[Effects of Changpu Yujin Decoction on PERK/eIF2α/ATF4 endoplasmic reticulum stress pathway in tourette syndrome...

This study investigated the potential mechanism of Changpu Yujin Decoction in the treatment of tourette syndrome(TS) based on the endoplasmic reticulum stress(ERS) protein kinase R-like ER kinase(PERK)/eukaryotic initiation factor 2α(eIF2α)/activating transcription factor 4(ATF4) pathway. A TS model was established by intraperitoneal injection of 3,3'-iminodipropionitrile(IDPN, 300 mg·kg~(-1)) for 7 days. After successful modeling, the rats were randomly divided into a model group, a Tiapridal group, and a Changpu Yujin Decoction group, with 10 rats in each group. The Tiapridal group received Tiapridal(47.91 mg·kg~(-1)) by gavage. The Changpu Yujin Decoction group received Changpu Yujin Decoction(77.28 g·kg~(-1)) by gavage. The control and model groups received an equal volume of physiological saline by gavage once daily for 28 days. Stereotyped and locomotor behaviors were scored by behavioral observation. HE staining was used to observe histopathological changes in striatal tissue. Transmission electron microscopy was used to examine endoplasmic reticulum ultrastructure in striatal neurons. ELISA was used to detect the levels of interleukin-1β(IL-1β) and tumor necrosis factor-α(TNF-α) in striatal tissue. Immunohistochemistry was used to detect PERK and eIF2α protein expression, and immunofluorescence was used to detect the co-expression of p-eIF2α and ATF4 proteins. RT-PCR and Western blot were employed to detect mRNA and protein expression of key factors in the PERK/eIF2α/ATF4 pathway in the striatum. The results showed that compared with the control group, the model group exhibited significantly increased stereotyped and locomotor behavior scores(P<0.05, P<0.01), aggravated pathological changes in striatal neurons and their endoplasmic reticulum and mitochondrial structures, elevated IL-1β and TNF-α levels, increased expression of PERK, eIF2α, ATF4, C/EBP-homologous protein(CHOP), and Bcl-2-associated X protein(Bax) mRNA and proteins(P<0.05, P<0.01), and decreased expression of B-cell lymphoma-2(Bcl-2) mRNA and protein(P<0.05, P<0.01). Compared with the model group, both the Tiapridal group and the Changpu Yujin Decoction group showed significantly reduced stereotyped and locomotor behavior scores(P<0.05, P<0.01), alleviated pathological changes in striatal neurons and their endoplasmic reticulum and mitochondrial structures, decreased IL-1β and TNF-α levels, reduced expression of PERK, eIF2α, ATF4, CHOP, and Bax mRNA and proteins(P<0.05, P<0.01), and increased expression of Bcl-2 mRNA and protein(P<0.05, P<0.01). In conclusion, Changpu Yujin Decoction may exert anti-tic effects by inhibiting the ERS PERK/eIF2α/ATF4 pathway, thereby improving striatal neuroinflammation and reducing neuronal apoptosis in TS model rats.