Prolonged intermittent theta burst stimulation restores the balance between A2AR- and A1R-mediated adenosine signaling in the 6-hydroxidopamine model of Parkinson’s disease

Abstract

An imbalance in adenosine-mediated signaling, particularly the increased A2AR-mediated signaling, plays a role in the pathogenesis of Parkinson’s disease. Existing therapeutic approaches fail to alter disease progression, demonstrating the need for novel approaches in PD. Repetitive transcranial magnetic stimulation is a non-invasive approach that has been shown to improve motor and non-motor symptoms of Parkinson’s disease. However, the underlying mechanisms of the beneficial effects of repetitive transcranial magnetic stimulation remain unknown. The purpose of this study is to investigate the extent to which the beneficial effects of prolonged intermittent theta burst stimulation in the 6-hydroxydopamine model of experimental parkinsonism are based on modulation of adenosine-mediated signaling. Animals with unilateral 6-hydroxydopamine lesions underwent intermittent theta burst stimulation for 3 weeks and were tested for motor skills using the Rotarod test. Immunoblot, quantitative reverse transcription polymerase chain reaction, immunohistochemistry, and biochemical analysis of components of adenosine-mediated signaling were performed on the synaptosomal fraction of the lesioned caudate putamen. Prolonged intermittent theta burst stimulation improved motor symptoms in 6-hydroxydopamine-lesioned animals.

A 6-hydroxydopamine lesion resulted in progressive loss of dopaminergic neurons in the caudate putamen. Treatment with intermittent theta burst stimulation began seven days after the lesion, coinciding with the onset of motor symptoms. After treatment with prolonged intermittent theta burst stimulation, complete motor recovery was observed. This improvement was accompanied by downregulation of the eN/CD73-A2AR pathway and a return to physiological levels of A1R-adenosine deaminase 1 after 3 weeks of intermittent theta burst stimulation. Our results demonstrated that 6-hydroxydopamine-induced degeneration reduced the expression of A1R and elevated the expression of A2AR. Intermittent theta burst stimulation reversed these effects by restoring the abundances of A1R and A2AR to control levels. The shift in ARs expression likely restored the balance between dopamine-adenosine signaling, ultimately leading to the recovery of motor control.