Repetitive Transcranial Magnetic Stimulation Alleviates MPTP-Induced Parkinson's Disease Symptoms by Regulating CaMKII-CREB-BMAL1 Pathway in Mice Model

Background: Repetitive transcranial magnetic stimulation (rTMS) is a noninvasive neuromodulation technique that shows promise for the treatment of Parkinson's disease (PD). However, there is still limited understanding of the optimal stimulation frequencies and whether rTMS can alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.

Methods: A PD mouse model was induced intraperitoneally with 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) and treated with 1 Hz, 5 Hz, and 10 Hz rTMS. The neurological function, survival of dopaminergic neurons, and protein levels of Tyrosine hydroxylase (TH), α-synuclein(α-syn), and brain-derived neurotrophic factor (BDNF) in the striatum were measured to determine the optimal stimulation frequencies of rTMS treatment in PD mice. The levels of melatonin, cortisol, and the circadian rhythm of Brain and muscle ARNT-like 1 (BMAL1) in PD model mice were detected after optimal frequency rTMS treatment. Additionally, KN-93 and Bmal1siRNA interventions were used to verify that rTMS could alleviate PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway.

Results: Administration of 10 Hz rTMS significantly improved neurological function, increased the protein levels of TH and BDNF, and inhibited abnormal aggregation of a-syn. Furthermore, administration of 10 Hz rTMS regulated the secretion profile of cortisol and melatonin and reversed the circadian arrhythmia of BMAL1 expression. After the KN-93 intervention, the MPTP+rTMS+KN-93 group exhibited decreased levels of P- CA²⁺/calmodulin-dependent protein kinase II (CaMKII)/CaMKII, P-cAMP-response-element-binding protein (CREB)/CREB, BMALI, and TH. After Bmal1siRNA intervention, the protein levels of BMAL1 and TH were significantly reduced in the MPTP+10 Hz+ Bmal1siRNA group. At the same time, there were no significant changes in the proportions of P-CaMKIIα/CaMKIIα and P-CREB/CREB expression levels. Finally, immunohistochemical analysis showed that the number of TH-positive neurons was high in the MPTP+10 Hz group, but decreased significantly after KN-93 and Bmal1siRNA interventions.

Conclusion: Treatment with 10 Hz rTMS alleviated MPTP-induced PD symptoms by regulating the CaMKII-CREB-BMAL1 pathway. This study provides a comprehensive perspective of the therapeutic mechanisms of rTMS in PD.

Ca2+/calmodulin-dependent protein kinase II; Parkinson’s disease; brain and muscle ARNT-like 1; cAMP-response-element-binding protein; transcranial magnetic stimulation.