The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

The proof-of-concept of ASS234: Peripherally administered ASS234 enters the central nervous system and reduces pathology in a male mouse model of Alzheimer disease

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J Psychiatry Neurosci 2017;42(1):59-69

Mari Paz Serrano, BS*; Raquel Herrero-Labrador, MSc*; Hunter S. Futch, BS; Julia Serrano, PhD; Alejandro Romero, PhD; Ana Patricia Fernandez, PhD; Abdelouahid Samadi, PhD; Mercedes Unzeta, PhD; Jose Marco-Contelles, PhD; Ricardo Martínez-Murillo, MD, PhD

Abstract

Background: The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both holinergic and monoamine oxidase dysfunctions are involved in the pathological process. Thus, we hypothesized that the development of therapies focused on these targets might be effective. We have developed and assessed a new product, coded ASS234, a multipotent acetyl and butyrylcholinesterase/monoamine oxidase A-B inhibitor with a potent inhibitory effect on amyloid-ß aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data.

Methods: We examined the effect of ASS234 on cognition in healthy adult C57BL/6J mice in a model of scopolamine-induced cognitive impairment that often accompanies normal and pathological aging. Also, in a characterized transgenic APPswe/PS1ΔE9 mouse model of Alzheimer disease, we examined the effects of short-term ASS234 treatment on plaque deposition and gliosis using immunohistochemistry. Toxicology of ASS234 was assessed using a quantitative high-throughput in vitro cytotoxicity screening assay following the MTT assay method in HepG2 liver cells.

Results: In vivo, ASS234 significantly decreased scopolamine-induced learning deficits in C57BL/6J mice. Also, reduction of amyloid plaque burden and gliosis in the cortex and hippocampus was assessed. In vitro, ASS234 exhibited lesser toxicity than donepezil and tacrine.

Limitations: The study was conducted in male mice only. Although the Alzheimer disease model does not recapitulate all features of the human disease, it exhibits progressive monoaminergic neurodegeneration.

Conclusion: ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.


Submitted June 2, 2015; Revised Jan. 3, 2016; Revised Mar. 10, 2016; Revised Mar. 22, 2016; Accepted Mar. 28, 2016; Early-released Sept. 20, 2016

*These authors contributed equally to this work.

Acknowledgements: The authors thank Soledad Martinez Montero for excellent technical assistance. The study received research support from the MINECO (Government of Spain grant SAF2015-65586 awarded to R. Martínez-Murillo and J. Marco-Contelles and grant SAF2012-33304 awarded to J. Marco-Contelles). The authors thank Universidad Camilo José Cela for support (grant 2014-35).

Affiliations: From the Neurovascular Research Group, Department of Translational Neurobiology, Cajal Institute (CSIC), Madrid, Spain (Serrano, Herrero-Labrador, Serrano, Fernandez, Martínez-Murillo); the Departament of Toxicology and Pharmacology, School of Veterinary, Complutense University of Madrid, Madrid, Spain (Romero); the Laboratory of Medicinal Chemistry, Institute of Organic Chemistry (CSIC), Madrid, Spain (Marco-Contelles); the College of Medicine, University of Florida, Gainesville, Florida. USA (Futch); the Departament de Bioquímica i Biología Molecular, Facultat de Medicina, Universitat Autònoma de Barcelona, Barcelona, Spain (Unzeta); and the Department of Chemistry, United Arab Emirates University, Abu Dhabi, United Arab Emirates (Samadi).

Competing interests: None declared.

Contributors: J. Marco-Contelles, M. Unzeta and R. Martínez-Murillo designed the study. M. Serrano, R. Herrero-Labrador, H. Futch and A. Romero acquired the data, which M. Serrano, R. Herrero-Labrador, A. Romero, J. Serrano, A. Fernandez, A. Samadi, M. Unzeta and R. Martínez-Murillo analyzed. H. Futch, J. Marco-Contelles and R. Martínez-Murillo wrote the article, which all authors reviewed and approved for publication.

DOI: 10.1503/jpn.150209

Correspondence to: R. Martinez-Murillo, Department of Translational Neurobiology, Neurovascular Research Group, Cajal Institute (CSIC), Avenida Doctor Arce 37, 28002-Madrid, Spain; r.martinez@cajal.csic.es