Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit beta-amyloid aggregation

Markowicz-Piasecka, Magdalena; Huttunen, Kristiina M.; Sikora, Joanna

doi:10.1080/14756366.2018.1499627

Cited by 20 publications

(5 citation statements)

References 58 publications

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“…[16][17][18] Similarly, another study has shown that Met, and its derivatives, can improve the activity of human acetylcholinesterase (AChE) and inhibit beta-amyloid aggregation. 19 However, epidemiological researchers have reported inconsistencies concerning the studies that Met is related to an increased risk of neurodegenerative diseases (NDs). 3,20,21 Some studies suggested a reduced risk of NDs with Met treatment, [22][23][24][25][26][27][28] while others reported no association.…”

Section: Introductionmentioning

confidence: 99%

Metformin and the risk of dementia based on an analysis of 396,332 participants

Zhao

Zhu

et al. 2022

Therapeutic Advances in Chronic Disease

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Background: AMPK has attracted widespread interest as a potential therapeutic target for age-related diseases, given its key role in controlling energy homeostasis. Metformin (Met) has historically been used to treat Type 2 diabetes and has been shown to counteract age-related diseases. However, studies regarding the relationship between Met and a variety of age-related classifications of cognitive decline have reported mixed findings. Objective: To assess the potential effect of Met on the onset of dementia and discuss the possible biological mechanisms involved. Methods: This study was registered in the PROSPERO database (CRD420201251468). PubMed, Embase, and Cochrane Library were searched from inception to 25 May 2021, for population-based cohort studies. Effect estimates with 95% confidence intervals (CIs) were pooled using the random-effects model. Meta-regression and subgroup analyses were performed to explore sources of heterogeneity and the stability of the results. Results: Fourteen population-based cohort studies (17 individual comparisons) involving 396,332 participants were identified. Meta-analysis showed that Met exposure was significantly associated with reduced risk of all subtypes of dementias [relative risk (RR) = 0.79, 95% CI = 0.68–0.91; p < 0.001]. Conversely, no significant reduction in risk was observed for those who received Met monotherapy at the onset of vascular dementia (VD), Parkinson’s disease (PD), and Alzheimer’s disease (AD). The effect was more prominent in patients who had long-term Met exposure (⩾4 years) (RR = 0.38, 95% CI = 0.32–0.46; p < 0.001), while no such significant effect was found with short-term Met exposure (1–2 years) (RR = 1.20, 95% CI = 0.87–1.66; p < 0.001). Moreover, no association was observed for Met exposure in participants of European descent (RR = 1.01, 95% CI = 0.66–1.54; p = 0.003) compared with those from other countries. Conclusion: Based on the evidence from population-based cohort studies, our findings suggest that the AMPK activator, Met, is a potential geroprotective agent for dementias, particularly among long-term Met users. Due to the significant heterogeneity among the included studies, we should interpret the results with caution.

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Section: Introductionmentioning

confidence: 99%

Metformin and the risk of dementia based on an analysis of 396,332 participants

Zhao

Zhu

et al. 2022

Therapeutic Advances in Chronic Disease

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“…Controversy may be raised in treating cancers and neurodegenerative diseases. Among the targeted therapeutic agents, AMPK activator drugs, e.g., metformin and berberine, have potential therapeutic applications in metabolic disorders, neurodegenerative diseases, and cancers [84][85][86][87][88][89][90][91]. Our recent works and this report revealed that n-BP can functionally activate AMPK [81], although the details of its mechanism in autophagy remain an effort to be addressed.…”

Section: Discussionmentioning

confidence: 81%

n-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway

Lee

Lin

Liu

et al. 2021

IJMS

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Spinocerebellar ataxia type 3 (SCA3), a hereditary and lethal neurodegenerative disease, is attributed to the abnormal accumulation of undegradable polyglutamine (polyQ), which is encoded by mutated ataxin-3 gene (ATXN3). The toxic fragments processed from mutant ATXN3 can induce neuronal death, leading to the muscular incoordination of the human body. Some treatment strategies of SCA3 are preferentially focused on depleting the abnormal aggregates, which led to the discovery of small molecule n-butylidenephthalide (n-BP). n-BP-promoted autophagy protected the loss of Purkinje cell in the cerebellum that regulates the network associated with motor functions. We report that the n-BP treatment may be effective in treating SCA3 disease. n-BP treatment led to the depletion of mutant ATXN3 with the expanded polyQ chain and the toxic fragments resulting in increased metabolic activity and alleviated atrophy of SCA3 murine cerebellum. Furthermore, n-BP treated animal and HEK-293GFP-ATXN3-84Q cell models could consistently show the depletion of aggregates through mTOR inhibition. With its unique mechanism, the two autophagic inhibitors Bafilomycin A1 and wortmannin could halt the n-BP-induced elimination of aggregates. Collectively, n-BP shows promising results for the treatment of SCA3.

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“…A previous study showed that phenformin with an AChE SI value of 0.052 indicating that it was BChE selective did not alter the AChE SI value of donepezil, whereas a metformin sulphonamide derivative with an AChE SI value of 3.23 increased the AChE SI value of donepezil around 200-fold higher. On the other hand, metformin with an AChE SI value of > 425.53 did not alter the AChE SI value of donepezil either (Markowicz-Piasecka et al, 2018). Many factors may thus, be at work for this apparent discrepancy.…”

Section: A R T I C L E I N P R E S Smentioning

confidence: 82%

Inhibition of Cholinesterases by Water-Soluble Palm Fruit Extract

Leow¹

2021

JOPR

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Cholinesterase (ChE) inhibitors are used for the symptomatic treatment of Alzheimer's disease and other neurological pathologies. There is interest in developing new ChE inhibitors from natural plant compounds. Water-soluble palm fruit extract (WSPFE) recovered from the aqueous oil palm vegetation liquor is rich in phenolic acids and has potential neuroprotective effects. Here, we investigated the effects of WSPFE samples on acetylcholinesterase (AChE) and butyrylcholinesterase (BChE). WSPFE ethyl acetate fraction (EAF) inhibited these enzymes the most (AChE IC 50 : 0.218 ± 0.029 µg ml -1 ; BChE IC 50 : 222.860 ± 5.777 µg ml -1 ) and had the highest AChE selectivity index (SI) value (1022.294) compared to whole samples and seven individual fractions but these effects were weaker than those of the AChE selective agent donepezil hydrochloride (DH) (AChE IC 50 : 0.013 ± 0.001 µg ml -1 ; BChE IC 50 : 19.820 ± 1.415 µg ml -1 ; AChE SI: 1524.615). Fractions containing p-hydroxybenzoic acid and protocatechuic acid had the lowest AChE SI values (7.584 and 9.367 respectively) and may thus, function as dual ChE inhibitors. Binary mixtures of DH and WSPFE EAF might have more potent inhibitory effects against these enzymes, as well as higher BChE/AChE selectivity. Further studies to investigate the ChE inhibition potential of these WSPFE samples are warranted.

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Metformin and its sulphonamide derivative simultaneously potentiateanti-cholinesterase activity of donepezil and inhibit beta-amyloid aggregation

Cited by 20 publications

References 58 publications

Metformin and the risk of dementia based on an analysis of 396,332 participants

Metformin and the risk of dementia based on an analysis of 396,332 participants

n-Butylidenephthalide Modulates Autophagy to Ameliorate Neuropathological Progress of Spinocerebellar Ataxia Type 3 through mTOR Pathway

Inhibition of Cholinesterases by Water-Soluble Palm Fruit Extract

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