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Machanism Associated with Apoptosis after Repetitive Transcranial Magnetic Stimulation in Permanent Stroke Rat Model

Sheng Lan Jin, Min Kyun Sohn and Sung Ju Jee

Purpose: Neuromodulation therapy has been used as an adjunct treatment to promote motor recovery in stroke patients. The objectives of the present study were to determine the effect of repetitive transcranial magnetic stimulation (rTMS) on neurobehavioural recovery, evoked potential, and underlying biological mechanisms associated with neuronal cell death in rats after permanent middle cerebral artery occlusion.

Methods: Our study included 10 control and 40 Sprague-Dawley (SD) rats; of them, 30 were successfully subjected to the induction of permanent middle cerebral artery occlusion (MCAO) stroke model (rTMS = 15, sham rTMS = 15). Ten-Hertz high-frequency rTMS was applied to the ipsilesional forepaw motor cortex for 2 weeks in the rTMS group. The somatosensory-evoked potential (SSEP) and motorevoked potential (MEP) were used to evaluate the electrophysiological changes. The behavioural function of the stroke rats was evaluated using the rotarod and Garcia tests. Stroke area was measured using a histological staining technique. Immunoblotting was used to explore the mechanisms of rTMS associated with neuronal apoptosis.

Results: 10 control and 20 MCAO rats (NrTMS = 10; Nsham = 10) completed the experimental course. Regarding MEP amplitude, repeated-measured analysis of variance (RMANOVA) showed a significant TIME effect [F (2, 0.106) = 11.241, P < 0.001] and TIME × INTERVENTION interaction [F (2, 0.057) = 6.053, P = 0.005] on MEP amplitude, suggesting the beneficial effect of rTMS on motor cortical excitability. Regarding peak to peak SSEP amplitude, RMANOVA showed a significant TIME effect [F (2, 4.920) = 3.4551, P = 0.042]. In terms of latency to fall, RMANOVA identified a significant TIME effect [F (7, 16640.335) = 24.425, P < 0.001] and INTERVENTION × TIME interaction [F (7, 2348.295) = 3.447, P = 0.002]. In terms of distance to fall, RMANOVA revealed a TIME effect [F (7, 101.679) = 26.515, P < 0.001] and INTERVENTION × TIME interaction [F (7, 13.607) = 3.548, P < 0.002]. In terms of Garcia score, RMANOVA revealed a significant effect of TIME [F (7, 69.282) = 153.689, P < 0.05] and INTERVENTION × TIME interaction [F (7, 2.282) = 5.063, P < 0.05], suggesting a beneficial effect of rTMS over sham treatment. In the Kruskal-Wallis test of endoplasmic reticulum (ER) stress protein, rTMS also inhibited the protein levels of glucose-regulated protein 78 (GRP78), CATT/EBP homologous protein (CHOP), and p-eukaryotic initiation factor 2α (eIF2α).

Conclusion: 10-Hertz rTMS leads to a rapid recovery in behavioural performance after permanent MCAO stroke model and maintains increased ipsilesional motor cortex activity 2 weeks after rTMS. The underlying beneficial effects of rTMS may be associated with ER stress protein in the neuronal cell death pathway.