohort study with standardized collection of CSF, blood, and phenotypic and imaging data, performed among 80 participants (20 healthy controls, 20 pre-manifest HD, and 40 manifest HD), the KP metabolites in CSF and plasma were stable over 6 weeks of observation.140 There were no differences regarding basal KYNA, L-kynurenine, or tryptophan levels. However, an increase in 3-HK/KYNA ratio was detected in the group of patients with evident HD compared with HD patients at early stage of disease.140

Pathologically, high levels of neurotoxic L-kynurenine metabolites accompanied by a relative lack of neuroprotective KYNA is a consistent finding in HD patients and in animal models of this disease. The deficiency of KYNA and malfunction of the neuroprotective arm of the KP may generate virtually identical consequences as an excessive production of QUIN and other neurotoxic kynurenines. In line with these observations, switching from the neurotoxic branch of the KP, yielding QUIN, to the neuroprotective branch producing KYNA was suggested to bring beneficial effects. Brain changes in KYNA and other KP metabolites can be considered the hallmarks of HD. The encouraging effects of KMO and TDO inhibition in HD models (vide paragraph 4.1.1) are the base for future clinical trials evaluating therapeutic potential of KMO inhibitors.

3.2 Parkinson's disease

Parkinson's disease (PD) is a common, progressive neurodegenerative disease, characterized by the gradual loss of dopaminergic brain neurons. Its most characteristic symptoms include resting tremor, limb rigidity, posture and gait instability, and bradykinesia. Loss of dopaminergic neurons in substantia nigra pars compacta and the appearance of intracytoplasmic proteinaceous inclusions, Lewy bodies, are characteristic morphological alterations.141 While 10 to 15% of cases represent the familial form of PD, the idiopathic form of disorder prevails.96 Disruptions in the ubiquitin-proteasome and autophagolysosomal pathways, mitochondrial dysfunction, excessive oxidative stress, and enhanced apoptosis were all implicated in the pathogenesis of PD.142 Furthermore, disturbed glutamate-mediated transmission and KYNA deficiency are also among important factors contributing to the development of PD. Neuroprotective and antiparkinsonian effect of glutamate receptor antagonists was demonstrated already 3 decades ago, using various experimental models.143, 144 In line with these observations, an increase in brain KYNA level, either through the direct application or through increased availability of L-kynurenine, effectively reduced neurodegeneration and behavioral symptoms in animal models of PD.

Canonical model of PD is based on the administration of lipophilic compound, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). In 1983, MPTP was discovered as contaminant of street heroin responsible for a rapid development of PD among young addicts.145, 146 This highly selective neurotoxin causing nigral degeneration, followed by a classical PD-like behavioral pattern in various species, including rodents and primates, quickly became a valuable research tool.146 The mechanisms underlying selective toxicity depend primarily on the glial conversion of MPTP to pyridinium metabolite (MPP+), which, upon release from astrocytes, inhibits neuronal mitochondrial respiratory chain and constitutes a source of free radicals.147 Interestingly, MPP+ was discovered to inhibit the cortical KAT activity and to reduce KYNA formation in vitro in rat cortical slices.126 The effect was confirmed in vivo, as MPTP decreased KYNA synthesis and the density of KAT I immunoreactive nigral neurons in mice.148, 149 Consistently, KYNA pretreatment was shown to reduce the apoptosis of neurons by downregulating Bax expression and maintaining mitochondrial function, in human neuroblastoma cell line exposed to MPP+.150

Human studies mostly demonstrate that in the brain of PD victims, the metabolism of tryptophan is shifted toward neurotoxic kynurenines with ensuing deficiency of KYNA. Postmortem studies reported diminished KYNA and L-kynurenine levels in frontal cortex, putamen, and substantia nigra, without change in tryptophan/L-kynurenine and L-kynurenine/KYNA ratios, in the brains of PD victims.151, 152 In caudate and precentral cortical gyrus, KYNA content did not differ from control values.80

In the periphery, the results are not consistent. In erythrocytes obtained from PD patients, higher levels of KYNA and enhanced activity of KAT II, but not of KAT I, were detected. In serum, KYNA level remained unchanged, while KAT I and KAT II activities were lower.153 Similarly, an increase in L-kynurenine/tryptophan ratio, depletion of plasma tryptophan level, and increase in L-kynurenine and KYNA were reported.154 Increase in serum KYNA was also observed among patients without dyskinesia, but not in dyskinetic PD patients.155

In contrast, the deficiency of KYNA was revealed in a metabolomic study performed on a larger cohort of PD patients. Findings included lower plasma KYNA/L-kynurenine ratio, higher QUIN level, and increased QUIN/KYNA ratio.156 Similarly, lower KYNA, higher QUIN, and an elevated QUIN/picolinic acid ratio in CSF, as well as high 3-HK in plasma, were detected.157

The above data suggest that deficient KYNA synthesis seems to be limited to the brain in the course of PD, whereas in the periphery, the direction of changes in the KP varies and may depend on the stage of disease and the presence of discrete inflammation. Future research should be aimed to analyze in detail the temporal dynamics of peripheral and central KYNA levels in PD. Prominent support to the concept of causal relationship between central KYNA deficiency and PD development comes from the studies utilizing pharmacological compounds to increase brain KYNA and indicating the beneficial effect of such approach in animal models (vide paragraph 4.1.2).

3.3 Alzheimer's disease

Alzheimer's disease (AD) is the major cause of age-related dementia among elderly population. This progressive neurodegenerative disorder leads inevitably to a severe deterioratio