Departamento de Farmacobiología, CINVESTAV, México City, Mexico.
Brain Res. 2011 Dec 2;1426:73-85. doi: 10.1016/j.brainres.2011.09.056. Epub 2011 Oct 1.
Intracerebroventricular (ICV) streptozotocin (STZ) treated rat has been described as a suitable model for sporadic Alzheimer's disease (AD). Central application of STZ has demonstrated behavioral and neurochemical features that resembled those found in human AD. Chronic treatments with antioxidants, acetylcholinesterase (AChE) inhibitors, or improving glucose utilization drugs have reported a beneficial effect in ICV STZ-treated rats. In the present study the post-training administration of a glycogen synthase kinase (GSK3) inhibitor, lithium; antidementia drugs: phenserine and memantine, and insulin sensitizer, pioglitazone on memory function of ICV STZ-rats was assessed. In these same animals the phosphorylated GSK3β (p-GSK3β) and total GSK3β levels were determined, and importantly GSK3β regulates the tau phosphorylation responsible for neurofibrillary tangle formation in AD. Wistar rats received ICV STZ application (3mg/kg twice) and 2 weeks later short- (STM) and long-term memories (LTM) were assessed in an autoshaping learning task. Animals were sacrificed immediately following the last autoshaping session, their brains removed and dissected. The enzymes were measured in the hippocampus and prefrontal cortex (PFC) by western blot. ICV STZ-treated rats showed a memory deficit and significantly decreased p-GSK3β levels, while total GSK3β did not change, in both the hippocampus and PFC. Memory impairment was reversed by lithium (100mg/kg), phenserine (1mg/kg), memantine (5mg/kg) and pioglitazone (30 mg/kg). The p-GSK3β levels were restored by lithium, phenserine and pioglitazone in the hippocampus, and restored by lithium in the PFC. Memantine produced no changes in p-GSK3β levels in neither the hippocampus nor PFC. Total GSK3β levels did not change with either drug. Altogether these results show the beneficial effects of drugs with different mechanisms of actions on memory impairment induced by ICV STZ, and restored p-GSK3β levels, a kinase key of signaling cascade of insulin receptor.
侧脑室（ICV）链脲佐菌素（STZ）处理的大鼠已被描述为散发性阿尔茨海默病（AD）的合适模型。STZ 的中枢应用表现出类似于人类 AD 中发现的行为和神经化学特征。抗氧化剂、乙酰胆碱酯酶（AChE）抑制剂或改善葡萄糖利用药物的慢性治疗已报告对 ICV STZ 处理的大鼠有有益的影响。在本研究中，评估了糖原合酶激酶（GSK3）抑制剂锂、抗痴呆药物苯丁嗪和美金刚以及胰岛素增敏剂吡格列酮在 ICV STZ 大鼠记忆功能中的作用。在这些相同的动物中，测定了磷酸化 GSK3β（p-GSK3β）和总 GSK3β 水平，重要的是 GSK3β 调节导致 AD 中神经原纤维缠结形成的 tau 磷酸化。Wistar 大鼠接受 ICV STZ 应用（3mg/kg 两次），2 周后在自动塑造学习任务中评估短期（STM）和长期记忆（LTM）。动物在最后一次自动塑造课程结束后立即被处死，取出大脑并进行解剖。通过 Western blot 在海马体和前额叶皮层（PFC）中测量酶。ICV STZ 处理的大鼠表现出记忆缺陷，并且 p-GSK3β 水平显著降低，而总 GSK3β 没有变化，在海马体和 PFC 中均如此。锂（100mg/kg）、苯丁嗪（1mg/kg）、美金刚（5mg/kg）和吡格列酮（30mg/kg）逆转了记忆障碍。p-GSK3β 水平在海马体中被锂、苯丁嗪和吡格列酮恢复，在 PFC 中被锂恢复。美金刚对海马体和 PFC 中的 p-GSK3β 水平均无影响。总 GSK3β 水平与任何药物均无变化。总之，这些结果表明具有不同作用机制的药物对 ICV STZ 诱导的记忆障碍具有有益的影响，并恢复了 p-GSK3β 水平，这是胰岛素受体信号级联的关键激酶。
