L-Kynurenine – Csn Chem

The L-kynurenine signalling pathway in trigeminal pain processing: A potential therapeutic target in migraine?

Song Guo1, L Vecsei2 and Messoud Ashina1

Abstract
Introduction: In recent years the kynurenine family of compounds, metabolites of tryptophan, has become an area of intensive research because of its neuroactive properties. Two metabolites of this family have become of interest in relation to migraine and pain processing.
Discussion: Experimental studies have shown that kynurenic acid (KYNA) plays an important role in the transmission of sensory impulses in the trigeminovascular system and that increased levels of KYNA decrease the sensitivity of the cerebral cortex to cortical spreading depression. Furthermore, another metabolite of the kynurenine family, L-kynurenine, exerts vasodilating effects similar to nitric oxide by increasing cyclic guanosine monophosphate.
Conclusion: This review summarizes current knowledge of the role of kynurenine signalling in trigeminal and central pain processing, including its therapeutic prospects in migraine treatment.

Keywords
Kynurenic acid, kynurenine, migraine, pain processing, trigeminal vascular system
Date received: 17 December 2010; revised: 23 February 2011; accepted: 24 February 2011

Introduction
The kynurenine family of compounds (kynurenines) are metabolites of the essential amino acid tryptophan (1). Kynurenines consist of L-kynurenine (L-KYN), kynurenic acid (KYNA), quinolinic acid, 3-hydroxyky- nurenine and anthranilic acid. In 1981, Stone and Perkins (2) reported that quinolinic acid may activate the subpopulation of neuronal glutamate receptors sen- sitive to N-methyl-D-aspartate (NMDA). Since then, around 4000 papers have been published on the inter- mediates of the kynurenine pathway and in particular on the role of KYNA because of its neuroprotective eﬀects by inhibiting glutamate release and neuronal transmission (3). In recent years there has been increas- ing interest in the role of KYNA in trigeminal pain

History
L-KYN has been recognized as a product of trypto- phan since 1931 (13), and in 1947 the kynurenine path- way was recognized as a major route of tryptophan metabolism (1). The whole kynurenine pathway and its metabolites were mapped for the ﬁrst time in 1969 (14). In 1981, Stone and Perkins (2) reported that qui- nolinic acid might activate NMDA-receptors and aﬀect neuronal transmission. A year later the neuro-inhibi- tory activities of KYNA were reported (3), and KYNA became an important focus of neurological research.

processing (4–7). Given the important role of the trigeminovascular system (8,9) and glutamate (10,11) in the pathophysiology of migraine, it would be plausible to suggest that the kynurenine pathway (see below, and Figure 1) (12) may be a new target for anti-migraine drugs. This review focuses primarily on the role of KYNA in nociception and in particular on the most recent ﬁndings in relation to trigeminal pain processing, and its therapeutic prospects in migraine treatment.

Figure 1. The kynurenine pathway. Reproduced by permission from reference (12).

The kynurenine pathway
L-KYN is a metabolite of the amino acid tryptophan. The tryptophan metabolic pathway leading to the syn- thesis of kynurenine (Figure 1) is the main route for non-protein metabolism of the essential amino acid tryptophan with nicotine adenine dinucleotide (NADþ) and NAD-phosphate (NADPþ) as end prod- ucts (15). About 80% of tryptophan metabolism is metabolized through the kynurenine pathway by the kynurenine aminotransferases (KATs) (16). Another important pathway of tryptophan metabolism is the serotonin pathway.
The ﬁrst step of the kynurenine pathway is engaged by two enzymes: tryptophan-2,3-dioxygenase and indo- leamine-2,3-dioxygenase (IDO), which diﬀer in their tissue localization and regulation. Tryptophan- 2,3-dioxygenase is predominantly expressed in the hepatic cells regulated by glucocorticoids (17), while IDO is distributed in peripheral tissues (lung, spleen, etc.) and the nervous system (neurons, glial cells, astro- cytes) (18–20) activated by proinﬂammatory cytokines (21–23).
L-KYN is converted from tryptophan by trypto- phan-2,3-dioxygenase/IDO and is the source for the synthesis of all the other metabolites (kynurenines) of the kynurenine pathway. In the brain, L-KYN can be converted to four metabolites: KYNA, quinolinic acid, 3-hydroxykynurenine and anthranilic acid. The synthe- sis of KYNA from L-KYN is catalysed in an irrevers- ible process by L-KYN aminotransferase, while quinolinic acid is produced indirectly from L-KYN catalysed by 3-hydroxy-ANA oxygenase in the last step of its synthesis (Figure 1). There are two types of L-KYN aminotransferases in the nervous system: KAT I and KAT II. KAT II is the one primarily responsible for the formation of KYNA in the brain (24).
There are several enzymes that take part in the cas- cade. Investigation of these enzymes may be of interest, because their modiﬁcation could shift L-KYN metabo- lism towards the excitotoxin quinolinic acid or the neu- roprotective KYNA, but so far no consistent patterns have emerged to identify speciﬁc functions of the cere- bral kynurenine pathway.

Distribution in the peripheral nervous system and central nervous system
L-KYN and its derivative KYNA are found in almost all organs and tissues of the human body because of the wide distribution of IDO (25), the crucial intracellular enzyme that engages the formation of L-KYN. At pre- sent there are, to our knowledge, no reports on L- KYN’s distribution in the peripheral nervous system (PNS) including the dorsal root ganglion or trigeminal ganglion. Approximately 40% of the L-KYN in the brain is synthesized there; the remainder is taken up from the periphery (60%). This indicates that L-KYN can be easily transported across the blood–brain barrier by the neutral amino acid carrier (26). In contrast to L- KYN, KYNA has only a very limited ability to cross the blood–brain barrier (26). However, experimental data suggest that peripheral treatment with L-KYN dose-dependently increases the concentration of KYNA in the brain (27). IDO has been shown to be distributed evenly throughout the brain (28). It is not normally expressed in cells but requires induction by IFN-g, tumour necrosis factor or lipopolysaccharides (22,23,29). During systemic inﬂammation, vascular endothelial cells are the primary site for IDO expression in vivo and induce formation of L-KYN (30). However, L-KYN can still be found widely in the brain under non-inﬂammatory conditions (25).
In the CNS, the metabolites of the kynurenine path- way, including L-KYN and KYNA, have been detected in macrophages, microglia cells, astrocytes and neurons (18–20). All the enzymes of the pathway are primarily contained in astrocytes and microglia cells (18,19,24). Interestingly, astrocytes seem not to contain kynure- nine 3-hydroxylase and therefore favour KYNA syn- thesis (Figure 1). In contrast, microglia cells have very little kynurenine aminotransferase activity (Figure 1) and therefore primarily form intermediates of the qui- nolinic acid branch of the pathway (20).
In summary, KYNA is produced primarily by astro- cytes and neurons in the CNS. Given that kynurenine metabolites are widely distributed in the brain, it is likely that KYNA is present in structures relevant for migraine such as the trigeminal nucleus caudalis, peri- aqueductal grey, nucleus raphe, thalamus and hypothalamus.

Receptors
L-KYN has been suggested to be an endothelium- derived vasodilator by activating the cGMP-dependent pathway, because of its ability to activate puriﬁed rat soluble guanylate cyclase and to increase tissue concen- trations of cGMP (31). Furthermore, data suggest that L-KYN also activates the cAMP pathway, as shown by its ability to increase the activity of adenylate cyclase and increase the cAMP content in porcine coronary arteries and in rat aortic smooth muscle cells (31,32). At present, it is unknown whether L-KYN per se exerts neuroprotective or neurotoxic eﬀects in the nervous system like its metabolites, which are known to exert notable neuroactive properties on the glutamate recep- tors, in particular on the NMDA receptors and alpha- amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) receptors (33).
The NMDA receptor is one of the major classes of ionotropic excitatory amino acid receptors. NMDA receptors require co-activation by two ligands, gluta- mate and glycine, and are known to play a crucial role in the development or maintenance of central sen- sitization, i.e. increased excitability of neurons in the CNS (34–37). KYNA is a neuroprotective agent, which acts on three diﬀerent receptors: the excitatory amino acid receptors (NMDA/AMPA), a7 nicotinic acetylcholine receptors and GPR35 receptors. KYNA is the only known endogenous NMDA receptor antag- onist, which in particular acts at the strychnine-insensi- tive glycine binding site of the NMDA receptor (Figure 2) (38). It also exerts a weak antagonistic eﬀect on the AMPA receptors (39). Experiments have shown that KYNA is a janus-faced compound that exerts diﬀerent eﬀects on the NMDA and AMPA receptors in high (micromolar) and low (nanomolar) concentrations. Thus, in vitro electrophysiological examinations on young rat hippocampus conﬁrmed that KYNA in micromolar concentrations exerts an inhibitory eﬀect (39,40). However, in nanomolar con- centrations, KYNA does not give rise to inhibition, but in fact facilitates the ﬁeld excitatory post-synaptic potentials. Based on these, it has been suggested that KYNA in the concentration range between a few hun- dred nanomolar and micromolar displays diﬀerent eﬀects (41).
KYNA also acts as a non-competitive blocker of the a7-nicotinic acetylcholine (a7-nACh) receptors (42). Data indicate that KYNA signiﬁcantly decreases extracellular glutamate levels in rat brain through its antagonist activity on a7-nACh receptors (43) and con- tributes to the inhibitory eﬀects of KYNA.
Recent studies have shown that KYNA is a ligand for the orphan G-protein-coupled receptor GPR35, evoking a speciﬁc rise in [Ca2þ]i in cells expressing human GPR35 (44), which is expressed by nociceptive neurons in the dorsal root ganglion (45). KYNA can inhibit the over-excitation of glutamatergic transmis- sion by modulating the activity of NMDA receptors and a7-nACh receptors. Interestingly, KYNA might have a role in stimulating the peripheral glutamate receptors as well (46).
In summary, L-KYN per se does not seem to have any direct neuroactive properties. It increases cAMP and cGMP through activation of adenylate cyclase and soluble guanylate cyclase in arteries. On the other hand, L-KYN may modulate neuro-inhibitory activi- ties indirectly through its derivative KYNA, which aﬀects the NMDA receptors and modulates glutamate levels in the CNS.

Peripheral and central pain processing
A growing body of evidence indicates that KYNA has a mediatory and modulatory role for glutamate and its receptors in peripheral and central pain processing (25,37,47,48). A recent study has demonstrated that KYNA inhibited forskolin-stimulated cAMP produc- tion by cultured rat dorsal root ganglion neurons (45). It has been reported that KYNA exerts an anti- nociceptive eﬀect by inactivating peripheral glutamate receptors and attenuating sensitization of cutaneous nociceptors (49,50). Furthermore, intraperitoneal administration of KYNA decreases the nociceptive behaviour in both the tail ﬂick and hot plate tests (51). Injection of glutamate into the rat masseter muscle in vivo, which increased muscle blood ﬂow by 250%, can be attenuated by KYNA (52). Given that injection of glutamate into the human masseter muscle evokes pain with increased blood ﬂow (53), it is possible that KYNA may have peripheral analgesic eﬀects medi- ated through inhibition of peripheral glutamate receptors.
Regarding the CNS, iontophoretic administration of KYNA to the spinal cord can markedly reduce the nociceptor response of the spinal cord neurons after cutaneous and muscular noxious stimulation (48). The nociceptive response was found by measuring the activ- ity of the wide dynamic range neurons in laminae IV–VI of the dorsal horn and the results suggest that NMDA receptors preferentially mediate transmission of nociceptive information originating in skin and muscle. Furthermore, intracisternal injection of KYNA may attenuate capsaicin and formalin-induced nociception in the rat (37,54). In addition, noxious acti- vation of the locus coeruleus neurons is blocked by intracerebroventricular injection of KYNA (34). The increase in KYNA in the locus coeruleus was obtained by a potent inhibitor of kynurenine 3-hydroxylase, which is able to dose-dependently increase the levels of KYNA in the brain. This treatment abolished the increase in ﬁring rate of locus coeruleus neurons. Another study (55) examined how blockade of the glu- tamatergic system by injection of L-KYN leading to a rise of KYNA within the periaqueductal grey modiﬁes the projection pathway of medial pre-optic nucleus of the hypothalamus to nucleus raphe magnus. It showed that the periaqueductal grey cell activity can be inhib- ited signiﬁcantly by the injection of L-KYN in the peri- aqueductal grey and modulates the neural transmission between the structures involved (55). Moreover, gluta- matergic stimulation of the nucleus raphe magnus could be abolished by KYNA administration (56).
Collectively, these data show that KYNA has an inhibitory eﬀect and can modulate neuronal transmis- sion in both the PNS and CNS.

The kynurenine pathway in trigeminal pain processing
Kynurenines may exert inhibitory and excitatory actions on both pre- and post-synaptic sites in the tri- geminovascular system (Figure 3). It has been shown that Schwann cell membranes surrounding nerve ﬁbres in the supratentorial dura mater display kynurenine aminotransferase-immunoreaction (57). Interestingly, stimulation of the trigeminal ganglion decreased the kynurenine aminotransferase immunoreaction consid- erably, probably due to decrease in the concentration of KYNA (57). At the same time, the Schwann cells in the dura mater became conspicuously swollen, while nitric oxide synthase of nerve ﬁbres in the dura mater increased, suggesting release of nitric oxide. The latter is known to be involved in NMDA receptor activation leading to vasodilatation followed by neurogenic inﬂammation (58).
Recent studies have suggested that KYNA plays an important role in the transmission of impulses in the trigeminal nucleus caudalis from the central terminals of the ﬁrst-order to second-order trigeminal neurons, the latter projecting to the thalamus (4–7). A rat model of trigeminovascular activation by electrical stimulation has shown that L-KYN, in combination with probenicid, is able to reduce c-fos activation in the trigeminal nucleus caudalis and to increase KYNA levels in the nucleus (7). Probenicid aids the transport of L-KYN over the blood–brain barrier, and inhibits the transport of organic acid from the cere- brospinal ﬂuid, thereby increasing the concentration of KYNA in the brain (4). Similar studies have also reported that KYNA could attenuate the nitrogly- cerin-induced neuronal nitric oxide synthase, calmodu- lin-dependent protein kinase II alpha (CamKIIa) and CGRP immune-reactivity in the rat trigeminal nucleus caudalis (6). The most likely explanation is that KYNA blocked the activation of ﬁrst-order neurons and the consecutive release of CGRP and nitric oxide from the nerve endings (6). In the rat, nitroglycerin activates second-order neurons in the trigeminal nucleus cauda- lis, and increases the expression of neuronal nitric oxide synthase and CamKIIa, and induces CGRP release (5,59).
In addition to the peripheral eﬀects, KYNA may also act at the central level. Intrathecal injection of KYNA produces dose-dependent and reversible anal- gesic eﬀects in the hot plate, tail ﬂick and formalin tests of nociception in mice and in rats (37,60,61). Furthermore, KYNA exerts a modulating eﬀect by inhibiting the neural activity on brain stem structures such as the locus coeruleus, periaqueductal grey and nucleus raphe magnus (34,55,56,62).
Cortical spreading depression (CSD), an event believed to underlie visual aura in migraine, may acti- vate and sensitize trigeminal nociceptors in animal models of migraine (63–65). CSD increases the level of KYNA in the rat cortex (66). The increase of KYNA after CSD is possibly a neuroprotective response. Injection of probenicid probably produces a much greater increase in KYNA concentration in the CNS. Moreover, administration of probenicid via microdialysis showed a marked decrease in CSD in the rat striatum, possibly by increasing the brain KYNA concentration (67).
Taken together, these data suggest that KYNA may play an important role in trigeminal pain processing.

A potential therapeutic target in migraine?
The pathophysiological mechanisms underlying migraine pain include abnormal processing in trigemi- nal nociceptors in the dura mater and deep brain struc- tures including the trigeminal nucleus caudalis, periaqueductal grey and thalamus (68,69). Provocation studies in migraine suﬀerers using intrave- nous administration of vasoactive substances such as the nitric oxide donor glyceryl trinitrate and CGRP have identiﬁed two major signalling pathways in migraine pathogenesis: nitric oxide-cGMP (70,71) and CGRP-cAMP (72,73). In addition, 5-HT1B/1D agonists still represent the gold standard for the treatment of migraine attacks. The question is whether the kynure- nine pathway interacts with cGMP, cAMP and seroto- nin signalling relevant for migraine and whether the modulation of kynurenine signalling may provide a novel target for migraine prevention.
Recent data indicate that L-KYN has vasodilating eﬀects like nitric oxide, and also activates the cGMP- dependent pathway (74). Intravenous infusion of L-KYN decreases mean arterial blood pressure of hypertensive rats in a dose-dependent manner and relaxes constricted arteries (31). L-KYN increases both cGMP and cAMP concentrations during inﬂam- mation, because of induced activation of IDO (Figure 4) (31). L-KYN stimulates the activities of soluble gua- nylyl cyclase and adenylyl cyclase in smooth muscle cells from porcine coronary arteries (31). The ﬁnding that L-KYN stimulates mainly the haem-free form of soluble guanylyl cyclase is interesting, because normally nitric oxide leads to an increase in soluble guanylyl cyclase activity which, in turn, catalyses the conversion of guanosine triphosphate to cGMP and pyrophos- phate (32). However under inﬂammatory conditions, soluble guanylyl cyclase is oxidized to become a haem-free enzyme that is refractory to activation by nitric oxide (31,32). Thus, L-KYN can stimulate this inactive soluble guanylyl cyclase to produce cGMP. Furthermore, intravenous infusion of L-tryptophan dilates coronary arteries and produces an increase in the regional cerebral blood ﬂow (75). However the dilating eﬀect of tryptophan requires the presence of active IDO and an intact endothelium, whereas the eﬀect of kynurenine was endothelium-independent (31). These ﬁndings suggest that L-KYN might be the vasoactive metabolite of tryptophan, but the study cannot exclude the possibility that a kynurenine deriv- ative present in the preparation of kynurenine was in fact responsible for some of the activities observed. Nonetheless, the kynurenine is able to activate the cGMP and cAMP pathways, which are important sig- nalling pathways in migraine.
The formation of the L-KYN seems directly propor- tional to tryptophan concentrations (76). Tryptophan has been used both experimentally and therapeutically as a mean of increasing tryptophan conversion to serotonin (77). Interestingly, it has been shown that the activation of IDO shifts tryptophan metabolism from serotonin synthesis to formation of the kynurenines (78). The formation of L-KYN, which competes for cerebral transport and cellular uptake with L-trypto- phan, may actually decrease the production of cerebral serotonin (76). Low cerebral serotonin levels have been implicated in the pathophysiology of migraine (79,80). Based on these data it would be plausible to suggest that L-KYN may have a notable role in the pathogenesis of migraine because of its vasodilating properties similar to nitric oxide, by activating the cGMP pathway and its presumed ability to aﬀect the cAMP and serotonin path- ways as well. Development of drugs that inhibit the eﬀect of IDO or L-KYN on soluble guanylyl cyclase or serotonin pathways might therefore be a target of further migraine research and drug development.
Another way to modulate the kynurenine pathway is to raise the concentration of the neuroprotective KYNA in the brain. As an endogenous NMDA recep- tor antagonist and acting at the strychnine-insensitive glycine binding (38), KYNA exerts an antinociceptive action in the trigeminovascular system (81,82). Furthermore, increased levels of KYNA decrease the sensitivity of the cerebral cortex to CSD (83). These data suggest that KYNA could be a possible candidate for the treatment of migraine with and without aura.

Conclusion
Growing evidence suggests that the metabolites of the kynurenine pathway may play a crucial role in the mod- ulation of pain processing both peripherally and cen- trally. Animal studies have shown that elevating levels of KYNA by inhibiting the glycine co-agonist site of the NMDA receptors in the brain may modify or inhi- bit nociceptive transmission and reduce extracellular glutamate. A proof of concept study on the eﬀect of a metabotropic glutamate receptor 5 (MGluR5) antago- nist in the treatment of migraine attacks (88) supports the involvement of glutamate and NMDA receptors in migraine pathogenesis. MGluR5 increases NMDA receptor activity, thus eﬀects on this receptor alter the activity of the ionotropic receptors (89). KYNA is involved in sensory processing in the PNS and CNS, including in migraine-relevant structures such as the trigeminal nucleus caudalis, periaqueductal grey and locus coerulus. L-KYN exerts vasodilating eﬀects sim- ilar to nitric oxide by increasing cGMP, which is an integral part of migraine pathogenesis. Furthermore, L-KYN also modulates the cAMP and serotonin path- ways. Collectively, drugs interacting on the kynurenine pathway may provide a novel target for migraine prevention.

Acknowledgements
The authors thank Professor Jes Olesen for reading the manuscript and giving valuable comments.

Funding
This work was supported by The Lundbeck Foundation Center for Neurovascular Signaling (LUCENS).

Conflict of interest
None in relation to this paper.

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