Small‑molecule PKR‑like endoplasmic reticulum kinase inhibitors as a novel targeted therapy for Parkinson's disease

Parkinson's disease (PD) is the second most common neurodegenerative disorder in worldwide and remains a therapeutic challenge due to the low efficacy of current treatments. Numerous studies have demonstrated the pivotal role of endoplasmic reticulum (ER) stress in PD pathogenesis. ER stress, followed by activation of the protein kinase RNA‑like endoplasmic reticulum kinase (PERK)‑dependent branch of the unfolded protein response signaling pathway, ultimately leads to neural cell death and dopaminergic neurodegeneration in PD. Therefore, the present study evaluated the effectiveness of the small‑molecule PERK inhibitor LDN‑87357 in an in vitro PD model using the human neuroblastoma SH‑SY5Y cell line. To assess the mRNA expression levels of the pro‑apoptotic ER stress markers, the TaqMan Gene Expression Assay was performed. Cytotoxicity was assessed using a colorimetric 2,3‑bis‑(2‑methoxy‑4‑nitro‑5‑sulfophenyl)‑
2H‑tetrazolium‑5‑carboxanilide assay and apoptosis was assessed using a caspase‑3 assay. Moreover, cell cycle progression was evaluated using flow cytometry. The results indicated that LDN‑87357 treatment induced a significant decrease in ER stress markers gene expression in SH‑SY5Y cells exposed to ER stress. Furthermore, LDN‑87357 significantly increased viability, diminished apoptosis and restored the normal cell cycle distribution of SH‑SY5Y cells after ER stress induction. Therefore, the evaluation of small‑molecule PERK inhibitors, such as LDN‑87357, may lead to the development of novel therapeutic strategies against PD.