Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy.
Fluoxetine reverses the memory impairment and reduction in proliferation and survival of hippocampal cells caused by methotrexate chemotherapy.
复制标题
DOI：
10.1007/s00213-010-2122-2
复制
发表时间：
2011-05
影响因子：
3.4
通讯作者：
Wigmore, Peter
中科院分区：
文献类型：
--
作者：
Lyons, Laura;ElBeltagy, Maha;Umka, Jariya;Markwick, Rachel;Startin, Carla;Bennett, Geoffrey;Wigmore, Peter
辅助癌症化疗可导致长期的认知缺陷。据推测，这些损害是由于这些药物靶向成年海马内的神经前体，其损失与记忆障碍有关。本研究探讨了化疗，甲氨蝶呤（MTX）对空间工作记忆和参与海马神经发生的神经前体细胞的增殖和存活的影响，以及抗抑郁药氟西汀可能的神经保护特性。对雄性Lister hooded大鼠给予MTX（75 mg/kg，一周间隔两次静脉内给药），然后给予甲酰四氢叶酸补救（MTX给药后18 h，6 mg/kg，26、42和50 h，3 mg/kg）和/或氟西汀（10 mg/kg/天，饮用水，持续40天）。使用新的位置识别（NLR）测试来测试记忆。使用标记物，定量齿状回中的细胞增殖（Ki 67）和存活（溴脱氧尿苷/BrdU）。MTX治疗的大鼠表现出认知缺陷的NLR任务相比，车辆和氟西汀治疗组。接受MTX和氟西汀治疗的组的认知能力得到恢复。MTX降低了SGZ中增殖细胞的数量和它们的存活率。这是防止共同管理的氟西汀，它单独增加细胞数量。这些结果表明，MTX诱导空间工作记忆的损害，并对海马神经发生具有负面的长期影响，这是抵消了氟西汀的共同管理。如果可以转化为患者，这一发现有可能预防许多癌症幸存者所经历的化疗诱导的认知缺陷。本文的在线版本（doi：10.1007/s 00213 -010-2122-2）包含补充材料，可供授权用户使用。
Adjuvant cancer chemotherapy can cause long-lasting, cognitive deficits. It is postulated that these impairments are due to these drugs targeting neural precursors within the adult hippocampus, the loss of which has been associated with memory impairment. The present study investigates the effects of the chemotherapy, methotrexate (MTX) on spatial working memory and the proliferation and survival of the neural precursors involved in hippocampal neurogenesis, and the possible neuroprotective properties of the antidepressant fluoxetine. Male Lister hooded rats were administered MTX (75 mg/kg, two i.v. doses a week apart) followed by leucovorin rescue (i.p. 18 h after MTX at 6 mg/kg and at 26, 42 and 50 h at 3 mg/kg) and/or fluoxetine (10 mg/kg/day in drinking water for 40 days). Memory was tested using the novel location recognition (NLR) test. Using markers, cell proliferation (Ki67) and survival (bromodeoxyuridine/BrdU), in the dentate gyrus were quantified. MTX-treated rats showed a cognitive deficit in the NLR task compared with the vehicle and fluoxetine-treated groups. Cognitive ability was restored in the group receiving both MTX and fluoxetine. MTX reduced both the number of proliferating cells in the SGZ and their survival. This was prevented by the co-administration of fluoxetine, which alone increased cell numbers. These results demonstrate that MTX induces an impairment in spatial working memory and has a negative long-term effect on hippocampal neurogenesis, which is counteracted by the co-administration of fluoxetine. If translatable to patients, this finding has the potential to prevent the chemotherapy-induced cognitive deficits experienced by many cancer survivors. The online version of this article (doi:10.1007/s00213-010-2122-2) contains supplementary material, which is available to authorized users.
登录
查看更多内容
影响因子：
3.1
作者：
Carneiro, BA;Lima, IPF;Lima, AAM
通讯作者：
Lima, AAM
影响因子：
9.8
作者：
Dupret D;Fabre A;Döbrössy MD;Panatier A;Rodríguez JJ;Lamarque S;Lemaire V;Oliet SH;Piazza PV;Abrous DN
通讯作者：
Abrous DN
影响因子：
2.7
作者：
Dix, SL;Aggleton, JP
通讯作者：
Aggleton, JP
影响因子：
3.3
作者：
Gandal, M. J.;Ehrlichman, R. S.;Siegel, S. J.
通讯作者：
Siegel, S. J.
影响因子：
5
作者：
Conley, Rachel K.;Hutson, Peter H.
通讯作者：
Hutson, Peter H.