RESUMEN

BACKGROUND: Although amyotrophic lateral sclerosis (ALS) is a devastating neurodegenerative disease and unfortunately incurable yet, incremental attention has been drawn to targeting the health of corticospinal motor neurons. Focused ultrasound combined with systemically circulating microbubbles (FUS/MB) is an emerging modality capable of site-specific molecular delivery temporarily and noninvasively within a range of appropriate parameters. OBJECTIVE: To investigate the effect of FUS/MB-enhanced delivery of therapeutics to the motor cortex on the disease progression by using a transgenic mouse model of ALS. METHODS: Multiple FUS/MB-enhanced deliveries of Edaravone (Eda) to the motor cortex were performed on the SOD1G93A mouse model of ALS. The motor function of the animals was evaluated by gait analysis, grip strength and wire hanging tests. Corticospinal and spinal motor neuronal health, misfolded SOD1 protein and neuroinflammation after treatments were evaluated by histological examination. RESULTS: Ultrasound-enhanced delivery of Eda in the targeted motor cortex was achieved by a two-fold increase without gross tissue damage. Compared with the ALS mice administered Eda treatments only, the animals given additionally FUS/MB-enhanced brain delivery of Eda (FUS/MB + Eda) exhibited further improvements in neuromuscular functions characterized by gait patterns, muscular strength, and motor coordination along with rescued muscle atrophy. FUS/MB + Eda treatments conferred remarkable neuroprotection to both upper and lower motor neurons revealed by normalized neuronal morphology with increasing cell body size and profoundly alleviated neuroinflammation and misfolded SOD1 protein in the brains and lumbar spinal cords. CONCLUSION: We report a pilot study that non-invasive ultrasound-enhanced brain delivery of Eda provides additive amelioration on disease progression of ALS and suggest that broadening the target from spinal to cortical network functions using the FUS/MB-enhanced delivery can be a rational therapeutic strategy of this debilitating disorder.

Asunto(s)

Esclerosis Amiotrófica Lateral , Enfermedades Neurodegenerativas , Ratones , Animales , Esclerosis Amiotrófica Lateral/diagnóstico por imagen , Esclerosis Amiotrófica Lateral/tratamiento farmacológico , Superóxido Dismutasa-1/metabolismo , Edaravona/metabolismo , Enfermedades Neuroinflamatorias , Proyectos Piloto , Superóxido Dismutasa/genética , Superóxido Dismutasa/metabolismo , Neuronas Motoras , Ratones Transgénicos , Encéfalo/metabolismo , Progresión de la Enfermedad , Modelos Animales de Enfermedad

RESUMEN

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.