Amelioration of Doxorubicin-Induced Cognitive Impairment by Quercetin in a Rat Model of Breast Cancer

Abstract

AbstractThe management of breast cancer by chemotherapeutic agents has significantly increased the survival rates and, at the same time, raised concerns about the side effects caused by these agents on healthy tissues. Chemotherapy-induced cognitive impairment resulting from non-CNS malignancies like breast cancer has emerged as a significant challenge among cancer survivors due to its negative impact on the quality of day-to-day life activities. Using doxorubicin-based chemotherapy as a preclinical model for chemotherapy-induced cognitive impairment, we assessed the effect of quercetin on behavioral memory alterations in tumor-bearing female rats in vivo and changes in neurite length and apoptosis in PC12 cell lines in vitro. Quercetin is purported to have neuroprotective effects in different preclinical models of human neurological conditions because of its possible anti-inflammatory and antioxidant properties. Mammary carcinoma was induced by intraperitoneal administration of N-methyl-N-nitrosourea followed by doxorubicin administration once in 5 days (50 days). Pre-treatment with quercetin began 1 week before the chemotherapy and continued till the end of the chemotherapy cycle. Mechanistically, quercetin produced protection against doxorubicin-induced neurotoxicity by decreasing apoptosis and had a neurogenic effect evidenced by the prevention of toxicant-induced inhibition of neurite establishment. Quercetin reversed episodic and spatial memory deficits caused by doxorubicin treatment assessed by novel object recognition memory and Morris water maze, respectively. Taken together, our findings suggest that cytotoxic effects of doxorubicin may be a contributor to neurogenic impairment in tumor-bearing animals, leading to memory deficits. Therefore, quercetin could be a promising therapeutic strategy for doxorubicin-related cognitive impairment, thus imparting hope for improved quality of life among cancer survivors. Graphical Abstract