[Effects of Compound Dihuang Granules on PERK/ATF4/CHOP pathway in substantia nigra of rat model of Parkinson's disease with syndrome of Yin deficiency and stirring wind].
[Effects of Compound Dihuang Granules on PERK/ATF4/CHOP pathway in substantia nigra of rat model of Parkinson's disease with syndrome of Yin deficiency and stirring wind].
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Original abstract
This study aims to investigate the therapeutic mechanism of Compound Dihuang Granules in a rat model of Parkinson's disease(PD) with the syndrome of Yin deficiency and stirring wind, by examining their effects on the expression of activating transcription factor 4(ATF4), CCAAT/enhancer-binding protein homologous protein(CHOP), eukaryotic initiation factor 2 alpha(eIF2α), and protein kinase RNA-like endoplasmic reticulum kinase(PERK) in the substantia nigra. A rat model of PD with the syndrome of Yin deficiency and stirring wind was established via unilateral injection of 6-hydroxydopamine into the substantia nigra. Seventy-five successfully modeled rats were randomly assigned to a model group, a madopar group, and low-, medium-, and high-dose Compound Dihuang Granules groups, each receiving the corresponding agents by oral gavage. Additional 30 rats were allocated to a normal control group and a sham-operated group. The two groups, together with the model group, were administered an equal volume of normal saline. Behavioral performance was evaluated by the apomorphine-induced rotation test, pole-climbing test, and hanging test. Histopathological alterations and ultrastructural changes in the substantia nigra were assessed by HE staining and transmission electron microscopy. Furthermore, immunohistochemistry, Western blot, and RT-qPCR were employed to quantify the protein and mRNA levels of ATF4, CHOP, eIF2α, phosphorylated(p)-eIF2α, PERK, and p-PERK in the substantia nigra tissue. Compared with the normal control and sham-operated groups, the model group exhibited a reduction in hanging time(P<0.01), accompanied by increases in rotation count and pole-climbing time(P<0.01). Compared with the model group, the madopar group and all Compound Dihuang Granules groups demonstrated improvements in behavioral performance, as evidenced by prolonged hanging time(P<0.05), reduced rotation count(P<0.01), and shortened pole-climbing time(P<0.01). These functional improvements were paralleled by attenuation of neuronal injury in the substantia nigra and amelioration of mitochondrial ultrastructural abnormalities. Western blot and RT-qPCR analyses revealed that Compound Dihuang Granules dose-dependently downregulated the protein and mRNA levels of key molecules in the PERK/ATF4/CHOP signaling pathway(P<0.05 or P<0.01). Notably, the effects observed in the high-dose group were comparable to those of the madopar group. Compound Dihuang Granules may exert neuroprotective effects in the rat model of PD with the syndrome of Yin deficiency and stirring wind by suppressing the PERK/ATF4/CHOP signaling pathway, thereby alleviating endoplasmic reticulum stress and neuronal apoptosis. These findings provide experimental support for the clinical study of Compound Dihuang Granules in the treatment of PD.