Mechanisms of intermittent theta-burst stimulation attenuating nerve injury after ischemic reperfusion in rats through endoplasmic reticulum stress and ferroptosis

Abstract Background Repetitive transcranial magnetic stimulation (rTMS) exerts neuroprotective effects early in cerebral ischemia/reperfusion (I/R) injury. Intermittent theta-brust stimulation (iTBS), a more time-efficient modality of rTMS, improves the efficiency without at least decreasing the efficacy of the therapy. iTBS elevates cortical excitability, and in recent years it has become increasingly common to apply iTBS to patients in the early post-IS period. However, little is known about the neuroprotective mechanisms of iTBS. Endoplasmic reticulum stress (ERS), and ferroptosis have been shown to be involved in the development of I/R injury. We aimed to investigate the potential regulatory mechanisms by which iTBS attenuates neurological injury after I/R in rats. Methods Rats were randomly divided into three groups: sham-operated group, MCAO/R group, and MCAO/R + iTBS group, and were stimulated with iTBS 36 h after undergoing middle cerebral artery occlusion (MCAO) or sham-operated. The expression of ERS, ferroptosis, and apoptosis-related markers was subsequently detected by western blot assays. We also investigated the mechanism by which iTBS attenuates nerve injury after ischemic reperfusion in rats by using the modified Neurological Severity Score (mNSS) and the balance beam test to measure nerve function. Results iTBS performed early in I/R injury attenuated the levels of ERS, ferroptosis, and apoptosis, and improved neurological function, including mNSS and balance beam experiments. It is suggested that this mode of stimulation reduces the cost per treatment by several times without compromising the efficacy of the treatment and could be a practical and less costly intervention.