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

Abstract

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.

Hippocampal long‐term synaptic depression and memory deficits induced in early amyloidopathy are prevented by enhancing G‐protein‐gated inwardly rectifying potassium channel activity

“…LTP has been shown to have a capital role in the hippocampal CA3—CA1 synapse for learning and new memories formation processes (Kumar, ). Synaptic plasticity deficits have been previously reported for AD acute models (Eslami, Sadeghi, & Goshadrou, ; Kimura, MacTavish, Yang, Westaway, & Jhamandas, ). However, the effect of GirK channels modulation on Aβ‐induced LTP impairments has not been deeply investigated.…”

“…The soluble forms of Aβ 1–42 peptide are pathological species present in AD that are widely used to investigate their contribution to the pathogenesis and progression of the disease (Selkoe & Hardy, ). In vitro acute application of Aβ 1–42 causes hippocampal hyperexcitability (Tamagnini et al, ; Varga et al, ) and deficits in LTP (Eslami et al, ; Kimura et al, ; Lei, Xu, & Li, ). Similarly, different in vivo experiments show that the administration of Aβ 1–42 triggers behavioral deficits because of alterations in neural excitability and LTP process (Kalweit et al, ; Sanchez‐Rodriguez et al, , ).…”

New Insights Into the Pathogenesis of Alzheimer's Disease

“…GHSR1α may be a target for AD treatment. GHSR1α agonists such as MK0677 and LY444711 showed protective effects in animal and cell models (102,103). However, clinical trials of MK0677 in AD patients failed to show clinical benefit.…”

Rapid anti‐depressant‐like effects of ketamine and other candidates: Molecular and cellular mechanisms

“…This suggests us that combining monoamine with non‐monoamine may be a new strategy for treating MDD. Some studies showed that CR regulated the release of orexin 106‐109 and ghrelin, 110‐117 producing some anti‐depressant effects. But this evidence on synaptic plasticity is weak, and we mention here only for reference (Figure 3).…”