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

Nandini Pathak,Karthik Gourishetti,Suhani Sumalatha,Vanishree Rao,Sri Pragnya Cheruku,C Mallikarjuna Rao,R J A Vibhavari,Nitesh Kumar

doi:10.1007/s13205-020-02427-7

Nandini Pathak, Karthik Gourishetti + Show 6 more

Open Access

https://doi.org/10.1007/s13205-020-02427-7

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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.

Highlights

Chemotherapy is one of the oldest treatment modalities aimed at reducing the tumor burden and improving progression-free overall survival after surgery or radiation therapy
The process resulted in a yellowish-orange colored product that was analyzed by LC–MS, for characterization and evaluation of purity
Chemotherapy mediated neurotoxicity is manifested by impaired attention, executive functions, memory, etc., even after cessation of therapy, compromising the quality of life

Summary

Introduction

Chemotherapy is one of the oldest treatment modalities aimed at reducing the tumor burden and improving progression-free overall survival after surgery or radiation therapy It is ill-famed to cause cognitive deficits in 70% of cancer patients, of which about 50% report a significant decline in cognitive processes. Glioma/glioblastoma is the most common and aggressive primary tumor of the glial cells manifested by memory problems, headaches, personality changes, seizures, speech problems, and weakness/numbness in the arms, legs, and face It is the 3rd most cause of death by cancer in patients of 15–34 years of age. TMZ, an imidazole derivative, is a prodrug that readily converts into an active metabolite, 5-(3-methyl)-1-triazen-1-yl-imidazole-4-carboxamide (MTIC) systemically This metabolite acts by hypermethylation at GGG DNA sequences and inactivation of repair enzyme O6 methylguanine-DNA methyltransferase (MGMT) which initiates apoptosis, resulting in glioma cell death (Dietrich et al 2015b; Barciszewska et al 2015). The present study was designed to evaluate the protective effect of DHZ in TMZ-induced cognitive impairment in normal (chemobrain) and C6-induced glioblastoma rats

Materials and methods

Results

Discussion

Compliance with ethical standards