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Hesperidin Alleviates Methotrexate-Induced Memory Deficits via Hippocampal Neurogenesis in Adult Rats

Department of Anatomy, Faculty of Medicine, Khon Kaen University, Khon Kaen 40002, Thailand
Faculty of Medical Science, Nakhonratchasima College, Nakhon Ratchasima 30000, Thailand
School of Life Sciences, Medical School, Queen’s Medical Centre, Nottingham University, Nottingham NG7 2RD, UK
Neuroscience Research and Development Group, Khon Kaen University, Khon Kaen 40002, Thailand
Author to whom correspondence should be addressed.
Nutrients 2019, 11(4), 936;
Received: 27 March 2019 / Revised: 18 April 2019 / Accepted: 22 April 2019 / Published: 25 April 2019
(This article belongs to the Special Issue Nutrition, Cognition and Brain Integrity)
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Methotrexate (MTX), a folic acid antagonist, is widely used in cancer treatment. However, treatment with MTX reduces hippocampal neurogenesis, leading to memory deficits. Hesperidin (Hsd) is a flavonoid glycoside that promotes anti-inflammation, acts as an antioxidant, and has neuroprotective properties. Consumption of Hsd enhances learning and memory. In the present study, we investigated the protective effects of Hsd against MTX-induced impairments of memory and neurogenesis; male Sprague Dawley rats were administered with a single dose of MTX (75 mg/kg) by intravenous (i.v.) injection on days 8 and 15 or Hsd (100 mg/kg) by oral gavage for 21 days. Memory was tested using novel object location (NOL) and novel object recognition (NOR) tasks. Immunofluorescence staining of Ki-67, bromodeoxyuridine (BrdU), and doublecortin (DCX) was performed to assess cell proliferation, survival, and immature neurons. The data showed that Hsd and MTX did not disable locomotor ability. The MTX animals exhibited memory deficits in both memory tests. There were significant decreases in the numbers of cell proliferation, survival, and immature neurons in the MTX animals. However, co-administration with MTX and Hsd alleviated memory loss and neurogenesis decline. These results revealed that Hsd could protect against MTX side effects in the animals in this study. View Full-Text
Keywords: methotrexate; hesperidin; memory; neurogenesis methotrexate; hesperidin; memory; neurogenesis

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This is an open access article distributed under the Creative Commons Attribution License which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited (CC BY 4.0).

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Naewla, S.; Sirichoat, A.; Pannangrong, W.; Chaisawang, P.; Wigmore, P.; Welbat, J.U. Hesperidin Alleviates Methotrexate-Induced Memory Deficits via Hippocampal Neurogenesis in Adult Rats. Nutrients 2019, 11, 936.

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