Neuroprotective properties of chrysin on decreases of cell proliferation, immature neurons and neuronal cell survival in the hippocampal dentate gyrus associated with cognition induced by methotrexate

Abstract

Methotrexate (MTX) is a drug widely used for chemotherapy and can reduce cancer cell production by inhibiting dihydrofolate reductase and decreasing cancer cell growth. MTX has a neurotoxic effect on neural stem and glial cells, leading to memory deficits. Chrysin is a natural flavonoid that contains essential biological activities, such as neuroprotective and cognitive-improving properties. Therefore, the aim of the present study was to investigate the protective effect of chrysin against MTX-induced memory impairments related to hippocampal neurogenesis. Seventy-two male Sprague Dawley rats were divided into six groups: control, MTX, chrysin (10 and 30 mg/kg), and MTX+ chrysin (10 and 30 mg/kg) groups. Chrysin (10 and 30 mg/kg) was administered by oral gavage for 15 days. MTX (75 mg/kg) was administered by intravenous injection on days 8 and 15. Spatial and recognition memories were evaluated using the novel object location (NOL) and novel object recognition (NOR) tests, respectively. Moreover, cell proliferation, neuronal cell survival, and immature neurons in the subgranular zone of the hippocampal dentate gyrus were quantified by Ki-67, bromodeoxyuridine/neuronal nuclear protein (BrdU/NeuN), and doublecortin (DCX) immunohistochemistry staining. The results of the MTX group demonstrated that spatial and recognition memories were both impaired. Furthermore, cell division reduction, neuronal cell survival reduction, and immature neuron decreases were detected in the MTX group and not observed in the co-administration groups. Therefore, these results revealed that chrysin could alleviate memory and neurogenesis impairments in MTX-treated rats.