Modulating balance of synaptic and extrasynaptic NMDA receptors as strategy for Alzheimer disease drug discovery

The unbalance between synaptic(Glu N2 A, mediating the protective pathway) and extrasynaptic NMDA receptors(NMDARs)(Glu N2 B, mediating the excitotoxic pathway) has been found in Alzheimer disease(AD), indicating restoring the balance of Glu N2 A and Glu N2 B should be beneficial for AD therapy. In this study, the Glu N2 B-selective antagonist, ifenprodil, and the non-selective NMDAR agonist, NMDA, had little effects on amyloid-beta(Abeta)-induced long-term potentiation(LTP) deficits.Enhancing the activity of Glu N2 A had a protective effect against Abeta, and specific activation of Glu N2 A and inhibition of Glu N2 B showed a better protective effect. The combination of ifenprodil and D-cycloserine(a co-activator of NMDRs similar to D-serine) led to greater improvement in behavior tests than ifenprodil or D-cycloserine alone, meanwhile, the combination of ifenprodil and D-cycloserine reversed the signal pathway more significantly than ifenprodil or D-cycloserine alone. These results indicate that enhancing synaptic NMDARs and inhibiting extrasynaptic NMDARs concurrently showed protective effects against Abeta-induced neurotoxicity, suggesting that modulation of the balance between Glu N2 A and Glu N2 B might be a good strategy for drug discovery against AD.

瑞芬太尼抑制大鼠炎症性疼痛及其机制

目的探究瑞芬太尼(Remifentanil)对大鼠炎症性疼痛的抑制作用。方法2 月龄雄性Wistar 大鼠32 只,体重180 ~ 220 g,随机分为4 组(每组8 只):空白组(Group Naive),福尔马林注射组(Formalin),福尔马林+瑞芬太尼注射30 min 组(P-30 min),福尔马林+瑞芬太尼注射组(P-2h)。其中瑞芬太尼尾静脉注射[0.6 mg/(kg·min)]1 h后福尔马林被注射进大鼠右后爪跖骨。记录注射福尔马林后20 min 内大鼠出现舔舐啃咬右后足的次数,酶联免疫吸附实验(ELISA)法检测大鼠血浆中TNF-α、IL-10 浓度,检测脊髓组织内Glu-N2B,p-Glu-N2B, ERK1/2, p38, c-Jun 蛋白表达;免疫荧光染色检测脊髓背角处神经元激活情况。结果瑞芬太尼注射后明显减少实验鼠疼痛反应,与模型组相比,瑞芬太尼注射后能明显降低大鼠血浆中促炎因子含量而增加抑炎因子含量,并且可抑制脊髓组织内因福尔马林激活的Glu-N2B, p-Glu-N2B, ERK1/2 蛋白表达,也可降低p38, c-Jun 蛋白表达(<0.05)。另外,瑞芬太尼也可降低脊髓神经元的激活和c-Fos, p-ERK 的表达(<0.05)。结论瑞芬太尼可通过GluN2B 受体和ERK1/2 信号通路预防神经炎症性疼痛。