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Inflammation and the glutamate system in schizophrenia: implications for therapeutic targets and drug development.

机译:精神分裂症的炎症和谷氨酸系统:对治疗靶标和药物开发的影响。

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摘要

Background: Despite the progress in antipsychotic therapy for schizophrenia, the effects are still not satisfactory. There is a high percentage of therapy-resistant patients and the overall course of the disease is unfavourable in many affected individuals. Therefore, other therapeutic targets than dopaminergic and serotonergic neurotransmitters are being considered. Objective: Glutamatergic hypofunction, mediated mainly by NMDA receptor blockade, is suggested to be indirectly responsible for dopaminergic dysfunction in schizophrenia. Increased levels of kynurenic acid (KYN-A), an endogenous NMDA receptor antagonist, resulting from disturbed tryptophan/kynurenine metabolism can explain psychotic symptoms and cognitive deterioration. Methods: The role of the immune system in the production of KYN-A and therapeutic targets in the immune and glutamate systems are outlined. Conclusions: Therapeutic consequences are discussed. Glutamate modulators that particularly influence the NMDA co-transmitters glycineand serine, including inhibitors of glycine transporters, are described and initial clinical evidence is discussed. Another target of the glutamate system is the metabotropic mGlu2/3 receptor; Preliminary clinical results of a study with a mGlu2/3 receptor agonist in schizophrenia are mentioned.
机译:背景:尽管精神分裂症的抗精神病药物治疗取得了进展,但效果仍不令人满意。对治疗有抵抗力的患者比例很高,并且该疾病的整个病程在许多受影响的个体中都是不利的。因此,正在考虑除多巴胺能和血清素能神经递质以外的其他治疗靶标。目的:主要由NMDA受体阻滞介导的谷氨酸能功能低下被认为是精神分裂症多巴胺能功能障碍的间接原因。色氨酸/犬尿氨酸代谢紊乱导致的内源性NMDA受体拮抗剂-尿酸(KYN-A)水平升高,可以解释精神病性症状和认知能力下降。方法:概述了免疫系统在KYN-A产生中的作用以及免疫和谷氨酸系统中的治疗靶标。结论:讨论了治疗效果。描述了特别影响NMDA辅助递质甘氨酸和丝氨酸的谷氨酸调节剂,包括甘氨酸转运蛋白的抑制剂,并讨论了初步的临床证据。谷氨酸系统的另一个目标是代谢型mGlu2 / 3受体。提到了在精神分裂症中使用mGlu2 / 3受体激动剂进行研究的初步临床结果。

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