Inactive myocyte enhancer factor 2D (MEF2D) and alpha-synuclein (alpha-syn) aggregation will cause neuronal death. MEF2D or alpha-syn degradation is also associated with macroautophagy, chaperone-mediated autophagy (CMA) and heat-shock protein 70 (HSP70). We found that beta-asarone had positive effects on treating 6-hydroxydopamine (6-OHDA)-induced rats, but mechanisms of 13-asarone affecting on MEF2D and alpha-syn via regulating the HSP70/MAPK/MEF2D/Beclin-1 pathway remain unclear. Unilateral 6-OHDA injection into the medial forebrain bundle was used to create PD rats, which were divided into four groups and administered for 30 days: 6-OHDA model group, MEF2D inhibitor-treated group (SB203580, 0.5 mg/kg, i.p.), MEF2D activator-treated group (LiCI, 100 mg/kg, i.p.), beta-asarone-treated group (15 mg/kg, p.o.). Expressions of tyrosine hydroxylase (TH), alpha-syn, heat-shock cognate protein 70 (HSC70), lysosome-associated membrane protein type 2a (LAMP -2A), MEF2D, HSP70, Beclin-1, light chain 3 B (LC3B) and p62 in the mesencephalon were measured after 30-day administration. alpha-syn, Beclin-1 and LC3 B levels were higher in the 6-OHDA model group, while TH, MEF2D, HSC70, LAMP -2A, p62 levels were lower compared to the sham-operated group. Our results also showed that beta-asarone treatment reduced protein and mRNA levels of alpha-syn, Beclin-1 and LOB, but increased HSP70, TH, MEF2D, HSC70, LAMP-2A and p62 levels compared to the 6-OHDA model group. Additionally, certain correlations among alpha-syn, TH, Beclin-1, LC3B, p62, HSP70, LAMP -2A and MEF2D were also discovered in this study. These findings suggested that beta-asarone treatment could increase MEF2D and TH as well as reduce alpha-syn to protect against 6-OHDA induced damage in PD rat mesencephalon via modulating the HSP70/MAPK/MEF2D/Beclin-1 pathway. (C) 2016 Elsevier B.V. All rights reserved.