Melatonin reduces β-amyloid accumulation and improves short-term memory in streptozotocin-induced sporadic Alzheimer’s disease model

Andrade, Marcos K.; Souza, Leonardo C.; Azevedo, Evellyn M.; Bail, Ellen Larissa; Zanata, Sı́lvio M.; Andreatini, Roberto; Vital, Maria A.B.F.

doi:10.1016/j.ibneur.2023.01.005

Cited by 15 publications

(11 citation statements)

References 87 publications

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“…In line with prior research (Andrade et al, 2023), the administration of STZ (i.c.v) was found to negatively impact cognitive function in mice. Similarly, our study observed a decline in learning ability and memory among the STZ group when compared to the control group.…”

Section: Resultssupporting

confidence: 86%

N‐methylpiperazinyl and piperdinylalkyl‐O‐chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation

Sharma,

Singh,

Singh

2023

Chem Biol Drug Des

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The series of N‐methylpiperazinyl and piperdinylalkyl‐O‐chalcone derivatives as potential polyfuctional agents against Alzheimer's disease that have been designed, synthesized and then evaluated biologically using in vitro assays for the inhibition of acetylcholinesterase (AChE) activity, AGEs, and free radical formation. The majority of synthesized compounds inhibited AChE & AGEs with additional free radical scavenging activities at nanomolar concentrations. Among these, compound 5k was found to have potent AChE inhibitory activity (IC50 = 11.6 nM), superior than the reference compound donepezil (15.68 nM) along with the good anti‐AGEs and free radical formation effect. Its potency was justified by docking studies that revealed its dual binding characteristic with both catalytic active site and peripheral anionic site of AChE, simultaneously. Furthermore, the in vivo evaluation of 5k against streptozotocin (STZ)‐induced dementia in rats also showed improvement of memory functions (Morris water maze test) in animals. Also, 5k inhibited STZ‐inudced brain AChE activity and oxidative stress which further strengthen the observed in vitro effects. The stability of the ligand‐protein complex was then analyzed using a simulation‐based interaction protocol. The results revealed that these N‐methylpiperazinyl and piperdinylalkyl‐O‐chalcone derivatives could be considered for potential polyfunctional anti‐Alzheimer's molecules.

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Section: Resultssupporting

confidence: 86%

N‐methylpiperazinyl and piperdinylalkyl‐O‐chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation

Sharma,

Singh,

Singh

2023

Chem Biol Drug Des

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“…Previous studies have shown that STZ (i.c.v) administration impairs cognitive function in rodents [ 55 ]. Consistent with these findings, our study also found declined memory and learning ability in the STZ group than the control animals, which was significantly reversed by treatment with PS10 .…”

Section: Resultsmentioning

confidence: 99%

Recent Development of Novel Aminoethyl-Substituted Chalcones as Potential Drug Candidates for the Treatment of Alzheimer’s Disease

Sharma,

Singh,

Singh

et al. 2023

Molecules

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No drug on the market, as a single entity, participates in different pathways involved in the pathology of Alzheimer’s disease. The current study is aimed at the exploration of multifunctional chalcone derivatives which can act on multiple targets involved in Alzheimer’s disease. A series of novel aminoethyl-substituted chalcones have been developed using in silico approaches (scaffold morphing, molecular docking, and ADME) and reported synthetic methods. The synthesized analogs were characterized and evaluated biologically using different in vitro assays against AChE, AGEs, and radical formation. Among all compounds, compound PS-10 was found to have potent AChE inhibitory activity (IC50 = 15.3 nM), even more than the standard drug (IC50 = 15.68 nM). Further, the in vivo evaluation of PS-10 against STZ-induced dementia in rats showed memory improvement (Morris Water Maze test) in rats. Also, PS-10 inhibited STZ-induced brain AChE activity and oxidative stress, further strengthening the observed in vitro effects. Further, the molecular dynamic simulation studies displayed the stability of the PS-10 and AChE complex. The novel aminoethyl-substituted chalcones might be considered potential multifunctional anti-Alzheimer’s molecules.

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“…Our results showed that, while the novel hybrid compound 3c is ineffective against impaired non-spatial cognitive performance, such as the ORT in a rat model of pin+icvAβ 1-42 , this melatonin analogue has a comparable potency to the positive control melatonin in correcting the impaired short-term and spatial hippocampus-dependent memory. The beneficial role of melatonin supplementation on spatial memory decline has been demonstrated in several models of AD, including the hereditary form of AD, such as mouse transgenic and knockout mice [19,25,26], and the sporadic form of AD, such as senescence-accelerated OXYS rats [21], streptozotosin- [27,28] and icvAβ 1-42 -induced models [29].…”

Section: Discussionmentioning

confidence: 99%

Protective Effect of the Novel Melatonin Analogue Containing Donepezil Fragment on Memory Impairment via MT/ERK/CREB Signaling in the Hippocampus in a Rat Model of Pinealectomy and Subsequent Aβ1-42 Infusion

Tchekalarova,

Ivanova,

Krushovlieva

et al. 2024

IJMS

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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 icvAβ1-42 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 Aβ1-42 and pTAU in the pin+icvAβ1-42 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 MT1A and MT2B 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.

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Melatonin reduces β-amyloid accumulation and improves short-term memory in streptozotocin-induced sporadic Alzheimer’s disease model

Cited by 15 publications

References 87 publications

N‐methylpiperazinyl and piperdinylalkyl‐O‐chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation

N‐methylpiperazinyl and piperdinylalkyl‐O‐chalcone derivatives as potential polyfunctional agents against Alzheimer's disease: Design, synthesis and biological evaluation

Recent Development of Novel Aminoethyl-Substituted Chalcones as Potential Drug Candidates for the Treatment of Alzheimer’s Disease

Protective Effect of the Novel Melatonin Analogue Containing Donepezil Fragment on Memory Impairment via MT/ERK/CREB Signaling in the Hippocampus in a Rat Model of Pinealectomy and Subsequent Aβ1-42 Infusion

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