Neuroprotective Effect of Low-Intensity Pulsed Ultrasound Against MPP⁺-Induced Neurotoxicity in PC12 Cells: Involvement of K2P Channels and Stretch-Activated Ion Channels

Parkinson's disease is the second most common neurodegenerative disease. It is characterized by the loss of dopaminergic neurons in the substantia nigra pars compacta. 1-Methyl-4-phenylpyridinium (MPP⁺) is a dopaminergic neuronal toxin that is widely used in constructing Parkinson's disease models in vitro. Low-intensity pulsed ultrasound (LIPUS) is a non-invasive therapeutic approach that has neuromodulation and neuroprotective effects in the central neural system; however, whether LIPUS can provide protection for dopaminergic neurons against MPP⁺-induced neurocytotoxicity remains unknown. In this study, we found that pre-treatment with LIPUS (1 MHz, 50 mW/cm², 20% duty cycle and 100-Hz pulse repetition frequency, 10 min) inhibited MPP⁺-induced neurotoxicity and mitochondrial dysfunction in PC12 cells. LIPUS decreased MPP⁺-induced oxidative stress by modulating antioxidant proteins, including thioredoxin-1 and heme oxygenase-1, and prevented neurocytotoxicity via the phosphoinositide 3-kinase (PI3K)-Akt and ERK1/2 pathways. Furthermore, these beneficial effects were attributed to the activation of K2P channels and stretch-activated ion channels by LIPUS. These data indicate that LIPUS protects neuronal cells from MPP⁺-induced cell death through the K2P channel- and stretch-activated ion channel-mediated downstream pathways. The data also suggest that LIPUS could be a promising therapeutic method in halting or retarding the degeneration of dopaminergic neurons in Parkinson's disease in a non-invasive manner.