Baran Halina, Kepplinger Berthold, Draxler Markus
Neurochemical Laboratory, Karl Landsteiner Research Institute for Pain Treatment and Neurorehabilitation, LKM Mauer-Amstetten.
Int J Tryptophan Res. 2010;3:13-22. doi: 10.4137/ijtr.s3682. Epub 2010 May 11.
The endogenous neuroinhibitory amino acid receptor antagonist kynurenic acid (KYNA) has been hypothetically linked to physiological processes and to the pathogenesis of several brain disorders. The aim of this study was to search KYNA metabolism i.e. KYNA levels and enzymes synthesising KYNA kynurenine aminotransferase I and II (KAT I and II) in the central nervous system (CNS) and in the peripheral nervous system. Within the investigated species we found a remarkably low KYNA content (3.4 nM) in piglet's serum compared to rat and human serum. Furthermore, in contrast to high KAT activity present in rat and human livers, a lack of KAT I and KAT II activity was found in piglet liver and other piglet peripheral organs. Therefore we attempted to find a reason for the absence of KYNA formation in piglet peripheral tissue and we researched to find if KYNA formation in rat liver homogenate (measured under standard assay conditions for KAT activity) can be influenced by the application of piglet tissue homogenates and other body fluids. KYNA formation in rat liver homogenate was investigated in the presence of piglet liver, piglet brain, rat brain and human brain homogenates, and also in the presence of cerebrospinal fluid (CSF) of the control and of Multiple Sclerosis patients. We found a significant and dose dependent reduction of rat liver KAT I and KAT II activities in the presence of piglet brain, piglet liver, and human brain, but not in the presence of rat brain homogenate. Interestingly, CSF of the human control subjects significantly lowered rat liver KAT I activity. Furthermore, the inhibitory effect of CSF of Multiple Sclerosis (MS) patients was significantly weaker when compared to the CSF of control subjects. Our data, for the first time, indicated the presence of active component(s)-depressing factor-in the body, which was able to block KYNA formation. Reduced KAT inhibitory effect by CSF of MS patients would suggest a lowered "depressing factor" level in CSF of MS patients and is possibly responsible for an enhancement of KYNA formation and for glia activation and gliosis in the CNS. Subsequently, two fractions obtained after centrifugation of CSF from patients with Neuroborreliosis showed a significantly different ability to block KAT I activity. The CSF-sediment fraction exerts a stronger inhibitory activity than the CSF-supernatant fraction, supporting further the presence of a depressing factor. For the first time, data revealed and demonstrated the ability of endogenous components to block KYNA's synthesis. We propose that a glia depressing factor (GDF), which is abundantly present in the body, might simultaneously control glia cell's KAT activity, respectively KYNA synthesis and also glia proliferation. The mechanism(s) of action, the composition and structure of this factor needs to be further elaborated.
内源性神经抑制性氨基酸受体拮抗剂犬尿喹啉酸（KYNA）被推测与生理过程以及几种脑部疾病的发病机制有关。本研究的目的是探寻中枢神经系统（CNS）和外周神经系统中KYNA的代谢情况，即KYNA水平以及合成KYNA的酶——犬尿氨酸转氨酶I和II（KAT I和II）。在所研究的物种中，我们发现仔猪血清中的KYNA含量（3.4 nM）相较于大鼠和人类血清显著较低。此外，与大鼠和人类肝脏中存在的高KAT活性相反，在仔猪肝脏和其他仔猪外周器官中未发现KAT I和KAT II活性。因此，我们试图找出仔猪外周组织中缺乏KYNA形成的原因，并研究大鼠肝脏匀浆中KYNA的形成（在KAT活性的标准测定条件下测量）是否会受到仔猪组织匀浆和其他体液的影响。在存在仔猪肝脏、仔猪脑、大鼠脑和人类脑匀浆的情况下，以及在对照和多发性硬化症患者的脑脊液（CSF）存在的情况下，研究了大鼠肝脏匀浆中KYNA的形成。我们发现，在存在仔猪脑、仔猪肝脏和人类脑的情况下，大鼠肝脏KAT I和KAT II活性显著且呈剂量依赖性降低，但在存在大鼠脑匀浆的情况下则不然。有趣的是，人类对照受试者的脑脊液显著降低了大鼠肝脏KAT I活性。此外，与对照受试者的脑脊液相比，多发性硬化症（MS）患者的脑脊液的抑制作用明显较弱。我们的数据首次表明体内存在活性成分——抑制因子，其能够阻断KYNA的形成。MS患者脑脊液对KAT抑制作用的降低表明MS患者脑脊液中“抑制因子”水平降低，这可能是导致CNS中KYNA形成增加以及胶质细胞活化和胶质增生的原因。随后，对神经莱姆病患者脑脊液离心后得到的两个组分显示出阻断KAT I活性的能力存在显著差异。脑脊液沉淀物组分比脑脊液上清液组分具有更强的抑制活性，这进一步支持了抑制因子的存在。数据首次揭示并证明了内源性成分阻断KYNA合成的能力。我们提出，体内大量存在的胶质抑制因子（GDF）可能同时控制胶质细胞的KAT活性，进而控制KYNA的合成以及胶质细胞的增殖。该因子的作用机制、组成和结构有待进一步阐明。
