Anti-neuroinflammatory effects of Eucommia ulmoides Oliv. In a Parkinson's mouse model through the regulation of p38/JNK-Fosl2 gene expression

Eucommia ulmoides Oliv., a Chinese medicinal herb called “Duzhong” from the bark of Eucommia ulmoides Oliv., has been shown to possess significant protective effects in Parkinson's disease (PD). However, the molecular mechanism remains unclear. In this study, we explored the anti-neuroinflammatory mechanisms of Duzhong on the 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced PD mouse model to elucidate the traditional medical theories with modern pharmacological methods and to provide a reference for further clarifying its mechanisms of action. The representative components in Duzhong extract were identified by UPLC-Q-TOF/MS. Male C57BL/6J mice were intraperitoneally injected with MPTP to establish an in vivo PD model. The pole, rotarod, and grip strength tests were performed to evaluate the motor coordination ability of the PD mice. HPLC-ECD was used to detect the striatal levels of dopamine (DA), 3,4- dihydroxyphenylacetic acid (DOPAC) and homovanillic acid (HVA). The expression of tyrosine hydroxylase (TH) was studied by immunohistochemistry (IHC) and Western blot assays. ELISA and Q-PCR were used examined the levels of proinflammatory cytokines in the serum and midbrain, respectively. Whole-transcriptome analysis of the midbrain was performed to explore the therapeutic effect of Duzhong on PD mice, and Q-PCR was then used to validate the differential gene expression changes in the PD mice treated with Duzhong. Ten compounds were identified from Duzhong extract. Duzhong significantly alleviated the behavioral impairments and dopaminergic neuron degeneration of PD mice, and inhibited the expression of proinflammatory cytokines. Whole-transcriptome analysis revealed nine oppositely regulated genes, and the Fosl2 gene was consistent with the trend of observed by RNA-seq. Furthermore, Duzhong downregulated mRNA expression of p38 and JNK, which are key upstream genes of Fosl2. Duzhong has promising therapeutic potential in PD mice, and its molecular mechanism is mediated by downregulating p38/JNK-Fosl2 gene expression to alleviate neuroinflammation.