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Kynurenine (KYN) is an intermediate in the pathway of the tryptophan (TRP) metabolism. This pathway is known to be responsible for nicotinamide adenine dinucleotide (NAD) and nicotinamide adenine dinucleotide phosphate (NADP) (Fig. 1). KYN is formed in the mammalian brain (40%) and is taken up from the periphery (60%). The rate of cerebral KYN synthesis was 0.29nmol/g/h (Gal and Sherman, 1978). In the brain, KYN can be converted to other components of the pathway: the neurotoxic 3-hydroxy-kynurenine (3-HK) or quinolinic acid (QUIN) and the neuroprotective kynurenic acid (KYNA).

Some 25 years ago it was found that intermediates of the kynurenine pathway (KP) have neuroactive properties: convulsions were appeared after mice received QUIN (Lapin, 1978). QUIN is a selective ligand of N-methyl-D-aspartate (NMDA) receptor (Stone and

Kynurenine Pathway
Fig. 1. The kynurenine pathway

Perkins, 1981), which can therefore cause neuronal damage (Schwarcz and Kohler, 1983; Schwarcz et al., 1984). It has similar neurotoxic effects to those of glutamate in the neocortex, striatum and hippocampus (Perkins and Stone, 1983).

It was hypothesized already in 1983 that QUIN plays an important role in Huntington's disease (Schwarcz et al., 1983). Three years later, it was proved that the injection of QUIN into the rat striatum duplicated the neurochemical features of this disorder (Beal et al., 1986).

Intrastriatal injection of QUIN induces a substantial neuronal loss, which is potentiated by the administration of 3-HK (Guidetti and Schwarcz, 1999). It produces early changes in the activity of the striatal neurons and movements of several cations, which may contribute to subsequent abnormalities in energy metabolism and to cell death (Bordelon et al., 1998).

The other important metabolite of KP is kynurenic acid (KYNA) which is one of the few known endogenous broad-spectrum antagonist of excitatory amino acid (EAA) receptors (Swartz et al., 1990), especially the NMDA receptors. KYNA behaves as a neuroprotective agent: it can inhibit the over-excitation of these receptors by binding the glycine allosteric site. Pharmacological studies have proved that KYNA is derived primarily from kynurenine aminotransferase II (KAT II) activity in most brain regions (Guidetti et al., 1997), which is located primarily in the glia (Du et al., 1992). Moreover, KYNA non-competitively blocks the activity of presynaptic a7-nicotinic acethylcholine

Table 1. Observations with kynurenine and related compounds in animal experiments

1947

The kynurenine pathway was recognized as a major route

(Beadle et al., 1947)

of tryptophan metabolism

1978

Convulsions were appeared after quinolinic acid injection

(Lapin, 1978)

into the brain of mice

40% of KYN is formed in the brain and 60% is taken up

(Gal and Sherman, 1978)

from the periphery

1981

Quinolinic acid is a selective ligand of N-methyl-D-aspartate

(Stone and Perkins, 1981)

(NMDA) receptor

1982

Kynurenic acid may be a neuroprotective agent

(Perkins and Stone, 1982)

1984

Seizures activity and lesions were found after intrahippocampal

(Schwarcz et al., 1984)

quinolinic acid injection

1987

Blockade of the excitatory amino acid receptors protects

(Clark and Rothman, 1987)

anoxic hippocampal slices

1988

7-Chloro-kynurenic acid is a selective ligand of the glycine

(Kemp et al., 1988)

site of NMDA receptors

The concentration of the kynurenic acid is 10-150 nM

(Moroni et al., 1988)

in the mammalian brain

1990

Kynurenine produces slight, but kynurenic acid marked

(Vecsei and Beal, 1990b)

behavioural changes in rats

1991

Kynurenine can cross easily via the blood-brain barrier

(Fukui et al., 1991)

by neutral amino acid carriers

Quinolinic acid produces toxic free radicals

(Rios and Santamaria, 1991)

1992

Kynurenine-aminotransferase (KAT) II is located primarily

(Du et al., 1992)

in the glia

1997

Kynurenic acid derives from KAT II activity in most brain

(Guidetti et al., 1997)

regions

2001

Kynurenic acid non-competitively block the activity

(Hilmas et al., 2001)

of a-nACh receptors

(nACh) receptors and can increase the expression of non-a7-nACh receptors (Hilmas et al., 2001). Cross-talk between KYNA and the nicotinic cholinergic system has been presumed to play a role in the patho-genesis of numerous brain disorders, including Alzheimer's disease and schizophrenia, in which brain KYNA levels are elevated and nicotinic functions are impaired (Alkondon et al., 2004).

Earlier observations are summarized in Table 1 concerning the kynurenine and its derivatives.

Changes in the absolute or relative concentration of KYNA or QUIN in the brain have been implicated in numerous neurological and psychiatric disorders, e.g. Parkinson's disease, Huntington's and Alzheimer's diseases, stroke, epilepsy, multiple sclerosis, depression and schizophrenia. Elevated QUIN level or decreased KYNA concentration causes impairment in the cellular energy metabolism by overexciting the glutamate receptors, in particular the NMDA receptors. Glutamate-mediated excitotoxic damage decreases the voltage-dependent Mg2+ blockade, causes abnormalities in cellular Ca2+ homeostasis and elevated production of reactive oxygen species (Greene and Greenamyre, 1996).

It is extremely important that the suitable prevention or correction of the KP's abnormality should be used which could attenuate the pathological processes.

There are at least two ways in which therapeutic agents are being developed with the aim of modulation of the KP.

One approach is to use analogues of KYNA as antagonists at glutamate receptors, because KYNA is able to pass the BBB only poorly that makes its use difficult. The aim here is to develop different analogues of KYNA, which can cross the BBB easily and display similar effectiveness on the affected receptors to that of KYNA. Some synthetic KYNA derivatives can behave as antagonists of NMDA receptors and provide an attractive strategy for the development of novel neuroprotective and anticonvulsive agents. 7-chloro-KYNA (7-Cl-KYNA) is a potent selective antagonist at the glycine site (Kemp et al., 1988), but its penetration through the BBB is poorly. Its prodrug, 4-chloro-KYN (Wu et al., 1997) readily enters the brain from the circulation and prevents QUIN-induced neurotoxicity in the rat hippocampus (Wu et al., 2000a) and striatum (Lee and Schwarcz, 2001) after systemic administration (Fig. 2). Furthermore, D-glucose or D-galactose esters of 7-chloro-

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