Neuroprotective effect of Mulmina Mango against chemotherapy-induced cognitive decline in mouse model of mammary carcinoma

Jeena John,Rajesh N Jagdale,Jayesh Mudgal,K Nandakumar,Raghuvir Keni,Pawan Ganesh Nayak,Syed M Ahmed,Kaggundi V Raghavendra,Manas Kinra,Niraja Ranadive

doi:10.1038/s41598-022-06862-9

Abstract

The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain. The aim of this study was to assess the effect of a proprietary ayurvedic formulation Mulmina Mango against chemotherapy-induced cognitive impairment (CICI). Mammary carcinoma was induced by subcutaneously inoculating 4T1 cells into the mammary fat pad of the animals. Intraperitoneal administration of Cyclophosphamide, Methotrexate, 5-Fluorouracil (CMF) regimen was carried out once a week for three weeks. Treatment of Mulmina began one week before chemotherapy and continued till the end of the chemotherapy cycle. After three cycles of chemotherapy, cognitive decline was assessed by Morris water maze task followed by assessment of locomotor activity by open-field test. Tumor progression was evaluated by measurement of tumor volume. Oxidative and neuroinflammatory markers were also evaluated from the isolated brain samples. CMF treatment resulted in a considerable reduction in tumour volume. We found chemotherapy negatively affected behavioral and biochemical parameters in animals and Mulmina treatment ameliorated these cognitive impairments by restoring antioxidant and maintaining cytokine levels. The combination of phytochemicals in Mulmina proved its possible ability to alleviate CICI without affecting chemotherapeutic efficiency and could pave the way for identifying treatment strategies to combat chemobrain.

Highlights

The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain
Mulmina Mango which consists of Mangifera indica fruit pulp, Centella asiatica, Curcuma longa rhizome, and nutrients and vitamins was analyzed against CMF induced cognitive impairment in a mouse model of mammary carcinoma without compromising the anticancer potential of CMF therapy
Administration of lower dose of Mulmina (40 ml/Kg) significantly attenuated CMF induced cognitive impairment evidenced by a decrease in escape latency on days 3 and 4 and higher dose of Mulmina (80 ml/Kg) increased path efficiency on day 2 compared to tumor + CMF treated group (Fig: 3)

Summary

Introduction

The post-treatment status of breast cancer survivors has become a concern because of the toxicity induced by chemotherapeutic agents in the brain tissues resulting in cognitive deficits, which is generally referred as chemobrain. The aim of this study was to assess the effect of a proprietary ayurvedic formulation Mulmina Mango against chemotherapy-induced cognitive impairment (CICI). Abbreviations CICI Chemotherapy-induced cognitive impairment BBB Blood–brain barrier CPP Cyclophosphamide MTX Methotrexate 5-FU 5-Fluorouracil DPL Donepezil TNBC Triple negative breast cancer CMF Cyclophosphamide + Methotrexate + 5-Fluorouracil OFT Open-field test MWM Morris water maze MN Mulmina MDA Malondialdehyde LPO Lipid peroxidation GSH Reduced glutathione. CPP & 5-FU crosses B BB12,13, but the possibility of MTX to reach brain is low All these agents have individually proved to cause neuroinflammation and cognitive impairment in different preclinical studies. The study is designed to understand the neuroprotective role of Mulmina and to decipher its behavioral, biochemical and neuroinflammatory alterations in tumor-bearing animals

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