title: 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.
abstract: The heterogeneity of Alzheimer disease requires the development of multitarget drugs for treating the symptoms of the disease and its progression. Both cholinergic 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-β aggregation as well as antioxidant and antiapoptotic properties. But there is a need to reliably correlate in vitro and in vivo drug release data.
  
  
  
  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.
  
  
  
  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.
  
  
  
  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.
  
  
  
  ASS234 is a promising alternative drug of choice to treat the cognitive decline and neurodegeneration underlying Alzheimer disease.
authors.affiliation: 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).
authors.forename: Mari Paz
authors.initials: MP
authors.lastname: Serrano
authors.affiliation: 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).
authors.forename: Raquel
authors.initials: R
authors.lastname: Herrero-Labrador
authors.affiliation: 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).
authors.forename: Hunter S
authors.initials: HS
authors.lastname: Futch
authors.affiliation: 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).
authors.forename: Julia
authors.initials: J
authors.lastname: Serrano
authors.affiliation: 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).
authors.forename: Alejandro
authors.initials: A
authors.lastname: Romero
authors.affiliation: 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).
authors.forename: Ana Patricia
authors.initials: AP
authors.lastname: Fernandez
authors.affiliation: 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).
authors.forename: Abdelouahid
authors.initials: A
authors.lastname: Samadi
authors.affiliation: 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).
authors.forename: Mercedes
authors.initials: M
authors.lastname: Unzeta
authors.affiliation: 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).
authors.forename: Jose
authors.initials: J
authors.lastname: Marco-Contelles
authors.affiliation: 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).
authors.forename: Ricardo
authors.initials: R
authors.lastname: Martínez-Murillo
mesh_terms: D000544:Alzheimer Disease / Q000188:drug therapy* / Q000473:pathology; D000818:Animals; D002470:Cell Survival / Q000187:drug effects; D002540:Cerebral Cortex / Q000187:drug effects* / Q000473:pathology; D004195:Disease Models, Animal; D000077265:Donepezil; D005911:Gliosis / Q000188:drug therapy / Q000473:pathology; D056945:Hep G2 Cells; D006624:Hippocampus / Q000187:drug effects* / Q000378:metabolism; D006801:Humans; D007189:Indans / Q000633:toxicity; D007211:Indoles / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D007858:Learning / Q000187:drug effects*; D008297:Male; D008810:Mice, Inbred C57BL; D018697:Nootropic Agents / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D010880:Piperidines / Q000008:administration & dosage* / Q000737:chemistry / Q000633:toxicity; D058225:Plaque, Amyloid / Q000188:drug therapy / Q000473:pathology; D000075082:Proof of Concept Study; D021641:Recognition, Psychology / Q000187:drug effects; D012601:Scopolamine; D013619:Tacrine / Q000633:toxicity
chemical_list: D007189:Indans; D007211:Indoles; C570530:N-((5-(3-(1-benzylpiperidin-4-yl)propoxy)-1-methyl-1H-indol-2-yl)methyl)-N-methylprop-2-yn-1-amine; D018697:Nootropic Agents; D010880:Piperidines; D013619:Tacrine; D000077265:Donepezil; D012601:Scopolamine