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Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model

Autism has clinical manifestations such as social interaction disorder, speech and intellectual development disorder, narrow interest range, and stereotyped and repetitive behavior, all of which bring considerable economic and mental burden to society and families, and represent a public health prob...

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Detalles Bibliográficos
Autores principales: Shen, Yuanyuan, Li, Nana, Sun, Shuneng, Dong, Lei, Wang, Yongling, Chang, Liansheng, Zhang, Xinyu, Wang, Feng
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Frontiers Media S.A. 2022
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9475200/
https://www.ncbi.nlm.nih.gov/pubmed/36117626
http://dx.doi.org/10.3389/fnins.2022.986571
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author Shen, Yuanyuan
Li, Nana
Sun, Shuneng
Dong, Lei
Wang, Yongling
Chang, Liansheng
Zhang, Xinyu
Wang, Feng
author_facet Shen, Yuanyuan
Li, Nana
Sun, Shuneng
Dong, Lei
Wang, Yongling
Chang, Liansheng
Zhang, Xinyu
Wang, Feng
author_sort Shen, Yuanyuan
collection PubMed
description Autism has clinical manifestations such as social interaction disorder, speech and intellectual development disorder, narrow interest range, and stereotyped and repetitive behavior, all of which bring considerable economic and mental burden to society and families, and represent a public health problem requiring urgent attention. Brain-derived neurotrophic factor (BDNF) plays an important role in supporting survival, differentiation, growth, and synapse formation of neurons and participates in the plasticity of nerves. However, it is difficult for BDNF to penetrate the blood-brain barrier (BBB) due to its large molecular weight. Low-frequency focused ultrasound (FUS) combined with microbubbles (MBs) has been demonstrated to be a promising method for opening the BBB non-invasively, transiently, and locally. Here, we studied the therapeutic effect of FUS combined with BDNF plasmid-loaded cationic microbubbles (BDNFp-CMBs) in a rat model of autism. BDNF-CMBs were prepared and the transfection efficiency of FUS combined with BDNF-CMBs was tested in vitro. A rat model of autism was established from the juvenile male offspring of Sprague-Dawley (SD) pregnant rats treated with sodium valproate (VPA) solution through intraperitoneal injection. The autism rats were randomized into three groups: the VPA group, which received no treatment, the BDNFp group, which was treated by injection of BDNFp, and the FUS + BDNFp-CMBs group, which was administered FUS combined with BDNFp-CMBs. Age-matched normal rats served as the control group (Con). Following treatment, stereotyped, exploratory, and social–behavioral tests were performed on the animals in each group. The rat brains were then collected for subsequent histological examination, and the changes in synaptic structures in the prefrontal cortex (PFC) were detected under transmission electron microscopy. The results showed that the constructed BDNFp could be loaded onto CMBs with high loading efficiency. The BDNFp-CMBs prepared in this study showed good stability in vivo. FUS combined BDNFp-CMBs could effectively and non-invasively open the BBB of rats. The stereotyped, exploratory, and social behaviors of the FUS + BDNFp-CMBs group were significantly improved. Compared to the VPA group, the abnormality of neuronal morphology and number in the PFC of the FUS + BDNFp-CMBs was alleviated to a certain extent and was accompanied by restoration of the damaged synapses in the encephalic region. Our work demonstrates the positive therapeutic effect of BDNF delivered by FUS non-invasively across the BBB into the PFC in a rat model of autism, offering a potential strategy for treating autism.
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spelling pubmed-94752002022-09-16 Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model Shen, Yuanyuan Li, Nana Sun, Shuneng Dong, Lei Wang, Yongling Chang, Liansheng Zhang, Xinyu Wang, Feng Front Neurosci Neuroscience Autism has clinical manifestations such as social interaction disorder, speech and intellectual development disorder, narrow interest range, and stereotyped and repetitive behavior, all of which bring considerable economic and mental burden to society and families, and represent a public health problem requiring urgent attention. Brain-derived neurotrophic factor (BDNF) plays an important role in supporting survival, differentiation, growth, and synapse formation of neurons and participates in the plasticity of nerves. However, it is difficult for BDNF to penetrate the blood-brain barrier (BBB) due to its large molecular weight. Low-frequency focused ultrasound (FUS) combined with microbubbles (MBs) has been demonstrated to be a promising method for opening the BBB non-invasively, transiently, and locally. Here, we studied the therapeutic effect of FUS combined with BDNF plasmid-loaded cationic microbubbles (BDNFp-CMBs) in a rat model of autism. BDNF-CMBs were prepared and the transfection efficiency of FUS combined with BDNF-CMBs was tested in vitro. A rat model of autism was established from the juvenile male offspring of Sprague-Dawley (SD) pregnant rats treated with sodium valproate (VPA) solution through intraperitoneal injection. The autism rats were randomized into three groups: the VPA group, which received no treatment, the BDNFp group, which was treated by injection of BDNFp, and the FUS + BDNFp-CMBs group, which was administered FUS combined with BDNFp-CMBs. Age-matched normal rats served as the control group (Con). Following treatment, stereotyped, exploratory, and social–behavioral tests were performed on the animals in each group. The rat brains were then collected for subsequent histological examination, and the changes in synaptic structures in the prefrontal cortex (PFC) were detected under transmission electron microscopy. The results showed that the constructed BDNFp could be loaded onto CMBs with high loading efficiency. The BDNFp-CMBs prepared in this study showed good stability in vivo. FUS combined BDNFp-CMBs could effectively and non-invasively open the BBB of rats. The stereotyped, exploratory, and social behaviors of the FUS + BDNFp-CMBs group were significantly improved. Compared to the VPA group, the abnormality of neuronal morphology and number in the PFC of the FUS + BDNFp-CMBs was alleviated to a certain extent and was accompanied by restoration of the damaged synapses in the encephalic region. Our work demonstrates the positive therapeutic effect of BDNF delivered by FUS non-invasively across the BBB into the PFC in a rat model of autism, offering a potential strategy for treating autism. Frontiers Media S.A. 2022-09-01 /pmc/articles/PMC9475200/ /pubmed/36117626 http://dx.doi.org/10.3389/fnins.2022.986571 Text en Copyright © 2022 Shen, Li, Sun, Dong, Wang, Chang, Zhang and Wang. https://creativecommons.org/licenses/by/4.0/This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) and the copyright owner(s) are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.
spellingShingle Neuroscience
Shen, Yuanyuan
Li, Nana
Sun, Shuneng
Dong, Lei
Wang, Yongling
Chang, Liansheng
Zhang, Xinyu
Wang, Feng
Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model
title Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model
title_full Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model
title_fullStr Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model
title_full_unstemmed Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model
title_short Non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model
title_sort non-invasive, targeted, and non-viral ultrasound-mediated brain-derived neurotrophic factor plasmid delivery for treatment of autism in a rat model
topic Neuroscience
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC9475200/
https://www.ncbi.nlm.nih.gov/pubmed/36117626
http://dx.doi.org/10.3389/fnins.2022.986571
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