Title:Development of Neuroprotective Agents for the Treatment
of Alzheimer's Disease using Conjugates of Serotonin with
Sesquiterpene Lactones
Volume: 31
Issue: 5
Author(s): Margarita Neganova, Junqi Liu, Yulia Aleksandrova, Natalia Vasilieva, Alexey Semakov, Ekaterina Yandulova, Olga Sukocheva*, Konstantin Balakin, Sergey Klochkov and Ruitai Fan*
Affiliation:
- Discipline of Health Sciences, College of Nursing and Health Sciences, Flinders University, Bedford Park, South Australia, Australia
- Department of Radiation Oncology, The First Affiliated Hospital of Zhengzhou University, Erqi, Zhengzhou, China
- Cancer Center, The First Affiliated Hospital of Zhengzhou University, Zhengzhou, China
Keywords:
Natural compounds, sesquiterpene lactones, conjugates, antioxidant effect, mitoprotective properties, β-amyloid aggregation, 5xFAD transgenic mice, Alzheimer’s disease.
Abstract:
Background: Sesquiterpene lactones are secondary plant metabolites with a wide variety
of biological activities. The process of lactone conjugation to other pharmacophores can increase the
efficacy and specificity of the conjugated agent effect on molecular targets in various diseases, including
brain pathologies. Derivatives of biogenic indoles, including neurotransmitter serotonin, are of
considerable interest as potential pharmacophores. Most of these compounds have neurotropic activity
and, therefore, can be used in the synthesis of new drugs with neuroprotective properties.
Aim: The aim of this experimental synthesis was to generate potential treatment agents for
Alzheimer's disease using serotonin conjugated with natural sesquiterpene lactones.
Methods: Three novel compounds were obtained via the Michael reaction and used for biological testing.
The obtained conjugates demonstrated complex neuroprotective activities. Serotonin conjugated
to isoalantolactone exhibited strong antioxidant and mitoprotective activities.
Results: The agent was also found to inhibit β-site amyloid precursor protein cleaving enzyme 1
(BACE-1), prevent the aggregation of β-amyloid peptide 1-42, and protect SH-SY5Y neuroblastoma
cells from neurotoxins such as glutamate and H2O2. In a transgenic animal model of Alzheimer's disease
(5xFAD line), the conjugated agent restored declined cognitive functions and improved learning
and memory.
Conclusion: In conclusion, the obtained results indicate that serotonin conjugates to sesquiterpene
lactones are promising agents for the treatment of symptoms associated with Alzheimer's disease.
