Müller N, Schwarz M J
Klinik für Psychiatrie und Psychotherapie, Ludwig-Maximilians-Universität, Nussbaumstrasse 7, 80336 München.
Nervenarzt. 2007 Mar;78(3):253-6, 258-60, 262-3. doi: 10.1007/s00115-006-2108-9.
This manuscript deals with whether immune-mediated mechanisms of inflammation contribute to the pathogenesis of schizophrenia. A model is presented which integrates psychoneuroimmunologic findings and actual results from pharmacological, neurochemical, and genetic studies in schizophrenia. A pivotal role in the neurobiology of schizophrenia is played by dopaminergic neurotransmission, which is modulated by influences of the glutamatergic system. The decreased function of the glutamate system described in schizophrenia seems primarily mediated by N-methyl-D-aspartate (NMDA) receptor antagonism. Kynurenine acid is the only known endogenous NMDA receptor antagonist. In higher concentrations it blocks the NMDA receptor, but in lower concentrations it blocks the nicotinergic acetylcholin receptor, which has a prominent role in cognitive functions. Therefore, higher levels of kynurenine acid may explain psychotic symptoms and cognitive dysfunction. Several findings point out that prenatal infection, associated with an early sensitisation of the immune system, may result in an imbalance of the immune response (type 1 vs type 2) in schizophrenia. This immune constellation leads to inhibition of the enzyme indoleamin dioxigenase (IDO). It and tryptophane 2,3-dioxygenase (TDO) both catalyse the degradation from tryptophan to kynurenine. Due to the inhibition of IDO, tryptophan is metabolised to kynurenine primarily by TDO. In the CNS, TDO is located only in astrocytes, which are in particular activated in schizophrenia and in which kynurenine acid is the final product and can not be further metabolised. Therefore kynurenine acid accumulates in the CNS of schizophrenics and - due to its NMDA-antagonistic properties - leads to cognitive dysfunction and psychotic symptoms. This model describes the pathway of immune-mediated glutamatergic-dopaminergic dysregulation, which may lead to the clinical symptoms of schizophrenia. Therapeutic consequences (e.g. cyclo-oxygenase-2 inhibitors) are discussed.
本手稿探讨了免疫介导的炎症机制是否有助于精神分裂症的发病机制。文中提出了一个模型，该模型整合了精神神经免疫学的研究结果以及精神分裂症药理学、神经化学和遗传学研究的实际成果。多巴胺能神经传递在精神分裂症的神经生物学中起着关键作用，它受到谷氨酸能系统的影响调节。精神分裂症中所描述的谷氨酸系统功能下降似乎主要是由N-甲基-D-天冬氨酸（NMDA）受体拮抗作用介导的。犬尿氨酸是唯一已知的内源性NMDA受体拮抗剂。在较高浓度时，它会阻断NMDA受体，但在较低浓度时，它会阻断烟碱型乙酰胆碱受体，而该受体在认知功能中起重要作用。因此，较高水平的犬尿氨酸可能解释精神病症状和认知功能障碍。多项研究结果指出，与免疫系统早期致敏相关的产前感染可能导致精神分裂症患者免疫反应失衡（1型与2型）。这种免疫状态导致吲哚胺双加氧酶（IDO）受到抑制。IDO和色氨酸2,3-双加氧酶（TDO）都催化色氨酸向犬尿氨酸的降解。由于IDO受到抑制，色氨酸主要通过TDO代谢为犬尿氨酸。在中枢神经系统中，TDO仅位于星形胶质细胞中，而星形胶质细胞在精神分裂症中会特别活化，且犬尿氨酸是其最终产物，无法进一步代谢。因此，犬尿氨酸在精神分裂症患者的中枢神经系统中积累，并且由于其NMDA拮抗特性，导致认知功能障碍和精神病症状。该模型描述了免疫介导的谷氨酸能-多巴胺能失调途径，这可能导致精神分裂症的临床症状。文中还讨论了治疗方面的影响（如环氧化酶-2抑制剂）。
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