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<p>Patients with Alzheimer’s disease (AD) have two types of abnormal protein buildups: amyloid plaques and neurofibrillary tangles, in addition to the early synaptic dysfunction associated with the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Impairment of the glutamatergic system is also crucial for neuronal survival, as it can cause synaptic dysfunction that overstimulates glutamate receptors, especially N-methyl-d-aspartate receptors (NMDARs). Another protein affecting neuronal health is glycogen synthase kinase-3 (GSK3), a widely preserved serine/threonine protein kinase linked to neuronal disorders, including AD. In recent years, alkaloids from the Amaryllidaceae have received great attention for their known anticholinergic activity, as well as their antioxidant, antigenotoxic, and neuroprotective properties. In this context, the identification of compounds capable of interacting with different targets involved in AD provides a possible new therapeutic strategy. In this study, we conducted a combination of in vitro and in silico approaches to identify the potential of <i>C. subedentata</i> in regulating key proteins involved in AD. Viability and neuroprotection assays were performed to evaluate the neuroprotection exerted by <i>C. subedentata</i> extract against neurotoxicity induced by Aβ (1–42) peptide and Okadaic acid in SH-SY5Y cells. Computational methods such as docking and molecular dynamic and viability therapeutic analysis were conducted to explore the interaction of alkaloids from <i>C. subedentata</i> with target proteins (AChE, BuChE, NMDA, and GSK-3) involved in AD. Our findings show that C. <i>subedentata</i> extract exerts neuroprotective effects against neurotoxic stimuli induced by Aβ (1–42) peptide and Okadaic acid. In addition, in silico approaches provide insight into how <i>C. subedentata</i> extract alkaloids interact with key proteins involved in AD. These findings provide insights into the potential therapeutic effects and action mechanisms of these alkaloids. We hope these rapid findings can contribute as a bridge to the identification of new molecules with the potential to counteract the effects of AD.</p>

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Alkaloids from Caliphruria subedentata (Amaryllidaceae) as Regulators of AChE, BuChE, NMDA and GSK3 Activity: An In Vitro and In Silico Approach for Mimicking Alzheimer´s Disease

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2025年3月8日

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  • Willian Orlando Castillo Ordoñez,
  • Nilza Velasco Palomino,
  • Patricia Eugenia Vélez Varela,
  • Ivon Bolaños Martínez,
  • Levy Bueno Alves,
  • Silvana Giuliatti

摘要

Patients with Alzheimer’s disease (AD) have two types of abnormal protein buildups: amyloid plaques and neurofibrillary tangles, in addition to the early synaptic dysfunction associated with the enzymes acetylcholinesterase (AChE) and butyrylcholinesterase (BuChE). Impairment of the glutamatergic system is also crucial for neuronal survival, as it can cause synaptic dysfunction that overstimulates glutamate receptors, especially N-methyl-d-aspartate receptors (NMDARs). Another protein affecting neuronal health is glycogen synthase kinase-3 (GSK3), a widely preserved serine/threonine protein kinase linked to neuronal disorders, including AD. In recent years, alkaloids from the Amaryllidaceae have received great attention for their known anticholinergic activity, as well as their antioxidant, antigenotoxic, and neuroprotective properties. In this context, the identification of compounds capable of interacting with different targets involved in AD provides a possible new therapeutic strategy. In this study, we conducted a combination of in vitro and in silico approaches to identify the potential of C. subedentata in regulating key proteins involved in AD. Viability and neuroprotection assays were performed to evaluate the neuroprotection exerted by C. subedentata extract against neurotoxicity induced by Aβ (1–42) peptide and Okadaic acid in SH-SY5Y cells. Computational methods such as docking and molecular dynamic and viability therapeutic analysis were conducted to explore the interaction of alkaloids from C. subedentata with target proteins (AChE, BuChE, NMDA, and GSK-3) involved in AD. Our findings show that C. subedentata extract exerts neuroprotective effects against neurotoxic stimuli induced by Aβ (1–42) peptide and Okadaic acid. In addition, in silico approaches provide insight into how C. subedentata extract alkaloids interact with key proteins involved in AD. These findings provide insights into the potential therapeutic effects and action mechanisms of these alkaloids. We hope these rapid findings can contribute as a bridge to the identification of new molecules with the potential to counteract the effects of AD.