Tissue zinc restoration alleviates the levodopa-induced dyskinesia via impeding ERK phosphorylation

PURPOSE: Levodopa administration has been the standard therapy for Parkinson’s disease (PD) and prolonged treatment is associated with levodopa-induced dyskinesia (LID). This study aimed to identify the effects of zinc (Zn) supplements on LID and to explore the underlying mechanisms. METHODS: Male C57BL/6J mice were injected with 6-OHDA at medial forebrain bundle, followed by daily levodopa injection to induce LID. The mice were supplemented with Zn of 0, 0.3, 1.2, or 2.4 mg/kg for 4 weeks. RESULTS: In the LID mice, Zn supplements restored tissue Zn levels and alleviated global, forelimb, and orolingual abnormal involuntary movements (AIMs). Signaling pathway assessments showed that Zn supplements significantly reduced expressions of phosphorylated glutamate receptor 1 (p-GluR1) and phosphorylation levels of extracellular-signal-regulated kinase (p-ERK/ERK). Correlations between the AIMs score, p-ERK, and tissue Zn levels were established. In addition, Zn supplements reduced numbers of glial fibrillary acidic protein (GFAP) positive cells and compensatory tyrosine hydroxylase (TH) positive cells. These alleviating effects of Zn supplements were strictly regulated in a dose dependent manner. CONCLUSION: Appropriate doses of Zn supplements alleviated AIMs in the LID mouse model, potentially via impeding ERK phosphorylation, inhibiting astrocyte activation, and attenuating striatal compensation of TH positive cells.