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[P3–048]: COMPARATIVE EFFECTS OF DDP4 INHIBITOR AND SGLT2 INHIBITOR ON BRAIN FUNCTION UNDER OBESE‐INSULIN RESISTANT CONDITION
Author(s) -
Chattipakorn Siriporn C.,
Sanguanmoo Piangkwan,
Tanajak Pongpun,
Kerdphoo Sasiwan,
Jaiwongkam Thidarat,
Pratchayasakul Wasana,
Chattipakorn Nipon
Publication year - 2017
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 - 10.1016/j.jalz.2017.06.1861
Subject(s) - vildagliptin , dapagliflozin , insulin resistance , endocrinology , medicine , insulin , neuroprotection , cognitive decline , dipeptidyl peptidase 4 , hippocampal formation , diabetes mellitus , type 2 diabetes , dementia , disease
Background:Enhancing the efficacy of drugs targeting cognitive decline in Alzheimer disease (AD), together with improving their safety, has been a long-term goal of therapeutic development. Currently approved standards of care (SOCs) exhibit transient efficacy and their use is accompanied by undesirable side effects. Thus, drug combination therapies, particularly those applying low doses, may represent next generation therapies for AD. Methods:We previously demonstrated the synergistic effectiveness of a combination therapy (known as PXT864) consisting of two repurposed drugs – acamprosate and baclofen – in AD models. As patients are usually treated with a SOC, we investigated whether the efficacy of these SOCs at inactive doses is improved by combining them with low or inactive doses of PXT864. To this end, we assessed the efficacy of PXT864 combined with the SOCs, donepezil or memantine, on different cellular and behavioral endpoints in an in vitro neuronal primary culture model intoxicated with oligomeric b-amyloid peptides (Ab), and an in vivo intracebroventricular Ab-injection mouse model. Results:We found that tri-therapy with PXT864+donepezil or PXT864+memantine synergistically protected neuronal cells against Ab toxicity with a higher protective effect than the individual drugs alone. In AD model animals, doses of individual drugs selected for their inactivity, and binary combinations of such doses of individual drugs, were totally ineffective whereas the tri-therapeutic combination synergistically alleviated cognitive deficits. Conclusions:These findings highlight the value of using repurposed drugs combined with low doses of existing SOC therapeutics, and emphasize the value of network pharmacology approach that allows to discover combinations with new mechanisms of action.