Abstract
Neurotensin-polyplex nanoparticles provide efficient gene transfection of nigral dopaminergic neurons when intracerebrally injected in preclinical trials of Parkinson’s disease because they do not cross the blood–brain barrier (BBB). Therefore, this study aimed to open BBB with focused ultrasound (FUS) on the substantia nigra to attain systemic and intranasal transfections and evaluate its detrimental effect in rats. Systemically injected Evans Blue showed that a two-pulse FUS opened the nigral BBB. Accordingly, 35 μL of neurotensin-polyplex nanoparticles encompassing the green fluorescent protein plasmid (79.6 nm mean size and + 1.3 mV Zeta-potential) caused its expression in tyrosine hydroxylase(+) cells (dopaminergic neurons) of both substantiae nigrae upon delivery via internal carotid artery, retro-orbital venous sinus, or nasal mucosa 30 min after FUS. The intracarotid delivery yielded the highest transgene expression, followed by intranasal and venous administration. However, FUS caused neuroinflammation displayed by infiltrated lymphocytes (positive to cluster of differentiation 45), activated microglia (positive to ionized calcium-binding adaptor molecule 1), neurotoxic A1 astrocytes (positive to glial fibrillary acidic protein and complement component 3), and neurotrophic A2 astrocytes (positive to glial fibrillary acidic protein and S100 calcium-binding protein A10), that ended 15 days after FUS. Dopaminergic neurons and axonal projections decreased but recuperated basal values on day 15 after transfection, correlating with a decrease and recovery of locomotor behavior. In conclusion, FUS caused transient neuroinflammation and reversible neuronal affection but allowed systemic and intranasal transfection of dopaminergic neurons in both substantiae nigrae. Therefore, FUS could advance neurotensin-polyplex nanotechnology to clinical trials for Parkinson’s disease.
You have requested "on-the-fly" machine translation of selected content from our databases. This functionality is provided solely for your convenience and is in no way intended to replace human translation. Show full disclaimer
Neither ProQuest nor its licensors make any representations or warranties with respect to the translations. The translations are automatically generated "AS IS" and "AS AVAILABLE" and are not retained in our systems. PROQUEST AND ITS LICENSORS SPECIFICALLY DISCLAIM ANY AND ALL EXPRESS OR IMPLIED WARRANTIES, INCLUDING WITHOUT LIMITATION, ANY WARRANTIES FOR AVAILABILITY, ACCURACY, TIMELINESS, COMPLETENESS, NON-INFRINGMENT, MERCHANTABILITY OR FITNESS FOR A PARTICULAR PURPOSE. Your use of the translations is subject to all use restrictions contained in your Electronic Products License Agreement and by using the translation functionality you agree to forgo any and all claims against ProQuest or its licensors for your use of the translation functionality and any output derived there from. Hide full disclaimer
Details
1 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Av. Instituto Politécnico Nacional No. 2508, San Pedro Zacatenco, 07360, Ciudad de México, México (GRID: grid.512574.0)
2 Departamento de Ingeniería Eléctrica-Bioelectrónica, Centro de Investigación y de Estudios Avanzados, Ciudad de Mexico, México (GRID: grid.512574.0)
3 Departamento de Biología Molecular y Biotecnología, Instituto de Investigaciones Biomédicas, Universidad Nacional Autónoma de México Instituto de Investigaciones Biomédicas, Ciudad de Mexico, México (GRID: grid.9486.3) (ISNI: 0000 0001 2159 0001)
4 Institut für Chemie, Stranski-Laboratorium für Physikalische und Theoretische Chemie, Technische Universität Berlin, Berlin, Germany (ROR: https://ror.org/03v4gjf40) (GRID: grid.6734.6) (ISNI: 0000 0001 2292 8254)
5 Institut für Chemie , Universität Potsdam, Potsdam, Germany (ROR: https://ror.org/03bnmw459) (GRID: grid.11348.3f) (ISNI: 0000 0001 0942 1117)
6 Departamento de Fisiología, Biofísica y Neurociencias, Centro de Investigación y de Estudios Avanzados, Av. Instituto Politécnico Nacional No. 2508, San Pedro Zacatenco, 07360, Ciudad de México, México (GRID: grid.512574.0); Nanoparticle Therapy Institute, Aguascalientes, México
7 Nanoparticle Therapy Institute, Aguascalientes, México
8 Centro Interdisciplinario de Investigaciones y Estudios Sobre Medio Ambiente y Desarrollo, Departamento de Biociencias e Ingeniería, Instituto Politécnico Nacional, Ciudad de Mexico, México (ROR: https://ror.org/059sp8j34) (GRID: grid.418275.d) (ISNI: 0000 0001 2165 8782)
9 CONAHCYT - Unidad de Investigaciones Médicas en Enfermedades Neurológicas, Hospital de Especialidades “Dr. Bernardo Sepúlveda”, Centro Médico Nacional Siglo XXI, Instituto Mexicano del Seguro Social, Ciudad de Mexico, México (GRID: grid.419157.f) (ISNI: 0000 0001 1091 9430)