Department of Pharmacology, School of Medicine, Tehran University of Medical Sciences, Tehran, Iran; Brain and Spinal Injury Repair Research Center, Tehran University of Medical Sciences, Tehran, Iran.
Eur J Clin Invest. 2013 Oct;43(10):1039-51. doi: 10.1111/eci.12141. Epub 2013 Aug 13.
Alzheimer's disease (AD) is a neurodegenerative disorder featured by deposition of beta-amyloid (Aβ) plaques in the hippocampus and associated cortices and progressive cognitive decline. Tropisetron, a selective 5-HT3 receptor antagonist, is conventionally used to counteract chemotherapy-induced emesis. Recent investigations describe antiphlogistic properties for tropisetron. It has been shown that tropisetron protects against rat embolic stroke. We investigated protective properties of tropisetron in a beta-amyloid (Aβ) rat model of AD and possible involvement of 5-HT3 receptors.
Aβ (1-42) was injected into the hippocampus of male rats. Animals were treated intracerebroventricularly with tropisetron, mCPBG (selective 5-HT3 receptor agonist) or mCPBG plus tropisetron on days 1, 3, 5 and 7. Seven days following Aβ administration, inflammatory markers (TNF-α, COX-2, iNOS and NF-κB), apoptotic markers (caspase 3 cytochrome c release) and calcineurin phosphatase activity were assessed in hippocampus.
Seven days following Aβ inoculation, control animals displayed dramatic increase in TNF-α, COX-2, iNOS, NF-κB, active caspase 3, cytochrome c release and calcineurin phosphatase activity in the hippocampus. Tropisetron significantly diminished the elevated levels of these markers and reversed the cognitive deficit. Interestingly, tropisetron was also found to be a potent inhibitor of calcineurin phosphatase activity. The selective 5-HT3 receptor agonist mCPBG, when co-administered with tropisetron, completely reversed the procognitive and anti-apoptotic properties of tropisetron while it could only partially counteract the anti-inflammatory effects. mCPBG alone significantly aggravated Aβ-induced injury.
Our findings indicate that tropisetron protects against Aβ-induced neurotoxicity in vivo through both 5-HT3 receptor-dependent and independent pathways.
阿尔茨海默病（AD）是一种神经退行性疾病，其特征是β-淀粉样蛋白（Aβ）斑块在海马体和相关皮质中的沉积以及进行性认知能力下降。托烷司琼是一种选择性 5-HT3 受体拮抗剂，常用于对抗化疗引起的呕吐。最近的研究描述了托烷司琼的抗炎特性。已经表明，托烷司琼可以保护大鼠免受栓塞性中风的影响。我们研究了托烷司琼在 AD 的β-淀粉样蛋白（Aβ）大鼠模型中的保护特性，以及 5-HT3 受体的可能参与。
将 Aβ（1-42）注入雄性大鼠的海马体。动物在 Aβ 给药后第 7 天，通过脑室内给予托烷司琼、mCPBG（选择性 5-HT3 受体激动剂）或 mCPBG 加托烷司琼，在第 1、3、5 和 7 天。在 Aβ 给药后 7 天，评估海马体中的炎症标志物（TNF-α、COX-2、iNOS 和 NF-κB）、凋亡标志物（caspase 3 细胞色素 c 释放）和钙调神经磷酸酶活性。
在 Aβ 接种后 7 天，对照动物显示 TNF-α、COX-2、iNOS、NF-κB、活性 caspase 3、细胞色素 c 释放和钙调神经磷酸酶活性在海马体中显著升高。托烷司琼显著降低了这些标志物的升高水平，并逆转了认知缺陷。有趣的是，托烷司琼也被发现是钙调神经磷酸酶活性的有效抑制剂。选择性 5-HT3 受体激动剂 mCPBG 与托烷司琼共同给予时，完全逆转了托烷司琼的促认知和抗凋亡作用，而仅部分抵消了抗炎作用。mCPBG 本身显著加重了 Aβ 诱导的损伤。
我们的研究结果表明，托烷司琼通过 5-HT3 受体依赖和非依赖途径保护体内 Aβ 诱导的神经毒性。
