Kynurenate production by cultured human astrocytes

被引:92
作者
Kiss, C
Ceresoli-Borroni, G
Guidetti, P
Zielke, CL
Zielke, HR
Schwarcz, R [1 ]
机构
[1] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21201 USA
[2] Univ Maryland, Sch Med, Dept Pediat, Baltimore, MD USA
关键词
alpha 7 nicotinic acetylcholine receptor; anticonvulsants; 7-chlorokynurenic acid; glia; neuroprotection; NMDA;
D O I
10.1007/s00702-002-0770-z
中图分类号
R74 [神经病学与精神病学];
学科分类号
摘要
In the rodent brain, astrocytes are known to be the primary source of kynurenate (KYNA), an endogenous antagonist of both the glycine(B) and the alpha7 nicotinic acetylcholine receptor. In the present study, primary human astrocytes were used to examine the characteristics and regulation of de novo KYNA synthesis in vitro. To this end, cells were exposed to KYNA's bioprecursor L-kynurenine, and newly formed KYNA was recovered from the extracellular milieu. The production of KYNA was stereospecific and rose with increasing L-kynurenine concentrations, reaching a plateau in the high muM range. In an analogous experiment, astrocytes also readily produced and liberated the potent, specific glycine(B) receptor antagonist 7-chlorokynurenate from L-4-chlorokynurenine. KYNA synthesis was dose-dependently reduced by L-leucine or L-phenylalanine, two amino acids that compete with L-kynurenine for cellular uptake, and by aminooxyacetate, a non-specific aminotransferase inhibitor. In contrast, KYNA formation was stimulated by 5mM pyruvate or oxaloacetate, which act as co-substrates of the transamination reaction. Aglycemic or depolarizing (50 mM KCl or 100 muM veratridine) conditions had no effect on KYNA synthesis. Subsequent studies using tissue homogenate showed that both known cerebral kynurenine aminotransferases (KAT I and KAT 11) are present in astrocytes, but that KAT 11 appears to be singularly responsible for KYNA formation under physiological conditions. Taken together with previous results, these data suggest that very similar mechanisms control KYNA synthesis in the rodent and in the human brain. These regulatory events are likely to influence the neuromodulatory effects of astrocyte-derived KYNA in the normal and diseased human brain.
引用
收藏
页码:1 / 14
页数:14
相关论文
共 52 条
[1]  
BANKER G, 1991, CULTURING NERVE CELL, P75
[2]   Presynaptic kynurenate-sensitive receptors inhibit glutamate release [J].
Carpenedo, R ;
Pittaluga, A ;
Cozzi, A ;
Attucci, S ;
Galli, A ;
Raiteri, M ;
Moroni, F .
EUROPEAN JOURNAL OF NEUROSCIENCE, 2001, 13 (11) :2141-2147
[3]   Acute and chronic changes in kynurenate formation following an intrastriatal quinolinate injection in rats [J].
Ceresoli-Borroni, G ;
Guidetti, P ;
Schwarcz, R .
JOURNAL OF NEURAL TRANSMISSION, 1999, 106 (3-4) :229-242
[4]  
CERESOLIBORRONI.G, 2001, KYNURENIC ACID PRODU, V27
[5]   Kynurenine hydroxylase inhibitors reduce ischemic brain damage:: Studies with (m-nitrobenzoyl)-alanine (mNBA) and 3,4-dimethoxy-[-N-4-(nitrophenyl)thiazol-2YL]-benzenesulfonamide (Ro 61-8048) in models of focal or global brain ischemia [J].
Cozzi, A ;
Carpenedo, R ;
Moroni, F .
JOURNAL OF CEREBRAL BLOOD FLOW AND METABOLISM, 1999, 19 (07) :771-777
[6]  
Curatolo L, 1996, ADV EXP MED BIOL, V398, P273
[7]   RAPID COLORIMETRIC ASSAY FOR CELL-GROWTH AND SURVIVAL - MODIFICATIONS TO THE TETRAZOLIUM DYE PROCEDURE GIVING IMPROVED SENSITIVITY AND RELIABILITY [J].
DENIZOT, F ;
LANG, R .
JOURNAL OF IMMUNOLOGICAL METHODS, 1986, 89 (02) :271-277
[8]   Pharmacological elevation of endogenous kynurenic acid levels activates nigral dopamine neurons [J].
Erhardt, S ;
Öberg, H ;
Mathé, JM ;
Engberg, G .
AMINO ACIDS, 2001, 20 (04) :353-362
[9]  
Erhardt S, 2000, SYNAPSE, V37, P104, DOI 10.1002/1098-2396(200008)37:2<104::AID-SYN4>3.0.CO
[10]  
2-L