| Residential College | false |
| Status | 即將出版Forthcoming |
| Sigma-1 receptor positive allosteric modulator promotes the neuronal survival and improves cognitive deficits in AD mice via Sigma-1 receptor/ERK pathway | |
Xiaoyu Wang; Wenhua Zheng 
| |
| 2024-06 | |
| Conference Name | The 10th Macau Symposium on Biomedical Science |
| Conference Date | 2024-06-13-15 |
| Conference Place | University of Macau,University Hall |
| Abstract | The sigma-1 receptor is an important new therapeutic drug target for Alzheimer’s disease (AD). SOMCL-668 is a novel selective and potent sigma-1 receptor allosteric modulator, but its effect on AD is unknown. The present study discovered that SOMCL-668 is neuroprotective in AD both in vitro and in vivo. SOMCL-668 promoted the survival of PC12 cells against the toxicity of Aβ1-42 - induced ROS accumulation, caspase activation, LDH release, and apoptosis in a concentration dependent manner. The mechanistic study showed that SOMCL-668 stimulated the phosphorylation of ERK and CREB in a time- and concentration-dependent manner, while the inhibition of the ERK pathway by PD98059 or ERK knockout with CRISPR-Cas9 attenuated its protective effect. Further studies with the sigma-1 receptor inhibitors/activators and the sigma-1 receptor knockout with CRISPR-Cas9 indicated that the sigma-1 receptor is essential for the effect of SOMCL-668. These results demonstrated that the neuronal protective effect of SOMCL-668 is mediated by the sigma-1 receptor/ERK/CREB pathway in PC12 cells. Similar results were obtained in SY5Y and primary cortical culture neurons. In 3xTg-AD mice, SOMCL-668 improved the learning and memory deficits, inhibited neuronal apoptosis and oxidative stress, reduced Aβ deposition and tau protein phosphorylation via ERK/CREB pathway. Moreover, pretreatment with sigma-1 receptor antagonist BD1047 blocked the effect of SOMCL-668. These results demonstrated that SOMCL-668 is neuronal protective in AD and its effect is mediated by the sigma-1 receptor/ERK/CREB pathway both in vitro and in vivo. Our findings support that SOMCL-668 can be utilized as a potential drug for the prevention and treatment of Alzheimer’s disease. |
| Keyword | Alzheimer's Disease, Somcl-668, Neuronal Cells, 3xtg-ad Mice, Sigma-1 Receptor/erk/creb Pathway |
| Document Type | Conference paper |
| Collection | DEPARTMENT OF PHARMACEUTICAL SCIENCES |
| Corresponding Author | Wenhua Zheng |
| Recommended Citation GB/T 7714 | Xiaoyu Wang,Wenhua Zheng. Sigma-1 receptor positive allosteric modulator promotes the neuronal survival and improves cognitive deficits in AD mice via Sigma-1 receptor/ERK pathway[C], 2024. |
| APA | Xiaoyu Wang., & Wenhua Zheng (2024). Sigma-1 receptor positive allosteric modulator promotes the neuronal survival and improves cognitive deficits in AD mice via Sigma-1 receptor/ERK pathway. . |
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