Unilateral intranigral administration of β-sitosterol β-D-glucoside triggers pathological α-synuclein spreading and bilateral nigrostriatal dopaminergic neurodegeneration in the rat

Acta Neuropathologica Communications

America Padilla-Viveros¹  Cecilia Bañuelos¹  María E. Gutierrez-Castillo²  Irma A. Martínez-Dávila³  José Dávila-Ayala³  Bismark Gatica-Garcia³  Daniel Martinez-Fong³  David Reyes-Corona³  Linda Garcés-Ramírez⁴  Fidel De La Cruz-lópez⁴  Claudia Luna-Herrera⁴  Oriana Hidalgo-Alegria⁴  Víctor Manuel Blanco-Alvarez⁵  Luis O. Soto-Rojas⁶  Guadalupe Soto-Rodriguez⁷  María Elena Bringas Tobon⁸  Gonzalo Flores⁸  Francisco E. Lopez-Salas⁹ 

[1] Coordinación General de Programas de Posgrado Multidisciplinarios, Programa de Doctorado Transdisciplinario en Desarrollo Científico y Tecnológico para la Sociedad;Departamento de Biociencias e Ingeniería, Centro Interdisciplinario de Investigaciones y Estudios sobre Medio Ambiente y Desarrollo, Instituto Politécnico Nacional;Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados del Instituto Politécnico Nacional;Departamento de Fisiología, Escuela Nacional de Ciencias Biológicas, Instituto Politécnico Nacional, Av. Wilfrido Massieu s/n, Unidad Profesional “Adolfo López Mateos”;Facultad de Enfermeria, Benemérita Universidad Autónoma de Puebla;Facultad de Estudios Superiores Iztacala, Universidad Nacional Autónoma de México;Facultad de Medicina, Benemérita Universidad Autónoma de Puebla;Instituto de Fisiología, Benemérita Universidad Autónoma de Puebla;Programa de Doctorado en Nanociencias y Nanotecnología, Av. Instituto Politécnico Nacional No. 2508, Centro de Investigación y de Estudios Avanzados;

关键词: Lewy body-like synuclein aggregations;    Parkinson’s disease;    BSSG;    Sensorimotor alterations;    Bilateral affectation;    Synuclein spreading;   

DOI  :  10.1186/s40478-020-00933-6

来源: DOAJ

【 摘 要 】

Abstract The spreading and accumulation of α-synuclein and dopaminergic neurodegeneration, two hallmarks of Parkinson’s disease (PD), have been faithfully reproduced in rodent brains by chronic, oral administration of β-sitosterol β-D-glucoside (BSSG). We investigated whether a single injection of BSSG (6 μg BSSG/μL DMSO) in the left substantia nigra of Wistar rats causes the same effects. Mock DMSO injections and untreated rats formed control groups. We performed immunostainings against the pathological α-synuclein, the dopaminergic marker tyrosine hydroxylase (TH), the neuroskeleton marker β-III tubulin, the neurotensin receptor type 1 (NTSR1) as non-dopaminergic phenotype marker and Fluro-Jade C (F-J C) label for neurodegeneration. Using β-galactosidase (β-Gal) assay and active caspase-3 immunostaining, we assessed cell death mechanisms. Golgi-Cox staining was used to measure the density and types of dendritic spines of striatal medium spiny neurons. Motor and non-motor alterations were also evaluated. The study period comprised 15 to 120 days after the lesion. In the injured substantia nigra, BSSG caused a progressive α-synuclein aggregation and dopaminergic neurodegeneration caused by senescence and apoptosis. The α-synuclein immunoreactivity was also present within microglia cells. Decreased density of dopaminergic fibers and dendritic spines also occurred in the striatum. Remarkably, all the histopathological changes also appeared on the contralateral nigrostriatal system, and α-synuclein aggregates were present in other brain regions. Motor and non-motor behavioral alterations were progressive. Our data show that the stereotaxic BSSG administration reproduces PD α-synucleinopathy phenotype in the rat. This approach will aid in identifying the spread mechanism of α-synuclein pathology and validate anti-synucleinopathy therapies.

【 授权许可】

Unknown