Long-term iTBS promotes neural structural and functional recovery by enhancing neurogenesis and migration via miR-551b-5p/BDNF/TrkB pathway in a rat model of cerebral ischemia-reperfusion injury

As a novel form of repetitive transcranial stimulation, intermittent theta burst stimulation (iTBS) has potentials to be widely used in patients with stroke. Yet little is known about the idiographic actions of iTBS with different stimulation parameters on rehabilitative aspects of stroke patients, nor is the molecular mechanism underlying. In the present study, effects of iTBS with different stimulation parameters were evaluate to identify the optimal protocol of iTBS against damage induced by ischemia/reperfusion (I/R). Herein we found the short-term iTBS application seemed to have no significant effects on outcomes of rats during acute phase after I/R, including the neurological deficits, cerebral infarction and edema. However, behavioral functional tests demonstrated that long-term iTBS treatment provided effective therapy during subacute stage after two weeks post-stroke onset, which possibly by increasing proliferation and migration of adult neural stem cells. To explore the possible mechanisms of, microRNAs (miRs) expressional profiles were analyzed by microarray technology. Further bioinformatic analysis of binding sites revealed miR-551b-5p directly targeted the brain-derived neurotrophic factor (BDNF), which was confirmed by luciferase reporter and qRT-PCR. Moreover, the level phosphorylated-TrkB, the downstream of BDNF, was elevated accompanied by above-mentioned changes of long-term iTBS. Taken together, experimental data reveals a direct link between miR-551b-5p and BDNF-mediated signaling cascade in early convalescence of stroke. Our findings provide new insights into the molecular mechanisms underlying curative effects of iTBS on stroke, thus aiding in the prognosis and personalized therapies.