Chronic ghrelin administration restores hippocampal long‐term potentiation and ameliorates memory impairment in rat model of Alzheimer's disease

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.