神经发生是生成神经干细胞（NSCs）并使其功能成为神经元的过程，在化疗治疗后可以减少。甲氨蝶呤（MTX）是一种叶酸拮抗剂，用于癌症治疗，但会产生负面影响，包括氧化应激、神经细胞凋亡和认知功能障碍。橙皮素（Hsd）是一种存在于柑橘类水果中的黄酮类化合物，具有抗氧化和神经保护作用。本研究旨在探讨Hsd是否能够减轻MTX诱导的海马神经干细胞凋亡引起的损伤。斯普拉格-道利大鼠（n = 24）被分成4组：（1）车组接受丙二醇（21天）和0.9％生理盐水（第8天和第15天），（2）Hsd组接受100mg/kg（21天），（3）MTX组接受75mg/kg（第8天和第15天），（4）MTX+Hsd组接受MTX，75mg/kg（第8天和第15天）和Hsd，100mg/kg（21天）。我们的结果表明，MTX可以降低海马神经干细胞，包括SRY（性别决定区域Y）-盒2（SOX2）和网格蛋白。MTX减少了海马中与血管相关（VR）的Ki-67阳性细胞，但未减少与非血管相关（NVR）的Ki-67阳性细胞。此外，MTX降低了海马组织中的SOX2、网格蛋白、突触后密度蛋白95（PSD-95）和B细胞淋巴瘤-2蛋白家族（Bcl-2），而增强了Bax和半胱天冬酶-3。有趣的是，Hsd和MTX的联合处理显示出SOX2、网格蛋白和VR Ki-67阳性细胞的上调，以及升高的SOX2、网格蛋白、PSD-95和Bcl-2蛋白。此外，同时接受Hsd和MTX可以显著抑制Bax和半胱天冬酶-3的增加。这些结果证实了在海马NSC增殖和神经细胞凋亡方面，Hsd可以缓解MTX诱导的损伤。 版权所有2023年作者，出版Elsevier Masson SAS。保留所有权利。

Neurogenesis is a process of generating neural stem cells (NSCs) as functional neurons can be decreased after chemotherapy treatments. Methotrexate (MTX) is a folate antagonist that is used for cancer treatment but has negative effects, including oxidative stress, neuronal apoptosis and cognitive impairments. Hesperidin (Hsd), a flavonoid found in citrus fruits, has antioxidant and neuroprotection properties. This study investigated whether Hsd could attenuate impairments of hippocampal neural stem cells related to apoptosis induced by MTX. Spraque-Dawley rats (n = 24) were divided into 4 groups: (1) Vehicle group received propylene glycol (21 days) and 0.9% normal saline (day 8 and 15), (2) Hsd group received 100 mg/kg (21 days), (3) MTX group received 75 mg/kg (days 8 and 15) and (4) MTX+Hsd group received MTX, 75 mg/kg (day 8 and 15) and Hsd 100 mg/kg (21 days). Our results showed that MTX decreased hippocampal neural stem cells including SRY (sex determining region Y)-box 2 (SOX2) and nestin. MTX diminished vascular related (VR) Ki-67 positive cells in the hippocampus but not non-vascular related (NVR) Ki-67. Additionally, MTX reduced SOX2, nestin, postsynaptic density protein 95 (PSD-95) and B-cell lymphoma-2 family of proteins (Bcl-2), whereas Bax and caspase-3 were enhanced in the hippocampal tissues. Interestingly, co-treatment with Hsd and MTX revealed upregulation of SOX2, nestin and VR Ki-67 positive cells as well as elevated SOX2, nestin, PSD-95 and Bcl-2 proteins. Moreover, receiving both Hsd and MTX significantly suppressed increased Bax and caspase-3. These results confirm that Hsd can ameliorate MTX-induced impairments of hippocampal NSC proliferation and neuronal apoptosis.Copyright © 2023 The Authors. Published by Elsevier Masson SAS.. All rights reserved.