Brain Physiology and Metabolism Section, National Institute on Aging, National Institutes of Health, Bethesda, Maryland, USA.
J Neurochem. 2011 Oct;119(2):364-76. doi: 10.1111/j.1471-4159.2011.07410.x. Epub 2011 Sep 20.
The atypical antipsychotic, olanzapine (OLZ), is used to treat bipolar disorder, but its therapeutic mechanism of action is not clear. Arachidonic acid (AA, 20:4n-6) plays a critical role in brain signaling and an up-regulated AA metabolic cascade was reported in postmortem brains from bipolar disorder patients. In this study, we tested whether, similar to the action of the mood stabilizers lithium, carbamazepine and valproate, chronic OLZ treatment would reduce AA turnover in rat brain. We administered OLZ (6 mg/kg/day) or vehicle i.p. to male rats once daily for 21 days. A washout group received 21 days of OLZ followed by vehicle on day 22. Two hours after the last injection, [1-¹⁴C]AA was infused intravenously for 5 min, and timed arterial blood samples were taken. After the rat was killed at 5 min, its brain was microwaved, removed and analyzed. Chronic OLZ decreased plasma unesterified AA concentration, AA incorporation rates and AA turnover in brain phospholipids. These effects were absent after washout. Consistent with reduced AA turnover, OLZ decreased brain cyclooxygenase activity and the brain concentration of the proinflammatory AA-derived metabolite, prostaglandin E₂, In view of up-regulated brain AA metabolic markers in bipolar disorder, the abilities of OLZ and the mood stabilizers to commonly decrease prostaglandin E₂, and AA turnover in rat brain phospholipids, albeit by different mechanisms, may be related to their efficacy against the disease.
非典型抗精神病药奥氮平（OLZ）用于治疗双相情感障碍，但它的治疗作用机制尚不清楚。花生四烯酸（AA，20:4n-6）在大脑信号转导中起着关键作用，有报道称双相情感障碍患者死后大脑中的 AA 代谢级联反应上调。在这项研究中，我们测试了奥氮平（6mg/kg/天）是否像心境稳定剂锂、卡马西平和丙戊酸钠一样，慢性治疗会降低大鼠大脑中的 AA 周转率。我们每天给雄性大鼠腹腔注射奥氮平（6mg/kg/天）或载体，持续 21 天。洗脱组在第 22 天接受 21 天奥氮平治疗，然后接受载体。最后一次注射后 2 小时，经静脉内输注 [1-¹⁴C]AA 5 分钟，并采集定时动脉血样。在大鼠 5 分钟后处死，微波处理其大脑，取出并进行分析。慢性奥氮平降低了血浆未酯化 AA 浓度、AA 掺入率和大脑磷脂中的 AA 周转率。洗脱后这些作用消失。与 AA 周转率降低一致，奥氮平降低了大脑环加氧酶活性和促炎 AA 衍生代谢物前列腺素 E₂的脑浓度。鉴于双相情感障碍中大脑 AA 代谢标志物上调，奥氮平和心境稳定剂共同降低前列腺素 E₂和大鼠大脑磷脂中 AA 周转率的能力，尽管机制不同，但可能与它们对该疾病的疗效有关。
