Chronic polypharmacy impairs explorative behavior and reduces synaptic functions in young adult mice

Abstract

A major challenge in the health care system is the lack of knowledge about the possible harmful effects of multiple drug treatments in old age. The present study aims to characterize a mouse model of polypharmacy, in order to investigate whether long-term exposure to multiple drugs could lead to adverse outcomes. To this purpose we selected five drugs from the ten most commonly used by older adults in Sweden (metoprolol, paracetamol, aspirin, simvastatin and citalopram). Five-month-old wild type male mice were fed for eight weeks with control or polypharmacy diet. We report for the first time that young adult polypharmacy-treated mice showed a significant decrease in exploration and spatial working memory compared to the control group. This memory impairment was further supported by a significant reduction of synaptic proteins in the hippocampus of treated mice. These novel results suggest that already at young adult age, use of polypharmacy affects explorative behavior and synaptic functions. This study underlines the importance of investigating the potentially negative outcomes from concomitant administration of different drugs, which have been poorly explored until now. The mouse model proposed here has translatable findings and can be applied as a useful tool for future studies on polypharmacy.

Diversity of Plant Sterols Metabolism: The Impact on Human Health, Sport, and Accumulation of Contaminating Sterols

“…While Fgf1 and Shh were elevated after supplementation with sterols, Igf1 , Egf and Cntf were almost unaffected by sterols but regulated by cuprizone [ 82 ]. The apparent positive effect of plant sterols on the rate of myelination in MS models agrees with the finding of the decreased cholesterol synthesis after monotherapy treatment with statins inhibiting myelinations [ 110 , 111 ].…”

Deprescribing in the Older Patient: A Narrative Review of Challenges and Solutions

“…15 Polypharmacy for 8 weeks (metoprolol, simvastatin, paracetamol, aspirin and citalopram) in young male mice reduced exploration and spatial working memory. 18 A longitudinal study of treatment from middle to old age, found that polypharmacy regimens with increasing Drug Burden Index 19 (a measure of cumulative exposure to drugs with anticholinergic and sedative effects) impaired physical function in old male mice, which was attenuated by deprescribing. 17 This evidence that polypharmacy with high Drug Burden Index causes impaired function in old age, which is reversible with deprescribing, helps to fill the evidence gap on causation and provides a platform for future studies investigating mechanisms, such as complex drug interactions and the effects on aging biology.…”

Sex-dependent effects of CYP46A1 overexpression on cognitive function during aging

“…Hippocampal mouse tissue and hippocampal rat neurons in primary cultures were lysed in RIPA buffer (50 mM Tris, 150 mM NaCl, 1% Triton X-100, 0.1% SDS) supplemented with protease and phosphatase inhibitor cocktail (Sigma, Aldrich 1:100, 1 mM EDTA and 1 mM EGTA). Western blot was performed as previously described 29 . The following primary antibodies were used: anti-RAR alpha (Abcam ab28767, 1:500), anti-ER alpha (Abcam ab3575, 1:1000), anti-ER-beta (Santa Cruz Biotechnology sc-53494, 1:1000), Arc (Santa Cruz Biotechnology sc-15325, 1:1000), Aromatase (Abcam 18995, 1:1000), phospho-CREB (Cell Signaling 86B10, 1:1000), ADAM 10 (Abcam ab1997, 1:500).…”

“…The experiments were performed in white light and by the same experimenters. EPM, DLB and Y-Maze protocols were run as previously described in details 29 . For MWM test, the mice were trained to find a hidden escape (the platform) as previously described 4,16 .…”