Early Repetitive Transcranial Magnetic Stimulation Exerts Neuroprotective Effects and Improves Motor Functions in Hemiparkinsonian Rats

Abstract

Repetitive transcranial magnetic stimulation (rTMS) is a popular noninvasive technique for modulating motor cortical plasticity and has therapeutic potential for the treatment of Parkinson’s disease (PD). However, the therapeutic benefits and related mechanisms of rTMS in PD are still uncertain. Accordingly, preclinical animal research is helpful for enabling translational research to explore an effective therapeutic strategy and for better understanding the underlying mechanisms. Therefore, the current study was designed to identify the therapeutic effects of rTMS on hemiparkinsonian rats. A hemiparkinsonian rat model, induced by unilateral injection of 6-hydroxydopamine (6-OHDA), was applied to evaluate the therapeutic potential of rTMS in motor functions and neuroprotective effect of dopaminergic neurons. Following early and long-term rTMS intervention with an intermittent theta burst stimulation (iTBS) paradigm (starting 24 h post-6-OHDA lesion, 1 session/day, 7 days/week, for a total of 4 weeks) in awake hemiparkinsonian rats, the effects of rTMS on the performance in detailed functional behavioral tests, including video-based gait analysis, the bar test for akinesia, apomorphine-induced rotational analysis, and tests of the degeneration level of dopaminergic neurons, were identified. We found that four weeks of rTMS intervention significantly reduced the aggravation of PD-related symptoms post-6-OHDA lesion. Immunohistochemically, the results showed that tyrosine hydroxylase- (TH-) positive neurons in the substantia nigra pars compacta (SNpc) and fibers in the striatum were significantly preserved in the rTMS treatment group. These findings suggest that early and long-term rTMS with the iTBS paradigm exerts neuroprotective effects and mitigates motor impairments in a hemiparkinsonian rat model. These results further highlight the potential therapeutic effects of rTMS and confirm that long-term rTMS treatment might have clinical relevance and usefulness as an additional treatment approach in individuals with PD.

Long-Term Motor Cortical Electrical Stimulation Ameliorates 6-Hydroxydopamine-Induced Motor Dysfunctions and Exerts Neuroprotective Effects in a Rat Model of Parkinson’s Disease

“…Both forelimbs were placed at the same time on a horizontal acrylic bar (0.7 cm diameter), which was held 9 cm above the table surface. The total duration (in seconds) spent from placing of each forepaw on the bar to the first complete removal from the support bar was recorded ( Hsieh et al, 2011 ; Feng et al, 2020 ; Hsieh et al, 2021 ). All PD rats were measured over five subsequent trials and the durations of these trials were averaged.…”

“…To understand the motor behavioral changes in the PD rats before and after CES treatment, a detailed gait analysis was performed to assess gait disturbances in the PD rats. The procedure for measuring gait pattern was as described in previous works ( Hsieh et al, 2011 ; Lee et al, 2012 ; Hsieh et al, 2021 ). In brief, the walking track equipment consisted of an enclosed walkway made of transparent plexiglass (80 cm × 6 cm × 12 cm length, width, and height, respectively) with a mirror (tilting at 45°) positioned underneath the walkway.…”

“…In each slide, two fields, including SNpc and striatum in the non-lesioned and lesioned areas were chosen for further analysis. The numbers of TH-positive cells in the SNpc were counted by means of particle analysis using Image-Pro Plus 6.0 software (Media Cybernetics, Bethesda, MD, United States) and these values were then manually validated by two investigators to ensure the correct identification of TH-positive pattern ( Hsieh et al, 2021 ). The percentage of TH-positive cells was calculated in the ipsilateral hemisphere and normalized with respect to the contralateral side ( Feng et al, 2020 ; Hsieh et al, 2021 ).…”

“…The numbers of TH-positive cells in the SNpc were counted by means of particle analysis using Image-Pro Plus 6.0 software (Media Cybernetics, Bethesda, MD, United States) and these values were then manually validated by two investigators to ensure the correct identification of TH-positive pattern ( Hsieh et al, 2021 ). The percentage of TH-positive cells was calculated in the ipsilateral hemisphere and normalized with respect to the contralateral side ( Feng et al, 2020 ; Hsieh et al, 2021 ). With regard to the striatal TH-positive fibers, the same image analysis software (Image-Pro Plus 6.0, Media Cybernetics, Bethesda, MD, United States) was used to correct the non-specific background density measured at the corpus callosum, and the optical density of the TH-positive fibers in the striatum of each hemisphere was analyzed separately ( Hsieh et al, 2011 ; Feng et al, 2020 ; Hsieh et al, 2021 ).…”

“…The percentage of TH-positive cells was calculated in the ipsilateral hemisphere and normalized with respect to the contralateral side ( Feng et al, 2020 ; Hsieh et al, 2021 ). With regard to the striatal TH-positive fibers, the same image analysis software (Image-Pro Plus 6.0, Media Cybernetics, Bethesda, MD, United States) was used to correct the non-specific background density measured at the corpus callosum, and the optical density of the TH-positive fibers in the striatum of each hemisphere was analyzed separately ( Hsieh et al, 2011 ; Feng et al, 2020 ; Hsieh et al, 2021 ). The percentage of TH-positive fibers on the ipsilateral side was normalized and presented with respect to the contralateral side.…”