Active Targeted Nanoemulsions for Repurposing of Tegaserod in Alzheimer's Disease Treatment.

Line Séguy,Patrick Dallemagne,Audrey Davis,Vincent Lisowski,Pascal Verdié,Anne-Claire Groo,Manon Maurel,Aurélie Malzert-Fréon,Léna Guyon,Sophie Corvaisier

doi:10.3390/pharmaceutics13101626

Abstract

Background and Purpose: The activation of 5-HT4 receptors with agonists has emerged as a valuable therapeutic strategy to treat Alzheimer’s disease (AD) by enhancing the nonamyloidogenic pathway. Here, the potential therapeutic effects of tegaserod, an effective agent for irritable bowel syndrome, were assessed for AD treatment. To envisage its efficient repurposing, tegaserod-loaded nanoemulsions were developed and functionalized by a blood–brain barrier shuttle peptide. Results: The butyrylcholinesterase inhibitory activity of tegaserod and its neuroprotective cellular effects were highlighted, confirming the interest of this pleiotropic drug for AD treatment. In regard to its drugability profile, and in order to limit its peripheral distribution after IV administration, its encapsulation into monodisperse lipid nanoemulsions (Tg-NEs) of about 50 nm, and with neutral zeta potential characteristics, was performed. The stability of the formulation in stock conditions at 4 °C and in blood biomimetic medium was established. The adsorption on Tg-NEs of peptide-22 was realized. The functionalized NEs were characterized by chromatographic methods (SEC and C18/HPLC) and isothermal titration calorimetry, attesting the efficiency of the adsorption. From in vitro assays, these nanocarriers appeared suitable for enabling tegaserod controlled release without hemolytic properties. Conclusion: The developed peptide-22 functionalized Tg-NEs appear as a valuable tool to allow exploration of the repurposed tegaserod in AD treatment in further preclinical studies.

Highlights

Neuroprotective properties of tegaserod have been shown the present work, the repurposing of this 5-HT4R agonist should be a valuable option for Alzheimer’s disease (AD) treatment
To circumvent its poor drugability profile, biocompatible tegaserod-loaded nanoemulsions were successfully formulated and functionalized by the brain-targeting peptide-22 in order to optimize its biodistribution towards central nervous system (CNS), while limiting any adverse cardiac effect
Considering that the tegaserod appeared to be ten-times more effective than donecopride on neurite networks in vitro, the dose administered in vivo could be ten times lower

Summary

Introduction

Alzheimer’s disease (AD) is the most common form of senile dementia, characterized by memory loss and other cognitive impairment with aging. The neuropathological hallmarks of AD include neuronal loss, synaptic dysfunction, intraneuronal neurofibrillary tangles composed of hyperphosphorylated and misfolded tau protein, and extracellular senile plaques, due to the accumulation and the aggregation of β-amyloid peptides (Aβ) [2]. This peptide is a product of the proteolytic degradation of the amyloid precursor protein (APP) according to the amyloidogenic pathway, which involves β- and γ-secretases. The administration of a 5-hydroxytryptamine type-4 receptor (5-HT4 R)

Objectives

Methods

Results

Conclusion