AG-1031 and AG-1503 improve cognitive deficits by promoting apoptosis and inhibiting autophagy in C6 glioma model rats

摘要

High-grade gliomas (HGGs; grades III and IV) are the most common and aggressive adult primary brain tumors, and their invasive nature ranks them the fourth in the incidence of cancer death. In our previous study, we found that AG-1031 and AG-1503 showed inhibitory effects on several cancer cell lines. In this study, C6 glioma-bearing rats were treated with AG-1031 or AG-1503. Western blot results of autophagy-associated protein (LC3 II/I, Beclin-1) and apoptosis-associated proteins (caspase-3, Bcl-2, Bax) revealed that AG-1031 could activate apoptotic signal pathway via inhibiting autophagy process in cancer cells. HE staining indicated that the tumor volumes were significantly decreased in AG-1031 and AG-1503 treated rats compared to non-treated C6 glioma-bearing rats. Meanwhile, AG-1031 and AG-1503 significantly decreased the expression of VEGF, a marker of invasion ability of tumor, in tumor tissue. The novel object recognition test showed that cognitive functions in C6 glioma-bearing rats were considerably damaged, whereas AG-1031 and AG-1503 significantly impeded the cognitive impairment. AG-1031 and AG-1503 efficiently alleviated the glioma-induced impairments of long-term potentiation (LTP), which was damaged in C6 glioma-bearing rats. Furthermore, AG-1031 and AG-1503 augmented the expression of synaptophysin (SYP), which were decreased in glioma rats. In conclusion, our results suggest that AG-1031 and AG-1503 can inhibit the expansion of glioma, and improve the cognitive impairment caused by glioma in glioma-bearing rats.