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Dehydrozingerone protects temozolomide-induced cognitive impairment in normal and C6 glioma rats besides enhancing its anticancer potential.

ABSTRACT: Considering the cognitive impairment induced by temozolomide (TMZ) in glioblastoma survivors, the present study was aimed to evaluate the protective effect of dehydrozingerone (DHZ) against TMZ-induced cognitive impairment (chemobrain) and C6 cell line-induced glioma in male Wistar rats. In both chemobrain and glioma models, TMZ was administered at a dose of 18 mg/kg i.v every 5th day and DHZ at a dose of 100 mg/kg p.o. daily. Additionally, glioma was induced by intracerebral injection of 5?×?104 C6 rat glioma cells in the cortex in the glioma model. Upon disease induction and treatment with TMZ?+?DHZ, spatial memory was assessed by the Morris water maze (MWM) test and episodic memory by the novel object recognition test (NORT). The induction of glioma was confirmed by histology of the cortex. Hippocampus and frontal cortex were subjected to antioxidant evaluation. Significant loss of spatial and episodic memory was observed with TMZ treatment which was significantly restored by DHZ. DHZ showed significant improvement in oxidative stress markers reversed the histopathological features in the cortex. TMZ-induced elevation of the glutathione level was also reversed by DHZ, indicating the role of DHZ in the reversal of TMZ resistance. In the glioma model, the improvement in cognition by DHZ correlated with the decrease in tumor volume. Altogether, the study results reveal the role of TMZ in worsening the memory and DHZ in reversing it, besides, improving its anticancer potential.

SUBMITTER: Pathak N

PROVIDER: S-EPMC7498526 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Dehydrozingerone protects temozolomide-induced cognitive impairment in normal and C6 glioma rats besides enhancing its anticancer potential.

Pathak Nandini N Cheruku Sri Pragnya SP Rao Vanishree V Vibhavari R J A RJA Sumalatha Suhani S Gourishetti Karthik K Rao C Mallikarjuna CM Kumar Nitesh N

3 Biotech 20200917 10

Considering the cognitive impairment induced by temozolomide (TMZ) in glioblastoma survivors, the present study was aimed to evaluate the protective effect of dehydrozingerone (DHZ) against TMZ-induced cognitive impairment (chemobrain) and C6 cell line-induced glioma in male Wistar rats. In both chemobrain and glioma models, TMZ was administered at a dose of 18 mg/kg i.v every 5th day and DHZ at a dose of 100 mg/kg p.o. daily. Additionally, glioma was induced by intracerebral injection of 5 × 10 ...[more]

PMID: 32995109

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Project description:FOXO3a (forkhead box transcription factor 3a) is involved in regulating multiple biological processes in cancer cells. BNIP3 (Bcl-2/adenovirus E1B 19-kDa-interacting protein 3) is a receptor accounting for priming damaged mitochondria for autophagic removal. In this study we investigated the role of FOXO3a in regulating the sensitivity of glioma cells to temozolomide (TMZ) and its relationship with BNIP3-mediated mitophagy. We showed that TMZ dosage-dependently inhibited the viability of human U87, U251, T98G, LN18 and rat C6 glioma cells with IC50 values of 135.75, 128.26, 142.65, 155.73 and 111.60 μM, respectively. In U87 and U251 cells, TMZ (200 μM) induced DNA double strand breaks (DSBs) and nuclear translocation of apoptosis inducing factor (AIF), which was accompanied by BNIP3-mediated mitophagy and FOXO3a accumulation in nucleus. TMZ treatment induced intracellular ROS accumulation in U87 and U251 cells via enhancing mitochondrial superoxide, which not only contributed to DNA DSBs and exacerbated mitochondrial dysfunction, but also upregulated FOXO3a expression. Knockdown of FOXO3a aggravated TMZ-induced DNA DSBs and mitochondrial damage, as well as glioma cell death. TMZ treatment not only upregulated BNIP3 and activated autophagy, but also triggered mitophagy by prompting BNIP3 translocation to mitochondria and reinforcing BNIP3 interaction with LC3BII. Inhibition of mitophagy by knocking down BNIP3 with SiRNA or blocking autophagy with 3MA or bafilomycin A1 exacerbated mitochondrial superoxide and intracellular ROS accumulation. Moreover, FOXO3a knockdown inhibited TMZ-induced BNIP3 upregulation and autophagy activation. In addition, we showed that treatment with TMZ (100 mg·kg-1·d-1, ip) for 12 days in C6 cell xenograft mice markedly inhibited tumor growth accompanied by inducing FOXO3a upregulation, oxidative stress and BNIP3-mediated mitophagy in tumor tissues. These results demonstrate that FOXO3a attenuates temozolomide-induced DNA double strand breaks in human glioma cells via promoting BNIP3-mediated mitophagy.

Dataset Information

Dehydrozingerone protects temozolomide-induced cognitive impairment in normal and C6 glioma rats besides enhancing its anticancer potential.

Publications

Dehydrozingerone protects temozolomide-induced cognitive impairment in normal and C6 glioma rats besides enhancing its anticancer potential.

Similar Datasets

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