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.

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.

Caffeic Acid Alleviates Memory and Hippocampal Neurogenesis Deficits in Aging Rats Induced by D-Galactose.

Hippocampal neurogenesis occurs throughout life, but it declines with age. D-galactose (D-gal) enhances cellular senescence through oxidative stress leading to neurodegeneration and memory impairment. Caffeic acid (CA) acts as an antioxidant via decreasing brain oxidative stress. This study aims to investigate the advantages of CA in alleviating the loss of memory and neurogenesis production in the hippocampus in aged rats activated by D-gal. Fifty-four male Sprague-Dawley rats were unpredictably arranged into six groups. In the D-gal group, rats were administered D-gal (50 mg/kg) by intraperitoneal (i.p.) injection. For the CA groups, rats received 20 or 40 mg/kg CA by oral gavage. In the co-treated groups, rats received D-gal (50 mg/kg) and CA (20 or 40 mg/kg) for eight weeks. The results of novel object location (NOL) and novel object recognition (NOR) tests showed memory deficits. Moreover, a decline of neurogenesis in the hippocampus was detected in rats that received D-gal by detecting rat endothelial cell antigen-1 (RECA-1)/Ki-67, 5-bromo-2'-deoxyuridine (BrdU)/neuronal nuclear protein (NeuN), doublecortin (DCX) by means of staining to evaluate blood vessel associated proliferating cells, neuronal cell survival and premature neurons, respectively. By contrast, CA attenuated these effects. Our results postulate that CA attenuated the impairment of memory in D-gal-stimulated aging by up-regulating levels of hippocampal neurogenesis.

Hesperidin Reduces Memory Impairment Associated with Adult Rat Hippocampal Neurogenesis Triggered by Valproic Acid.

Treatment with valproic acid (VPA) deteriorates hippocampal neurogenesis, which leads to memory impairment. Hesperidin (Hsd) is a plant-based bioflavonoid that can augment learning and memory. This study aimed to understand the effect of Hsd on the impairment of hippocampal neurogenesis and memory caused by VPA. The VPA (300 mg/kg) was administered by intraperitoneal injection twice daily for 14 days, and Hsd (100 mg/kg/day) was administered by oral gavage once a day for 21 days. All rats underwent memory evaluation using the novel object location (NOL) and novel object recognition (NOR) tests. Immunofluorescent staining of Ki-67, BrdU/NeuN, and doublecortin (DCX) was applied to determine hippocampal neurogenesis in cell proliferation, neuronal survival, and population of the immature neurons, respectively. VPA-treated rats showed memory impairments in both memory tests. These impairments resulted from VPA-induced decreases in the number of Ki-67-, BrdU/NeuN-, and DCX-positive cells in the hippocampus, leading to memory loss. Nevertheless, the behavioral expression in the co-administration group was improved. After receiving co-administration with VPA and Hsd, the numbers of Ki-67-, BrdU/NeuN-, and DCX-positive cells were improved to the normal levels. These findings suggest that Hsd can reduce the VPA-induced hippocampal neurogenesis down-regulation that results in memory impairments.