Laboratory of Medicinal Pharmacology, Graduate School of Pharmaceutical Sciences, Osaka University, 1-6 Yamada-oka, Suita, Osaka, Japan.
Psychopharmacology (Berl). 2013 Feb;225(3):543-51. doi: 10.1007/s00213-012-2841-7. Epub 2012 Aug 30.
Galantamine, a drug for the treatment of Alzheimer's disease, has neuroprotection in several experimental models and stimulates adult neurogenesis in the rodent brain, but the exact mechanism remains unclear. This study examined whether galantamine affects the expression of neurotrophic/growth factors in the mouse hippocampus and prefrontal cortex.
Nine-week-old male ddY mice were used. The mRNA levels of neurotrophic/growth factors were analyzed by a real-time quantitative PCR. The protein levels of insulin-like growth factor 2 (IGF2) were analyzed by Western blotting.
Acute administration of galantamine (0.3-3 mg/kg, i.p.) increased IGF2 mRNA levels in the hippocampus, but not in the prefrontal cortex, in time- and dose-dependent manner. Galantamine (3 mg/kg, i.p.) caused a transient increase in fibroblast growth factor 2 mRNA levels and a decrease in brain-derived neurotrophic factor mRNA levels in the hippocampus, while it did not affect the mRNA levels of other neurotrophic/growth factors. The galantamine-induced increase in the hippocampal IGF2 mRNA levels was blocked by mecamylamine, a nonselective nicotinic acetylcholine (ACh) receptor (nAChR) antagonist, and methyllycaconitine, a selective α7 nAChR antagonist, but not by telenzepine, a preferential M(1) muscarinic ACh receptor antagonist. Moreover, the selective α7 nAChR agonist PHA-543613 increased the IGF2 mRNA levels, while donepezil, an acetylcholinesterase inhibitor, did not. Galantamine also increased hippocampal IGF2 protein, which was blocked by methyllycaconitine.
These findings suggest that galantamine increases hippocampal IGF2 levels via α7 nAChR activation in mice and imply that the effect may contribute to its neuroprotection or neurogenesis.
加兰他敏是一种治疗阿尔茨海默病的药物，在几种实验模型中具有神经保护作用，并刺激啮齿动物大脑中的成年神经发生，但确切机制尚不清楚。本研究探讨了加兰他敏是否影响小鼠海马体和前额叶皮层中的神经营养/生长因子的表达。
使用 9 周龄雄性 ddY 小鼠。通过实时定量 PCR 分析神经营养/生长因子的 mRNA 水平。通过 Western 印迹分析胰岛素样生长因子 2（IGF2）的蛋白水平。
加兰他敏（0.3-3mg/kg，腹腔注射）急性给药以时间和剂量依赖的方式增加海马体中的 IGF2 mRNA 水平，但不增加前额叶皮层中的 IGF2 mRNA 水平。加兰他敏（3mg/kg，腹腔注射）引起海马体中纤维母细胞生长因子 2 mRNA 水平的短暂增加和脑源性神经营养因子 mRNA 水平的降低，而不影响其他神经营养/生长因子的 mRNA 水平。加兰他敏诱导的海马体 IGF2 mRNA 水平增加被非选择性烟碱型乙酰胆碱受体（nAChR）拮抗剂美金刚胺和选择性 α7 nAChR 拮抗剂甲基金刚烷胺阻断，但不被优先 M1 毒蕈碱型乙酰胆碱受体拮抗剂替仑西平阻断。此外，选择性 α7 nAChR 激动剂 PHA-543613 增加 IGF2 mRNA 水平，而乙酰胆碱酯酶抑制剂多奈哌齐则没有。加兰他敏还增加了海马体中的 IGF2 蛋白水平，这一作用被甲基金刚烷胺阻断。
这些发现表明，加兰他敏通过激活小鼠海马体中的 α7 nAChR 增加 IGF2 水平，提示该作用可能有助于其神经保护或神经发生。
