Ultrasound-enhanced brain delivery of edaravone provides additive amelioration on disease progression in an ALS mouse model.

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 SOD1 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.