Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, MD 20892, USA.
Int J Neuropsychopharmacol. 2012 Aug;15(7):931-43. doi: 10.1017/S1461145711001003. Epub 2011 Jun 28.
An up-regulated brain arachidonic acid (AA) cascade and a hyperglutamatergic state characterize bipolar disorder (BD). Lamotrigine (LTG), a mood stabilizer approved for treating BD, is reported to interfere with glutamatergic neurotransmission involving N-methyl-d-aspartate receptors (NMDARs). NMDARs allow extracellular calcium into the cell, thereby stimulating calcium-dependent cytosolic phospholipase A2 (cPLA2) to release AA from membrane phospholipid. We hypothesized that LTG, like other approved mood stabilizers, would reduce NMDAR-mediated AA signalling in rat brain. An acute subconvulsant dose of NMDA (25 mg/kg) or saline was administered intraperitoneally to unanaesthetized rats that had been treated p.o. daily for 42 d with vehicle or a therapeutically relevant dose of LTG (10 mg/kg.d). Regional brain AA incorporation coefficients k* and rates J in, and AA signals, were measured using quantitative autoradiography after intravenous [1-14C]AA infusion, as were other AA cascade markers. In chronic vehicle-treated rats, acute NMDA compared to saline increased k* and J in in widespread regions of the brain, as well as prostaglandin (PG)E2 and thromboxane B2 concentrations. Chronic LTG treatment compared to vehicle reduced brain cyclooxygenase (COX) activity, PGE2 concentration, and DNA-binding activity of the COX-2 transcription factor, NF-κB. Pretreatment with chronic LTG blocked the acute NMDA effects on AA cascade markers. In summary, chronic LTG like other mood stabilizers blocks NMDA-mediated signalling involving the AA metabolic cascade. Since markers of the AA cascade and of NMDAR signalling are up-regulated in the post-mortem BD brain, mood stabilizers generally may be effective in BD by dampening NMDAR signalling and the AA cascade.
一个上调的脑花生四烯酸（AA）级联和一个高谷氨酸能状态是双相情感障碍（BD）的特征。拉莫三嗪（LTG），一种被批准用于治疗 BD 的情绪稳定剂，据报道，它会干扰涉及 N-甲基-D-天冬氨酸受体（NMDAR）的谷氨酸能神经传递。NMDAR 允许细胞外钙进入细胞，从而刺激钙依赖性胞质磷脂酶 A2（cPLA2）从膜磷脂中释放 AA。我们假设 LTG，像其他被批准的情绪稳定剂一样，会减少大鼠脑中 NMDAR 介导的 AA 信号。用 NMDA（25mg/kg）或生理盐水进行急性亚惊厥剂量腹膜内给药，未麻醉大鼠每天口服治疗 42 天，给予载体或治疗相关剂量的 LTG（10mg/kg.d）。静脉内 [1-14C]AA 输注后，使用定量放射自显影测量区域性脑 AA 结合系数 k和 J in，以及 AA 信号，并测量其他 AA 级联标记物。在慢性载体处理的大鼠中，与生理盐水相比，急性 NMDA 增加了大脑广泛区域的 k和 J in，以及前列腺素（PG）E2 和血栓素 B2 浓度。与载体相比，慢性 LTG 治疗降低了大脑环氧化酶（COX）活性、PGE2 浓度和 COX-2 转录因子 NF-κB 的 DNA 结合活性。慢性 LTG 预处理阻断了急性 NMDA 对 AA 级联标记物的作用。总之，像其他情绪稳定剂一样，慢性 LTG 阻断 NMDA 介导的涉及 AA 代谢级联的信号。由于 AA 级联和 NMDAR 信号的标志物在死后 BD 脑中上调，因此情绪稳定剂通常可能通过抑制 NMDAR 信号和 AA 级联而对 BD 有效。
