Compound Dihuang Granule Protects against 6-OHDA Induced Toxicity in Parkinson’s Disease Rats by Suppressing the Phosphorylation of MAPK/ERK1/2

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Abstract BackgroundParkinson’s disease (PD) is a multifactorial neurodegenerative disorder characterized by progressive loss of dopaminergic (DA) neurons in the substantia nigra pars compacta (SNpc) and the presence of Lewy bodies (LBs) consisting of misfolded α-synuclein protein in the substantia nigra pars compacta (SNpc). Compound Dihuang Granule (CDG), a famous traditional Chinese medicine (TCM) has been clinically used in PD therapy with curative effects. However, the specific functions and the mechanism of action remained unclear. This study explored the therapeutic effects and potential mechanisms of CDG in the PD rats induced by 6-OHDA toxicity.MethodsThe PD rat model was induced by unilaterally stereotactic injection of 6-OHDA into the SNpc of midbrain. The behavioral performances of rats were evaluated by rotation test, muscle strength assessment and balance beam walking test. The striatal contents of neurotransmitters were detected by HPLC.The numbers of dopaminergic (DA) neurons were determined with immunohistochemistry (IHC) staining and Western blotting assay. Indicators of oxidative stress were determined with colorimetric method. Apoptotic cells were detected by TUNEL assay. The expression levels of neurotrophic factors were examined with IHC staining and real-time quantitative PCR. The related protein expression levels were determined with Western blotting assay.ResultsCDG significantly attenuated the 6-OHDA induced abnormal rotational behaviors and alleviated the loss of DA neurons in the nigrostriatal axis of PD rats with a 6-week treatment. Consistently, the striatal contents of DA and its metabolites including DOPAC and HVA of PD rats were all significantly increased with CDG treatment. The 6-OHDA induced oxidative stress indicated with decreased superoxide dismutase (SOD), glutathione (GSH), glutathione peroxidase (GSH-Px) and increased malondialdehyde (MDA) was also suppressed by CDG treatment. Moreover, CDG treatment increased the expression levels of neurotrophic factors including nerve growth factor (NGF), brain-derived neurotrophic factor (BDNF) and glial-derived neurotrophic factor (GDNF) in the nigrostriatal axis of PD rats. Consistently, the 6-OHDA induced cell apoptosis was inhibited by the 6-week CDG treatment. Further, the phosphorylation of MAPK/ERK1/2 and CREB proteins in the striatum of PD rats was suppressed by CDG treatment and CDG showed synergistic effects with the MAPK/ERK1/2 phosphorylation inhibitor SL327.ConclusionCDG could ameliorate the 6-OHDA induced brain injuries and motor symptoms, and also inhibit the oxidative stress and cell apoptosis in the nigrostriatal axis, which was mainly mediated by enhancing the expression levels of the neurotrophic factors and suppressing the phosphorylation of MAPK/ERK1/2 pathway in the midbrain of rats.
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