Department of Physiology, School of Allied Medical Sciences, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Department of Physiology, School of Medicine, Shahid Beheshti University of Medical Sciences, Tehran, Iran.
Hippocampus. 2018 Oct;28(10):724-734. doi: 10.1002/hipo.23002. Epub 2018 Sep 5.
Alzheimer's disease (AD), as a common age-related dementia, is a progressive manifestation of cognitive decline following synaptic failure resulted majorly by senile plaques composed of deposits of amyloid beta (Aβ). Ghrelin is a multifunctional peptide hormone with receptors present in various brain tissues including hippocampus and has been associated with neuroprotection, neuromodulation, and memory processing. Here, we investigated the neuroprotective and therapeutic effects of intracerebroventricular (icv) ghrelin infusion for 2 weeks on passive avoidance learning (PAL), memory retention, and synaptic plasticity in the hippocampal dentate gyrus (DG) and CA1 of both normal rats and Aβ1-42-induced neurotoxicity in AD model. Male Wistar rats were evaluated for their passive memory performance using a shuttle box while some groups had already received Aβ1-42 and/or chronic ghrelin. Using field potential recording, the induction of short- and long-term potentiation (STP and LTP) was studied in DG granule cells along with the LTP changes in CA1 pyramidal neurons through stimulation of the medial perforant path (mPP) and Schaffer collaterals (SCs), respectively. Our results demonstrated that chronic ghrelin treatment not only improved memory processing and retrieval in normal rats during the PAL task, but also promoted memory retention and alleviated memory loss by amelioration of Aβ1-42-induced synaptic plasticity impairment in AD subjects through augmentation of field excitatory postsynaptic potential (fEPSP) slope that led to LTP restitution in both the mPP-DG and the CA3-CA1 synapses. Meanwhile, STP was not significantly changed, meaning that although ghrelin enhanced postsynaptic excitability in DG, it did not change presynaptic transmitter release significantly. This suggests the involvement of postsynaptic mechanisms in long-term ghrelin-enhanced memory. In conclusion, it can be inferred that chronic ghrelin administration has an auspicious therapeutic value for impaired cognitive performance and memory deficits in AD-like neuropathology.
阿尔茨海默病（AD）是一种常见的与年龄相关的痴呆症，是由于衰老斑块引起的突触功能障碍导致的认知能力进行性下降，而衰老斑块主要由淀粉样β（Aβ）沉积组成。胃饥饿素是一种多功能肽激素，其受体存在于包括海马体在内的各种脑组织中，与神经保护、神经调节和记忆处理有关。在这里，我们研究了脑室（icv）内注射胃饥饿素 2 周对正常大鼠的被动回避学习（PAL）、记忆保留和海马齿状回（DG）和 CA1 突触可塑性的神经保护和治疗作用，以及 AD 模型中 Aβ1-42 诱导的神经毒性。雄性 Wistar 大鼠通过穿梭箱评估其被动记忆性能，而一些大鼠已经接受了 Aβ1-42 和/或慢性胃饥饿素。通过场电位记录，研究了 DG 颗粒细胞中短期和长期增强（STP 和 LTP）的诱导，以及通过刺激内侧穿通路径（mPP）和 Schaffer 侧枝（SCs）分别研究 CA1 锥体神经元中的 LTP 变化。我们的结果表明，慢性胃饥饿素治疗不仅改善了正常大鼠在 PAL 任务中的记忆处理和检索，而且通过改善 Aβ1-42 诱导的突触可塑性损伤，促进了记忆保留并减轻了记忆丧失，通过增强场兴奋性突触后电位（fEPSP）斜率，导致 mPP-DG 和 CA3-CA1 突触中的 LTP 恢复。同时，STP 没有明显变化，这意味着尽管胃饥饿素增强了 DG 中的突触后兴奋性，但它并没有显著改变突触前递质释放。这表明长时程胃饥饿素增强记忆涉及突触后机制。总之，可以推断慢性胃饥饿素给药对 AD 样神经病理学中的认知功能障碍和记忆缺陷具有良好的治疗价值。
