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In the search for Alzheimer's disease (AD) therapies, most animal models focus on familial AD, which accounts for a small fraction of cases. The majority of AD cases arise from stress factors, such as oxidative stress, leading to neurological changes (sporadic AD). Early in AD progression, dysfunction in γ-secretase causes the formation of insoluble Aβ 1-42 peptides, which aggregate into senile plaques, triggering neurodegeneration, cognitive decline, and circadian rhythm disturbances. To better model sporadic AD, we used a new AD rat model induced by intracerebroventricular administration of Aβ 1-42 oligomers (icvAβ 1-42 ) combined with melatonin deficiency via pinealectomy (pin). We validated this model by assessing spatial memory using the radial arm maze test and measuring Aβ 1-42 and γ-secretase levels in the frontal cortex and hippocampus with ELISA. The icvAβ 1-42 + pin model experienced impaired spatial memory and increased Aβ 1-42 and γ-secretase levels in the frontal cortex and hippocampus, effects not seen with either icvAβ 1-42 or the pin alone. Chronic melatonin treatment reversed memory deficits and reduced Aβ 1-42 and γ-secretase levels in both structures. Our findings suggest that our icvAβ 1-42 + pin model is extremely valuable for future AD research.

A reduction in melatonin function contributes to the acceleration of Alzheimer's disease (AD), and understanding the molecular processes of melatonin-related signaling is critical for intervention in AD progression. Recently, we synthesized a series of melatonin analogues with donepezil fragments and tested them in silico and in vitro. In this study, one of the most potent compounds, 3c , was evaluated in a rat model of pinealectomy (pin) followed by icvAβ 1-42 infusion. Melatonin was used as the reference drug. Treatment with melatonin and 3c (10 mg/kg, i.p. for 14 days) had a beneficial effect on memory decline and the concomitant increase in hippocampal Aβ 1-42 and pTAU in the pin+icvAβ 1-42 rats. Melatonin supplementation facilitated non-amyloidogenic signaling via non-receptor (histone deacetylase sirtuin 1, SIRT1) and receptor-related signaling (MT/ERK/CREB). The hybrid 3c analogue up-regulated the MT 1A and MT 2B receptors, pERK and pCREB. Our results strongly support the hypothesis that melatonin-related analogues may become a promising drug candidate for Alzheimer's disease therapy.

Recently, we reported that the atypical antidepressant agomelatine (Ago) exerted a beneficial impact on behavioral changes and concomitant neuropathological events in icvSTZ rat model of sporadic Alzheimer diseases (AD). In the present study, we aimed to explore the effect of Ago (40 mg/kg, i.p. for 30 days) on beta-amyloid (Aβ) metabolism in icvAβ 1-42 rat model of AD. The melatonin analogue was administered either simultaneously with Aβ 1-42 (AβAgo1) or 30 days later during the late stage of the progression of AD (AβAgo2). Treatment with Ago in the early stage of AD attenuated anxiety and depressive-like responses but was inefficient against Aβ-induced impairment of hippocampus-dependent spatial memory. The melatonin analogue, administered both during the early and the late stage of AD, corrected to control level the elevated Aβ 1-42 in the frontal cortex (FC) and the hippocampus. The concentration of α-secretase was enhanced by AβAgo1 compared to the sham- and Aβ-veh groups in the hippocampus. No changes in the concentration of β-secretase in the FC and the hippocampus as well as of γ-secretase in the FC were observed among groups. Both the AβAgo1 and AβAgo2 attenuated to control level the Aβ-induced increased concentration of γ-secretase in the hippocampus. AβAgo1 exerted also structure-specific neuroprotection observed mainly in the CA1, septal CA3b subfield of the dorsal hippocampus and septo-temporal piriform cortex (Pir) and partially in the temporal CA3c, septal and temporal Pir. These findings suggest that Ago treatment in the early stage of AD can exert beneficial effects on concomitant behavioral impairments and neuroprotection in associated brain structures. The antidepressant administration both in the early stage and after the progression of AD affected Aβ metabolism via decreasing of γ-secretase concentration in the hippocampus., (Copyright © 2021 Elsevier Inc. All rights reserved.)

Experimental findings suggest that the melatonin system has a beneficial role in models of Alzheimer's disease (ADs). The aim of the present study was to explore whether the atypical antidepressant agomelatine (Ago), which is a melatonin MT 1 and MT 2 agonist and 5-HT 2C antagonist, is effective against behavioral, biochemical and histological impairments in streptozotocin (STZ)-induced model of ADs in male rats. Male Sprague Dawley rats were treated intraperitoneally (i.p.) with Ago (40 mg/kg) for 30 days starting three months following the intracerebroventricular (icv) injection of STZ. Chronic Ago treatment reduced anxiety-like behavior of STZ-treated rats in the elevated plus maze, increased the preference to saccharine and corrected the spatial memory impairment in the eight-arm radial arm maze test. This melatonin analogue restored STZ-induced biochemical changes, including an increase of beta amyloid (Aβ) protein, and signal markers of inflammation (TNF-alpha and IL-1 beta). Ago exerted partial neuroprotection, specifically in the temporal CA3b subfield of the dorsal hippocampus and temporal piriform cortex. The ability of Ago to alleviate behavioral symptoms and concomitant neuropathological events observed in a model of sporadic ADs suggests that this melatonin alternative can be considered a promising adjuvant in this disease., (Copyright © 2018 Elsevier Inc. All rights reserved.)