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Drug repurposing for Alzheimer’s disease: Selective serotonin reuptake inhibitors
Author(s) -
Rao Praveen P. Nekkar,
Tin Gary,
Mohamed Tarek,
Shakeri Arash,
Pham Amy Trinh
Publication year - 2020
Publication title -
alzheimer's and dementia
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 6.713
H-Index - 118
eISSN - 1552-5279
pISSN - 1552-5260
DOI - 10.1002/alz.039163
Subject(s) - paroxetine , fluvoxamine , citalopram , antidepressant , sertraline , drug repositioning , fluoxetine , escitalopram , drug , pharmacology , serotonin reuptake inhibitor , drug discovery , dementia , medicine , disease , bioinformatics , serotonin , psychiatry , biology , anxiety , receptor
Background Alzheimer’s disease (AD) is a devastating neurodegenerative disorder which affects more than 50 million people across the globe. Unfortunately, the current pharmacotherapy options are very limited and provide only symptomatic relief. Several drug discovery efforts to treat AD have failed in the clinical trials which is a setback in discovering novel anti‐AD therapies. Considering the cost, time and risks involved in bringing a new drug from the bench‐to‐bedside, drug repurposing or discovering novel therapeutic indications for drugs already in the market is an attractive alternative to find novel AD therapies. Targeting the amyloid (Aβ) cascade event in AD is one of the several potential targets to develop novel anti‐AD agents. Our studies looked at the possibility of repurposing marketed selective serotonin reuptake inhibitors (SSRIs) fluvoxamine, fluoxetine, paroxetine, sertraline and escitalopram in AD and investigated their anti‐Aβ aggregation properties. Method Experiments conducted include fluorescence aggregation kinetics using the dye thioflavin T (ThT), determining Aβ morphology in the presence and absence of SSRIs by transmission electron microscopy (TEM) and computational modeling using the software Discovery Studio Structure‐Based‐Design. Result These experiments demonstrated that among the SSRIs tested, paroxetine in particular was able to prevent the aggregation of both Aβ40 and Aβ42 peptides. Computational studies were used to understand the interactions of paroxetine with Aβ40 and Aβ42 oligomer and fibrils models. Conclusion These studies suggest that the antidepressant paroxetine has the potential to target the amyloid cascade in AD. Further studies are required to determine the suitability of repurposing paroxetine to treat AD.