The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease

Abstract Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immun...

Descripción completa

Guardado en:

Detalles Bibliográficos
Autores principales:	Diana L. Price, Maya A. Koike, Asma Khan, Wolfgang Wrasidlo, Edward Rockenstein, Eliezer Masliah, Douglas Bonhaus
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2018
Materias:	ASYN Misfolding Dementia With Lewy Bodies (DLB) Brain Penetrance University Of California At San Diego (UCSD) Tyrosine Hydroxylase Medicine R Science Q
Acceso en línea:	https://doaj.org/article/e92a50d06223471a8b71cbee5518de64
Etiquetas:	Agregar Etiqueta Sin Etiquetas, Sea el primero en etiquetar este registro!

id	oai:doaj.org-article:e92a50d06223471a8b71cbee5518de64
record_format	dspace
spelling	oai:doaj.org-article:e92a50d06223471a8b71cbee5518de642021-12-02T15:08:03ZThe small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease10.1038/s41598-018-34490-92045-2322https://doaj.org/article/e92a50d06223471a8b71cbee5518de642018-11-01T00:00:00Zhttps://doi.org/10.1038/s41598-018-34490-9https://doaj.org/toc/2045-2322Abstract Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.Diana L. PriceMaya A. KoikeAsma KhanWolfgang WrasidloEdward RockensteinEliezer MasliahDouglas BonhausNature PortfolioarticleASYN MisfoldingDementia With Lewy Bodies (DLB)Brain PenetranceUniversity Of California At San Diego (UCSD)Tyrosine HydroxylaseMedicineRScienceQENScientific Reports, Vol 8, Iss 1, Pp 1-12 (2018)
institution	DOAJ
collection	DOAJ
language	EN
topic	ASYN Misfolding Dementia With Lewy Bodies (DLB) Brain Penetrance University Of California At San Diego (UCSD) Tyrosine Hydroxylase Medicine R Science Q
spellingShingle	ASYN Misfolding Dementia With Lewy Bodies (DLB) Brain Penetrance University Of California At San Diego (UCSD) Tyrosine Hydroxylase Medicine R Science Q Diana L. Price Maya A. Koike Asma Khan Wolfgang Wrasidlo Edward Rockenstein Eliezer Masliah Douglas Bonhaus The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease
description	Abstract Accumulation of alpha-synuclein (ASYN) in neurons and other CNS cell types may contribute to the underlying pathology of synucleinopathies including Parkinson’s disease (PD), dementia with Lewy bodies (DLB) and Multiple Systems Atrophy (MSA). In support of this hypothesis for PD, ASYN immunopositive aggregates are a prominent pathological feature of PD, and mutations and gene multiplications of human wild type (WT) ASYN cause rare familial autosomal-dominant forms of PD. Targeted therapeutics that reduce the accumulation of ASYN could prevent or slow the neurodegenerative processes in PD and other synucleinopathies. NPT200-11 is a novel small molecule inhibitor of ASYN misfolding and aggregation. The effects of NPT200-11 on ASYN neuropathology were evaluated in animal models over expressing human alpha synuclein. Longitudinal studies using retinal imaging in mice expressing a hASYN::GFP fusion protein revealed that 2 months of once daily administration of NPT200-11 (5 mg/kg IP) resulted in a time-dependent and progressive reduction in retinal ASYN pathology. The effects of NPT200-11 on ASYN pathology in cerebral cortex and on other disease-relevant endpoints was evaluated in the Line 61 transgenic mouse model overexpressing human wild type ASYN. Results from these studies demonstrated that NPT200-11 reduced alpha-synuclein pathology in cortex, reduced associated neuroinflammation (astrogliosis), normalized striatal levels of the dopamine transporter (DAT) and improved motor function. To gain insight into the relationship between dose, exposure, and therapeutic benefit pharmacokinetic studies were also conducted in mice. These studies demonstrated that NPT200-11 is orally bioavailable and brain penetrating and established target plasma and brain exposures for future studies of potential therapeutic benefit.
format	article
author	Diana L. Price Maya A. Koike Asma Khan Wolfgang Wrasidlo Edward Rockenstein Eliezer Masliah Douglas Bonhaus
author_facet	Diana L. Price Maya A. Koike Asma Khan Wolfgang Wrasidlo Edward Rockenstein Eliezer Masliah Douglas Bonhaus
author_sort	Diana L. Price
title	The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease
title_short	The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease
title_full	The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease
title_fullStr	The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease
title_full_unstemmed	The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease
title_sort	small molecule alpha-synuclein misfolding inhibitor, npt200-11, produces multiple benefits in an animal model of parkinson’s disease
publisher	Nature Portfolio
publishDate	2018
url	https://doaj.org/article/e92a50d06223471a8b71cbee5518de64
work_keys_str_mv	AT dianalprice thesmallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT mayaakoike thesmallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT asmakhan thesmallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT wolfgangwrasidlo thesmallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT edwardrockenstein thesmallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT eliezermasliah thesmallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT douglasbonhaus thesmallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT dianalprice smallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT mayaakoike smallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT asmakhan smallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT wolfgangwrasidlo smallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT edwardrockenstein smallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT eliezermasliah smallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease AT douglasbonhaus smallmoleculealphasynucleinmisfoldinginhibitornpt20011producesmultiplebenefitsinananimalmodelofparkinsonsdisease
_version_	1718388288553746432

The small molecule alpha-synuclein misfolding inhibitor, NPT200-11, produces multiple benefits in an animal model of Parkinson’s disease

Ejemplares similares