Electroconvulsive Seizure Normalizes Motor Deficits and Induces Autophagy Signaling in the MPTP-Induced Parkinson Disease Mouse Model

Abstract

Objective Electroconvulsive seizure (ECS) is a potent treatment modality for various neuropsychiatric diseases, including Parkinson disease (PD). Recent animal studies showed that repeated ECS activates autophagy signaling, the impairment of which is known to be involved in PD. However, the effectiveness of ECS on PD and its therapeutic mechanisms have not yet been investigated in detail.Methods Systemic injection of a neurotoxin 1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine hydrochloride (MPTP), which destroys dopaminergic neurons in the substantia nigra compacta (SNc), in mice was utilized to induce an animal model of PD. Mice were treated with ECS 3 times per week for 2 weeks. Behavioral changes were measured with a rotarod test. Molecular changes related to autophagy signaling in midbrain including SNc, striatum, and prefrontal cortex were analyzed with immunohistochemistry and immunoblot analyses.Results Repeated ECS treatments normalized the motor deficits and the loss of dopamiergic neurons in SNc of the MPTP PD mouse model. In the mouse model, LC3-II, an autophagy marker, was increased in midbrain while decreased in prefrontal cortex, both of which were reversed by repeated ECS treatments. In the prefrontal cortex, ECS-induced LC3-II increase was accompanied with AMP-activated protein kinase (AMPK)-Unc-51-like kinase 1-Beclin1 pathway activation and inhibition of mamalian target of rapamycin signaling which promotes autophagy initiation.Conclusion The findings revealed the therapeutic effects of repeated ECS treatments on PD, which could be attributed to the neuroprotective effect of ECS mediated by AMPK-autophagy signaling.

Noninvasive Neuromodulation in Parkinson’s Disease: Insights from Animal Models

“…The reported effects were similar to the ones observed with TMS and tDCS, namely the improvement of motor deficits, the preservation of dopamine neurons, and increases in NFs. Intriguingly, one study [88] found evidence that ECT may impact autophagy pathways in PD, although it is unclear whether this finding would translate to human patients. Considering that other forms of non-invasive neuromodulations are likely to offer similar benefits based on the studies reviewed here, while being associated with fewer risks, ECT may be less preferable in clinical practice than other forms of non-invasive neuromodulation.…”

“…Autophagy. Huh, et al [88] investigated the role of ECT in autophagy in the MPTP mouse model and found that after two weeks of ECT treatment (once a day, three times a week), mice showed an improvement in motor deficits; increased count of TH+ neurons in the SNc; and the normalization of LC3-II levels in the PFC, striatum, and midbrain. LC3-II is an autophagy marker that has been shown to be dysregulated in PD [89] and was found to be modulated by tDCS [17], as reported above.…”

“…Another variable to consider is the placement of the electrodes. Some studies [83,85] utilized corneal electrodes which stimulate the brain through the eyes, while the others utilized earclip [84,87,88] or temple [86] electrodes. Considering that ECT and general anesthesia used to deliver it in humans both come with risks, rTMS and tDCS may be preferable for use in clinical practice, as they offer similar benefits based on the animal literature reviewed.…”