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Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients
Neuroscience Letters 331 (2002) 63–65 www.elsevier.com/locate/neulet
Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients Konrad Rejdak a,*, Halina Bartosik-Psujek a, Beata Dobosz a, Tomasz Kocki b,c, Pawel⁄ Grieb d, Gavin Giovannoni e, Waldemar A. Turski b,c, Zbigniew Stelmasiak a a
Department of Neurology, Medical University, 8 Jaczewskiego Street, 20-090 Lublin, Poland Department of Pharmacology, Medical University, 8 Jaczewskiego Strasse, 20-090 Lublin, Poland c Department of Toxicology, Institute of Agricultural Medicine, Lublin, Poland d Laboratory of Experimental Pharmacology, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland e Neuroimmunology Unit, Institute of Neurology, London, UK b
Received 18 February 2002; received in revised form 4 June 2002; accepted 14 June 2002
Abstract The present study was undertaken to measure cerebrospinal fluid (CSF) levels of kynurenic acid (KYNA) in patients with relapsing-onset multiple sclerosis (MS) during remission or not progressing for at least 2 months. In these patients the levels of CSF KYNA were found to be significantly lower compared with subjects with non-inflammatory neurological diseases, as well as those with inflammatory disease (median (interquartile range): 0.41 (0.3–0.5) pmol/ml, n ¼ 26 vs. 0.67 (0.5–1.1), n ¼ 23, P , 0:01 and 1.7 (1.5–2.6), n ¼ 16, P , 0:001, respectively). These results provide further evidence of the alterations in the kynurenine pathway during remitting-onset MS. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Kynurenic acid; Cerebrospinal fluid; Multiple sclerosis; Human
Metabolites of the kynurenine pathway are implicated in a number of pathological conditions within the central nervous system including excitotoxicity, epilepsy and inflammation. Quinolinic acid and 3-hydroxykynurenine, which are neurotoxic, may be involved in brain tissue damage, whereas kynurenic acid (KYNA), an intermediate metabolite of l-kynurenine and a broad-spectrum excitatory amino acid antagonist, may act as an endogenous neuroprotectant [13]. Some recent data indicate that the brain kynurenine pathway is altered in multiple sclerosis (MS), although the evidence seems contradictory. According to Kepplinger et al. [9], cerebrospinal fluid (CSF) KYNA levels are increased in MS patients during relapse, whereas Baran et al. [2] have found that activities of KYNA-synthesizing kynurenine aminotransferases (KAT I and KAT II) in post-mortem MS-affected brains are low. The issue may be of importance, because metabolites of the kynurenine pathway have the potential to participate in the pathogenesis of
* Corresponding author. Tel.: 148-81-7425420; fax: 148-817425420. E-mail address: [email protected] (K. Rejdak).
MS. Cammer [4] has provided evidence that quinolinic acid may induce apoptotic death of oligodendrocytes, which on the other hand is a hallmark of irreversible demyelination in MS. Chiarugi et al. [5] have demonstrated increased expression and activity of kynurenine 3-monooxygenase and accumulation of neurotoxic kynurenine metabolites in the spinal cord of rats with experimental allergic encephalomyelitis, which may be considered as an animal model of MS. The aim of present study was to assay the CSF levels of KYNA in stable relapse-onset MS patients. The group consisted of 26 patients with clinically definite relapse-onset MS (20 with relapsing-remitting (RR-MS) and six with secondary-progressive (SP-MS) disease). The mean disease duration was 6 ^ 3 years and the mean expanded disability status scale (EDSS) was 3.5 ^ 1.5. All these patients were positive for oligoclonal bands in CSF (measured according to a consensus method [1]), and none had received any immunomodulatory or immunosuppressive treatment within .2 preceding months. Prior to CSF sampling, each patient underwent neurological examination and the disability level was scored according to the Kurtzke’s EDSS.
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 2) 00 71 0- 3
64
K. Rejdak et al. / Neuroscience Letters 331 (2002) 63–65
For comparison, the level of CSF KYNA was measured in 16 patients with infectious inflammatory disease (ID), i.e. with clinical and CSF findings supportive of lymphocytic (viral) meningitis (ID) and in 23 patients with various noninflammatory neurological disorders (OND). The latter group consisted of 15 patients with transient, non-specific neurological symptoms without abnormalities in magnetic resonance imaging or CSF examination, three were diagnosed as having idiopathic polyneuropathy, and five had spondylotic myelopathy. The study was approved by local Ethical Committee. CSF samples were collected by lumbar puncture, immediately (within 1 h) centrifuged, aliquoted, frozen and stored at 280 8C. KYNA was assayed by a serial ion-exchange and high-performance liquid chromatography (HPLC) method described by Turski et al. [14] using HPLCpurity reagents purchased from Baker (USA). Briefly, CSF was deproteinized by 3% perchloric acid and centrifuged (5 min, 3000 revs./min). The supernatant was diluted (1:1) with 0.2 N HCl and applied to a Dowex 50-W ion-exchange column pre-washed with 0.1 N HCl. KYNA was eluted with 2 ml of water and quantitated by HPLC with a fluorometric detector. The method provides 97% intra-assay and 95% inter-assay coefficient of variance. Parallel CSF aliquots were used for routine analyses (glucose, total protein, and cell count). Samples contaminated with blood (red blood count, .10/ml) were excluded. To assess the statistical significance of differences between the groups, non-parametric Kruskall–Wallis analysis of variance was used, followed by Tukey–Kramer posthoc analysis. Correlations were assessed by the method of Spearman. Statistical tests were performed using the GraphPad InStat 3.05 software package. There were no significant differences in age (OND: 44 ^ 16; MS: 31 ^ 10; ID: 39 ^ 11) and female/male ratios between the groups (OND: 1.6; MS: 1.5; ID: 1.6). The results of routine assays were within a normal range, except for an increased leukocyte count in ID patients (528 ^ 120 SD cells/ml). There was a significant difference in CSF KYNA levels between the groups (main effect P , 0:0001). Post-hoc inter-group comparisons revealed that the levels of KYNA were lower in MS (median (interquartile range): 0.41 (0.3–0.5) pmol/ml) than those in either OND (0.67 (0.5–1.1); P , 0:01) or ID patients (1.7 (1.5– 2.6); P , 0:001; Fig. 1). In the sub-group analysis, the results for RR-MS patients (median (interquartile range): 0.39 (0.3–0.5) pmol/ml) did not differ from those for SPMS subjects (0.5 (0.4–0.6)), and RR-MS patients had lower CSF KYNA compared with either OND (P , 0:01) or ID patients (P , 0:001). CSF KYNA of SP-MS patients was lower than that of ID patients (P , 0:01), but it did not differ from the results in the OND group (P ¼ 0:1). KYNA concentration in MS patients did not correlate with either the disease duration or EDSS disability score. In the ID group, there was no correlation between CSF cell count and CSF KYNA level. Our observation that MS patients have lowered CSF
Fig. 1. Combined scatter and box and whisker plot of CSF KYNA levels in other neurological disease (OND), MS and ID patients. The box represents the 25th–75th percentile divided horizontally by the median, the whiskers, the range, and the adjacent scatter plot the individual values from which the box and whiskers are derived. **P , 0:01 vs. OND; ^^^P , 0:001 vs. MS.
KYNA levels [11] seems to correspond with the finding of Baran et al. [2] that activities of KYNA-synthesizing enzymes are low in post-mortem MS-affected brains. However, it is the opposite to those of Kepplinger et al. [9] who have found increased levels of KYNA in the CSF of MS patients. The explanation may be that in the latter study, CSF samples were taken during relapses, while in our study CSF was sampled during clinical remissions. Activated lymphocytes, macrophages and microglia are abundant in acute MS lesions. These cells are able to catabolize tryptophan through the kynurenine pathway [6]. Since the burden of acute lesions correlates positively with clinical exacerbations (relapses), intracerebral metabolic activity of these cells may increase the KYNA CSF level only during MS relapses. We have also found, in agreement with the previous studies [7], that CSF KYNA is markedly increased in acute viral meningitis. However, the exact source of excessive KYNA in these patients remains unclear, since we did not find a correlation between KYNA levels and the CSF leukocyte count. This implies the passage of peripheral or systemic KYNA into the CSF. Concerning the mechanism of the altered CSF KYNA level in remitting-onset MS and its possible role in the pathophysiology of this disease, two hypotheses may be proposed. First, the increased KYNA level observed during MS relapses [9] may reflect activation of endogenous defence against glutamate toxicity and contribute to the induction of remissions or slowing disease progression. Glutamate-mediated neuronal damage has been described in an animal model of autoimmune demyelination [12]. In MS patients, no significant changes in CSF levels of glutamate were found [10], but excessive local
K. Rejdak et al. / Neuroscience Letters 331 (2002) 63–65
glutamate release during the inflammatory process within nervous tissue cannot be excluded [16]. Glutamate, however, has been shown to be a potent inhibitor of KYNA synthesis in rat cortical and spinal slices [15]. Therefore, increased extracellular concentration of glutamate may rather be expected to inhibit the production of KYNA. Second, a more plausible explanation of the observed alterations in the CSF KYNA level during remitting-onset MS may be related to the diminished global brain glucose metabolic uptake in this disease [3]. Hodgkins and Schwarcz [8] have demonstrated that KYNA synthesis is critically affected by the limited availability of pyruvate or other 2oxoacids which serve as co-substrates for the enzymatic transamination of l-kynurenine, the immediate precursor of KYNA. Since glucose catabolism is the main source of pyruvate in the brain, it is possible that during periods of disease inactivity, the rate of KYNA synthesis in the MSaffected brain is limited by pyruvate availability. During periods of disease inactivity, this effect results in the lowering of KYNA in CSF. However, during relapses, the effect of intrathecal KYNA production by activated leukocytes and microglia infiltrating acute MS lesions prevails and the level of KYNA in CSF is increased. In conclusion, the present results provide additional evidence for the altered levels of CSF KYNA in MS, namely for its decrease during remissions or periods of disease inactivity. Further studies of the dynamics of KYNA changes in the course of remitting-onset MS and their relation to the other tryptophan metabolites are indicated. [1] Andersson, M., Alvarez-Cermeno, J., Bernardi, G., Cogato, I., Fredman, P., Frederiksen, J., Fredrikson, S., Gallo, P., Grimaldi, L.M., Gronning, M., Keir, G., Lamers, K., Link, H., Magalhaes, A., Massaro, A.R., Ohman, S., Reiber, H., Ronnback, L., Schluep, M., Schuller, E., Sindic, C.J.M., Thompson, E.J., Trojano, M. and Wurster, U., Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report, J. Neurol. Neurosurg. Psychiatry, 57 (1994) 897–902. [2] Baran, H., Kepplinger, B., Newcombe, J., Stolze, K., Kainz, A. and Nohl, H., Lowered kynurenine aminotransferase activities in CNS of MS patients. Society for Neuroscience 30th Annual Meeting Abstracts, 2000, p. 1302. [3] Blinkenberg, M., Rune, K., Jensen, C.V., Ravnborg, M., Kyllingsbaek, S., Holm, S., Paulson, O.B. and Sorensen, P.S., Cortical cerebral metabolism correlates with MRI
[4] [5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
65
lesion load and cognitive dysfunction in MS, Neurology, 54 (2000) 558–564. Cammer, W., Oligodendrocyte killing by quinolinic acid in vitro, Brain Res., 30 (2001) 157–160. Chiarugi, A., Cozzi, A., Ballerini, C., Massacesi, L. and Moroni, F., Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis, Neuroscience, 102 (2001) 687–695. Heyes, M.P., Chen, C.Y., Major, E.O. and Saito, K., Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types, Biochem. J., 326 (1997) 351–356. Heyes, M.P., Saito, K., Major, E.O., Milstien, S., Markey, S.P. and Vickers, J.H., A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from l-tryptophan by 6-chlorotryptophan and 4chloro-3-hydroxyanthranilate, Brain, 116 (1993) 1425–1450. Hodgkins, P.S. and Schwarcz, R., Metabolic control of kynurenic acid formation in the rat brain, Dev. Neurosci., 20 (1998) 408–416. Kepplinger, B., Baran, H., Kainz, A., Newcombe, J. and Nohl, H., Altered kynurenic acid levels in CSF and serum of patients with multiple sclerosis. ECTRIMS’2001 Abstracts, Mult. Scler., 7 (Suppl. 1) (2001) S118. Klivenyi, P., Kekesi, K., Juhasz, G. and Vecsei, L., Amino acid concentrations in cerebrospinal fluid of patients with multiple sclerosis, Acta Neurol. Scand., 95 (1997) 96–98. Rejdak, K., Kocki, T., Dobosz, B., Turski, W.A. and Stelmasiak, Z., Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-remitting multiple sclerosis patients. ECTRIMS’2001 Abstracts, Mult. Scler., 7 (Suppl. 1) (2001) S118. Smith, T., Groom, A., Zhu, B. and Turski, L., Autoimmune encephalomyelitis ameliorated by AMPA antagonists, Nat. Med., 6 (2000) 62–66. Stone, T.W., Kynurenines in the CNS: from endogenous obscurity to therapeutic importance, Prog. Neurobiol., 64 (2001) 185–218. Turski, W.A., Nakamura, M., Todd, W.P., Carpenter, B.K., Whetsell Jr., W.O. and Schwarcz, R., Identification and quantification of kynurenic acid in human brain tissue, Brain Res., 454 (1988) 164–169. Urbanska, E.M., Chmielewski, M., Kocki, T. and Turski, W.A., Formation of endogenous glutamatergic receptors antagonist kynurenic acid—differences between cortical and spinal cord slices, Brain Res., 878 (2000) 210–212. Werner, P., Pitt, D. and Raine, C.S., Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage, Ann. Neurol., 50 (2001) 169–180.
Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-onset multiple sclerosis patients Konrad Rejdak a,*, Halina Bartosik-Psujek a, Beata Dobosz a, Tomasz Kocki b,c, Pawel⁄ Grieb d, Gavin Giovannoni e, Waldemar A. Turski b,c, Zbigniew Stelmasiak a a
Department of Neurology, Medical University, 8 Jaczewskiego Street, 20-090 Lublin, Poland Department of Pharmacology, Medical University, 8 Jaczewskiego Strasse, 20-090 Lublin, Poland c Department of Toxicology, Institute of Agricultural Medicine, Lublin, Poland d Laboratory of Experimental Pharmacology, Medical Research Center, Polish Academy of Sciences, Warsaw, Poland e Neuroimmunology Unit, Institute of Neurology, London, UK b
Received 18 February 2002; received in revised form 4 June 2002; accepted 14 June 2002
Abstract The present study was undertaken to measure cerebrospinal fluid (CSF) levels of kynurenic acid (KYNA) in patients with relapsing-onset multiple sclerosis (MS) during remission or not progressing for at least 2 months. In these patients the levels of CSF KYNA were found to be significantly lower compared with subjects with non-inflammatory neurological diseases, as well as those with inflammatory disease (median (interquartile range): 0.41 (0.3–0.5) pmol/ml, n ¼ 26 vs. 0.67 (0.5–1.1), n ¼ 23, P , 0:01 and 1.7 (1.5–2.6), n ¼ 16, P , 0:001, respectively). These results provide further evidence of the alterations in the kynurenine pathway during remitting-onset MS. q 2002 Elsevier Science Ireland Ltd. All rights reserved. Keywords: Kynurenic acid; Cerebrospinal fluid; Multiple sclerosis; Human
Metabolites of the kynurenine pathway are implicated in a number of pathological conditions within the central nervous system including excitotoxicity, epilepsy and inflammation. Quinolinic acid and 3-hydroxykynurenine, which are neurotoxic, may be involved in brain tissue damage, whereas kynurenic acid (KYNA), an intermediate metabolite of l-kynurenine and a broad-spectrum excitatory amino acid antagonist, may act as an endogenous neuroprotectant [13]. Some recent data indicate that the brain kynurenine pathway is altered in multiple sclerosis (MS), although the evidence seems contradictory. According to Kepplinger et al. [9], cerebrospinal fluid (CSF) KYNA levels are increased in MS patients during relapse, whereas Baran et al. [2] have found that activities of KYNA-synthesizing kynurenine aminotransferases (KAT I and KAT II) in post-mortem MS-affected brains are low. The issue may be of importance, because metabolites of the kynurenine pathway have the potential to participate in the pathogenesis of
* Corresponding author. Tel.: 148-81-7425420; fax: 148-817425420. E-mail address: [email protected] (K. Rejdak).
MS. Cammer [4] has provided evidence that quinolinic acid may induce apoptotic death of oligodendrocytes, which on the other hand is a hallmark of irreversible demyelination in MS. Chiarugi et al. [5] have demonstrated increased expression and activity of kynurenine 3-monooxygenase and accumulation of neurotoxic kynurenine metabolites in the spinal cord of rats with experimental allergic encephalomyelitis, which may be considered as an animal model of MS. The aim of present study was to assay the CSF levels of KYNA in stable relapse-onset MS patients. The group consisted of 26 patients with clinically definite relapse-onset MS (20 with relapsing-remitting (RR-MS) and six with secondary-progressive (SP-MS) disease). The mean disease duration was 6 ^ 3 years and the mean expanded disability status scale (EDSS) was 3.5 ^ 1.5. All these patients were positive for oligoclonal bands in CSF (measured according to a consensus method [1]), and none had received any immunomodulatory or immunosuppressive treatment within .2 preceding months. Prior to CSF sampling, each patient underwent neurological examination and the disability level was scored according to the Kurtzke’s EDSS.
0304-3940/02/$ - see front matter q 2002 Elsevier Science Ireland Ltd. All rights reserved. PII: S03 04 - 394 0( 0 2) 00 71 0- 3
64
K. Rejdak et al. / Neuroscience Letters 331 (2002) 63–65
For comparison, the level of CSF KYNA was measured in 16 patients with infectious inflammatory disease (ID), i.e. with clinical and CSF findings supportive of lymphocytic (viral) meningitis (ID) and in 23 patients with various noninflammatory neurological disorders (OND). The latter group consisted of 15 patients with transient, non-specific neurological symptoms without abnormalities in magnetic resonance imaging or CSF examination, three were diagnosed as having idiopathic polyneuropathy, and five had spondylotic myelopathy. The study was approved by local Ethical Committee. CSF samples were collected by lumbar puncture, immediately (within 1 h) centrifuged, aliquoted, frozen and stored at 280 8C. KYNA was assayed by a serial ion-exchange and high-performance liquid chromatography (HPLC) method described by Turski et al. [14] using HPLCpurity reagents purchased from Baker (USA). Briefly, CSF was deproteinized by 3% perchloric acid and centrifuged (5 min, 3000 revs./min). The supernatant was diluted (1:1) with 0.2 N HCl and applied to a Dowex 50-W ion-exchange column pre-washed with 0.1 N HCl. KYNA was eluted with 2 ml of water and quantitated by HPLC with a fluorometric detector. The method provides 97% intra-assay and 95% inter-assay coefficient of variance. Parallel CSF aliquots were used for routine analyses (glucose, total protein, and cell count). Samples contaminated with blood (red blood count, .10/ml) were excluded. To assess the statistical significance of differences between the groups, non-parametric Kruskall–Wallis analysis of variance was used, followed by Tukey–Kramer posthoc analysis. Correlations were assessed by the method of Spearman. Statistical tests were performed using the GraphPad InStat 3.05 software package. There were no significant differences in age (OND: 44 ^ 16; MS: 31 ^ 10; ID: 39 ^ 11) and female/male ratios between the groups (OND: 1.6; MS: 1.5; ID: 1.6). The results of routine assays were within a normal range, except for an increased leukocyte count in ID patients (528 ^ 120 SD cells/ml). There was a significant difference in CSF KYNA levels between the groups (main effect P , 0:0001). Post-hoc inter-group comparisons revealed that the levels of KYNA were lower in MS (median (interquartile range): 0.41 (0.3–0.5) pmol/ml) than those in either OND (0.67 (0.5–1.1); P , 0:01) or ID patients (1.7 (1.5– 2.6); P , 0:001; Fig. 1). In the sub-group analysis, the results for RR-MS patients (median (interquartile range): 0.39 (0.3–0.5) pmol/ml) did not differ from those for SPMS subjects (0.5 (0.4–0.6)), and RR-MS patients had lower CSF KYNA compared with either OND (P , 0:01) or ID patients (P , 0:001). CSF KYNA of SP-MS patients was lower than that of ID patients (P , 0:01), but it did not differ from the results in the OND group (P ¼ 0:1). KYNA concentration in MS patients did not correlate with either the disease duration or EDSS disability score. In the ID group, there was no correlation between CSF cell count and CSF KYNA level. Our observation that MS patients have lowered CSF
Fig. 1. Combined scatter and box and whisker plot of CSF KYNA levels in other neurological disease (OND), MS and ID patients. The box represents the 25th–75th percentile divided horizontally by the median, the whiskers, the range, and the adjacent scatter plot the individual values from which the box and whiskers are derived. **P , 0:01 vs. OND; ^^^P , 0:001 vs. MS.
KYNA levels [11] seems to correspond with the finding of Baran et al. [2] that activities of KYNA-synthesizing enzymes are low in post-mortem MS-affected brains. However, it is the opposite to those of Kepplinger et al. [9] who have found increased levels of KYNA in the CSF of MS patients. The explanation may be that in the latter study, CSF samples were taken during relapses, while in our study CSF was sampled during clinical remissions. Activated lymphocytes, macrophages and microglia are abundant in acute MS lesions. These cells are able to catabolize tryptophan through the kynurenine pathway [6]. Since the burden of acute lesions correlates positively with clinical exacerbations (relapses), intracerebral metabolic activity of these cells may increase the KYNA CSF level only during MS relapses. We have also found, in agreement with the previous studies [7], that CSF KYNA is markedly increased in acute viral meningitis. However, the exact source of excessive KYNA in these patients remains unclear, since we did not find a correlation between KYNA levels and the CSF leukocyte count. This implies the passage of peripheral or systemic KYNA into the CSF. Concerning the mechanism of the altered CSF KYNA level in remitting-onset MS and its possible role in the pathophysiology of this disease, two hypotheses may be proposed. First, the increased KYNA level observed during MS relapses [9] may reflect activation of endogenous defence against glutamate toxicity and contribute to the induction of remissions or slowing disease progression. Glutamate-mediated neuronal damage has been described in an animal model of autoimmune demyelination [12]. In MS patients, no significant changes in CSF levels of glutamate were found [10], but excessive local
K. Rejdak et al. / Neuroscience Letters 331 (2002) 63–65
glutamate release during the inflammatory process within nervous tissue cannot be excluded [16]. Glutamate, however, has been shown to be a potent inhibitor of KYNA synthesis in rat cortical and spinal slices [15]. Therefore, increased extracellular concentration of glutamate may rather be expected to inhibit the production of KYNA. Second, a more plausible explanation of the observed alterations in the CSF KYNA level during remitting-onset MS may be related to the diminished global brain glucose metabolic uptake in this disease [3]. Hodgkins and Schwarcz [8] have demonstrated that KYNA synthesis is critically affected by the limited availability of pyruvate or other 2oxoacids which serve as co-substrates for the enzymatic transamination of l-kynurenine, the immediate precursor of KYNA. Since glucose catabolism is the main source of pyruvate in the brain, it is possible that during periods of disease inactivity, the rate of KYNA synthesis in the MSaffected brain is limited by pyruvate availability. During periods of disease inactivity, this effect results in the lowering of KYNA in CSF. However, during relapses, the effect of intrathecal KYNA production by activated leukocytes and microglia infiltrating acute MS lesions prevails and the level of KYNA in CSF is increased. In conclusion, the present results provide additional evidence for the altered levels of CSF KYNA in MS, namely for its decrease during remissions or periods of disease inactivity. Further studies of the dynamics of KYNA changes in the course of remitting-onset MS and their relation to the other tryptophan metabolites are indicated. [1] Andersson, M., Alvarez-Cermeno, J., Bernardi, G., Cogato, I., Fredman, P., Frederiksen, J., Fredrikson, S., Gallo, P., Grimaldi, L.M., Gronning, M., Keir, G., Lamers, K., Link, H., Magalhaes, A., Massaro, A.R., Ohman, S., Reiber, H., Ronnback, L., Schluep, M., Schuller, E., Sindic, C.J.M., Thompson, E.J., Trojano, M. and Wurster, U., Cerebrospinal fluid in the diagnosis of multiple sclerosis: a consensus report, J. Neurol. Neurosurg. Psychiatry, 57 (1994) 897–902. [2] Baran, H., Kepplinger, B., Newcombe, J., Stolze, K., Kainz, A. and Nohl, H., Lowered kynurenine aminotransferase activities in CNS of MS patients. Society for Neuroscience 30th Annual Meeting Abstracts, 2000, p. 1302. [3] Blinkenberg, M., Rune, K., Jensen, C.V., Ravnborg, M., Kyllingsbaek, S., Holm, S., Paulson, O.B. and Sorensen, P.S., Cortical cerebral metabolism correlates with MRI
[4] [5]
[6]
[7]
[8]
[9]
[10]
[11]
[12]
[13]
[14]
[15]
[16]
65
lesion load and cognitive dysfunction in MS, Neurology, 54 (2000) 558–564. Cammer, W., Oligodendrocyte killing by quinolinic acid in vitro, Brain Res., 30 (2001) 157–160. Chiarugi, A., Cozzi, A., Ballerini, C., Massacesi, L. and Moroni, F., Kynurenine 3-mono-oxygenase activity and neurotoxic kynurenine metabolites increase in the spinal cord of rats with experimental allergic encephalomyelitis, Neuroscience, 102 (2001) 687–695. Heyes, M.P., Chen, C.Y., Major, E.O. and Saito, K., Different kynurenine pathway enzymes limit quinolinic acid formation by various human cell types, Biochem. J., 326 (1997) 351–356. Heyes, M.P., Saito, K., Major, E.O., Milstien, S., Markey, S.P. and Vickers, J.H., A mechanism of quinolinic acid formation by brain in inflammatory neurological disease. Attenuation of synthesis from l-tryptophan by 6-chlorotryptophan and 4chloro-3-hydroxyanthranilate, Brain, 116 (1993) 1425–1450. Hodgkins, P.S. and Schwarcz, R., Metabolic control of kynurenic acid formation in the rat brain, Dev. Neurosci., 20 (1998) 408–416. Kepplinger, B., Baran, H., Kainz, A., Newcombe, J. and Nohl, H., Altered kynurenic acid levels in CSF and serum of patients with multiple sclerosis. ECTRIMS’2001 Abstracts, Mult. Scler., 7 (Suppl. 1) (2001) S118. Klivenyi, P., Kekesi, K., Juhasz, G. and Vecsei, L., Amino acid concentrations in cerebrospinal fluid of patients with multiple sclerosis, Acta Neurol. Scand., 95 (1997) 96–98. Rejdak, K., Kocki, T., Dobosz, B., Turski, W.A. and Stelmasiak, Z., Decreased level of kynurenic acid in cerebrospinal fluid of relapsing-remitting multiple sclerosis patients. ECTRIMS’2001 Abstracts, Mult. Scler., 7 (Suppl. 1) (2001) S118. Smith, T., Groom, A., Zhu, B. and Turski, L., Autoimmune encephalomyelitis ameliorated by AMPA antagonists, Nat. Med., 6 (2000) 62–66. Stone, T.W., Kynurenines in the CNS: from endogenous obscurity to therapeutic importance, Prog. Neurobiol., 64 (2001) 185–218. Turski, W.A., Nakamura, M., Todd, W.P., Carpenter, B.K., Whetsell Jr., W.O. and Schwarcz, R., Identification and quantification of kynurenic acid in human brain tissue, Brain Res., 454 (1988) 164–169. Urbanska, E.M., Chmielewski, M., Kocki, T. and Turski, W.A., Formation of endogenous glutamatergic receptors antagonist kynurenic acid—differences between cortical and spinal cord slices, Brain Res., 878 (2000) 210–212. Werner, P., Pitt, D. and Raine, C.S., Multiple sclerosis: altered glutamate homeostasis in lesions correlates with oligodendrocyte and axonal damage, Ann. Neurol., 50 (2001) 169–180.