On the relationship between the two branches of the kynurenine pathway in the rat brain in vivo

被引:124
作者
Amori, Laura [1 ]
Guidetti, Paolo [1 ]
Pellicciari, Roberto [2 ]
Kajii, Yasushi [3 ]
Schwarcz, Robert [1 ]
机构
[1] Univ Maryland, Sch Med, Maryland Psychiat Res Ctr, Baltimore, MD 21228 USA
[2] Univ Perugia, Dipartimento Chim & Tecnol Farm, I-06100 Perugia, Italy
[3] Mitsubishi Tanabe Pharma Corp, Yokohama, Kanagawa, Japan
关键词
3-hydroxykynurenine; excitotoxicity; kynurenic acid; quinolinic acid; QUINOLINIC ACID; TRYPTOPHAN-METABOLISM; AMINOTRANSFERASE-II; 3-HYDROXYLASE INHIBITION; MICROGLIA; 3-HYDROXYKYNURENINE; MANIPULATION; ACTIVATION; INCREASE; TARGETS;
D O I
10.1111/j.1471-4159.2009.05893.x
中图分类号
Q5 [生物化学]; Q7 [分子生物学];
学科分类号
071010 ; 081704 ;
摘要
In the mammalian brain, kynurenine aminotransferase II (KAT II) and kynurenine 3-monooxygenase (KMO), key enzymes of the kynurenine pathway (KP) of tryptophan degradation, form the neuroactive metabolites kynurenic acid (KYNA) and 3-hydroxykynurenine (3-HK), respectively. Although physically segregated, both enzymes use the pivotal KP metabolite l-kynurenine as a substrate. We studied the functional consequences of this cellular compartmentalization in vivo using two specific tools, the KAT II inhibitor BFF 122 and the KMO inhibitor UPF 648. The acute effects of selective KAT II or KMO inhibition were studied using a radiotracing method in which the de novo synthesis of KYNA, and of 3-HK and its downstream metabolite quinolinic acid (QUIN), is monitored following an intrastriatal injection of H-3-kynurenine. In naive rats, intrastriatal BFF 122 decreased newly formed KYNA by 66%, without influencing 3-HK or QUIN production. Conversely, UPF 648 reduced 3-HK synthesis (by 64%) without affecting KYNA formation. Similar, selective effects of KAT II and KMO inhibition were observed when the inhibitors were applied acutely together with the excitotoxin QUIN, which impairs local KP metabolism. Somewhat different effects of KMO (but not KAT II) inhibition were obtained in rats that had received an intrastriatal QUIN injection 7 days earlier. In these neuron-depleted striata, UPF 648 not only decreased both 3-HK and QUIN production (by 77% and 66%, respectively) but also moderately raised KYNA synthesis (by 27%). These results indicate a remarkable functional segregation of the two pathway branches in the brain, boding well for the development of selective KAT II or KMO inhibitors for cognitive enhancement and neuroprotection, respectively.
引用
收藏
页码:316 / 325
页数:10
相关论文
共 61 条
[1]   Targeted deletion of the kynurenine aminotransferase II gene reveals a critical role of endogenous kynurenic acid in the regulation of synaptic transmission via α7 nicotinic receptors in the hippocampus [J].
Alkondon, M ;
Pereira, EFR ;
Yu, P ;
Arruda, EZ ;
Almeida, LEF ;
Guidetti, P ;
Fawcett, WP ;
Sapko, MT ;
Randall, WR ;
Schwarcz, R ;
Tagle, DA ;
Albuquerque, EX .
JOURNAL OF NEUROSCIENCE, 2004, 24 (19) :4635-4648
[2]  
AMORI L, 2003, THESIS U PERUGIA PER
[3]   Immunosuppression via tryptophan catabolism: The role of kynurenine pathway enzymes [J].
Belladonna, Maria Laura ;
Puccetti, Paolo ;
Orabona, Ciriana ;
Fallarino, Francesca ;
Vacca, Carmine ;
Volpi, Claudia ;
Gizzi, Stefania ;
Pallotta, Maria Teresa ;
Fioretti, Maria Cristina ;
Grohmann, Ursula .
TRANSPLANTATION, 2007, 84 (01) :S17-S20
[4]   THE PREFERRED ROUTE OF KYNURENINE METABOLISM IN THE RAT [J].
BENDER, DA ;
MCCREANOR, GM .
BIOCHIMICA ET BIOPHYSICA ACTA, 1982, 717 (01) :56-60
[5]  
BERGERON R, 2007, SOC NEUR ABSTR, V32, P807
[6]   SHORT-TERM AND LONG-TERM CONSEQUENCES OF INTRACRANIAL INJECTIONS OF THE EXCITOTOXIN, QUINOLINIC ACID, AS EVIDENCED BY GFA IMMUNOHISTOCHEMISTRY OF ASTROCYTES [J].
BJORKLUND, H ;
OLSON, L ;
DAHL, D ;
SCHWARCZ, R .
BRAIN RESEARCH, 1986, 371 (02) :267-277
[7]   Induction of cytosolic NADPH-diaphorase nitric oxide synthase in reactive microglia macrophages after quinolinic acid lesions in the rat striatum: An electron and light microscopical study [J].
Calka, J ;
Wolf, G ;
Schmidt, W .
HISTOCHEMISTRY AND CELL BIOLOGY, 1996, 105 (01) :81-89
[8]   INHIBITORS OF KYNURENINE HYDROXYLASE AND KYNURENINASE INCREASE CEREBRAL FORMATION OF KYNURENATE AND HAVE SEDATIVE AND ANTICONVULSANT ACTIVITIES [J].
CARPENEDO, R ;
CHIARUGI, A ;
RUSSI, P ;
LOMBARDI, G ;
CARLA, V ;
PELLICCIARI, R ;
MORONI, F ;
MATTOLI, L .
NEUROSCIENCE, 1994, 61 (02) :237-244
[9]   Metabolism of [5-H-3]kynurenine in the developing rat brain in vivo: Effect of intrastriatal ibotenate injections [J].
Ceresoli, G ;
Guidetti, P ;
Schwarcz, R .
DEVELOPMENTAL BRAIN RESEARCH, 1997, 100 (01) :73-81
[10]   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