不同化疗药物对小鼠学习记忆功能的影响比较
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摘要
目的:研究比较阿霉素、环磷酰胺联合使用以及单独注射5-氟尿嘧啶(5-FU)或阿霉素(DOX)对正常小鼠认知功能的影响。方法:成年雄性C57/BL小鼠随机分为正常(Control)组、阿霉素(D)组、5-氟尿嘧啶(5-FU)组、阿霉素与环磷酰胺联合(D+C)组。各组小鼠每周腹腔注射1次化疗药物,连续注射3周。采用旷场实验、新位置识别实验评价各组小鼠行为学变化;尼氏染色观察各组小鼠海马CA1和CA3区神经元变化。结果:行为学检测发现,与Control组相比,D+C组小鼠运动速度、活动距离、在中心区域活动时间及频率均无明显差异,新位置识别时间比则显著下降(P <0. 01); D组及5-FU组新位置识别时间比则明显减少(P <0. 05)。尼氏染色显示较Control组,D+C组小鼠海马CA1区和CA3区神经元均显著减少(P <0. 01),排列稀疏;而D组(P <0. 01)及5-FU组(P <0. 05)仅在海马CA3区出现神经元细胞数量降低。较D+C组,D组小鼠海马CA1区细胞数明显增多(P <0. 05)。结论:相较于单一使用阿霉素或5-氟尿嘧啶,阿霉素与环磷酰胺联合使用可以在短时间内造成小鼠严重认知功能障碍。
Objective: To investigate and compare the effects of Doxorubicin and Cyclophosphamide combination treatment with single chermotherapy injection on cognitive function impairment. Methods: C57/BL mice were randomly assigned to Control group,Doxorubicin( D) group,5-Fluorouracil( 5-FU) group,Doxorubicin and Cyclophosphamide combination( D + C) group. Mice were injected intraperitoneally with Chemotherapy drugs once a week for 3 weeks. We evaluated the behavior changes of mice in each group using Open field test and New object position test,Nissl staining was applied to observe the changes of neurons in the hippocampus CA1 and CA3 regions of each group. Results: Behavioral examination showed that comparing with the Control group there were no significant difference in the speed,activity distance,central region residence time and frequency cross to the central area in the D + C group( P > 0. 05),and the time ratio exploring new location in D + C group( P < 0. 01),D group( P < 0. 05),5-FU group( P < 0. 05) were obviously decreased. Nissl staining demonstrated that,compared with the Control group,the neurons in the hippocampus CA1 and CA3 regions of the D + C group were significantly reduced( P < 0. 01),in addition to the neurons were sparse; while the D group( P < 0. 01) and 5-FU group( P < 0. 05) showed a decrease only in the hippocampus CA3 region. Comparing with D + C group,the cell numbers in hippocampus CA1 region of the D group was significantly increased( P < 0. 05).Conclusion: Comparing with using single Doxorubicin or 5-Fluorouracil,Combined Doxorubicin with Cyclophosphamide treatment mice has displayed serious cognitive damage in a short time.
Objective: To investigate and compare the effects of Doxorubicin and Cyclophosphamide combination treatment with single chermotherapy injection on cognitive function impairment. Methods: C57/BL mice were randomly assigned to Control group,Doxorubicin( D) group,5-Fluorouracil( 5-FU) group,Doxorubicin and Cyclophosphamide combination( D + C) group. Mice were injected intraperitoneally with Chemotherapy drugs once a week for 3 weeks. We evaluated the behavior changes of mice in each group using Open field test and New object position test,Nissl staining was applied to observe the changes of neurons in the hippocampus CA1 and CA3 regions of each group. Results: Behavioral examination showed that comparing with the Control group there were no significant difference in the speed,activity distance,central region residence time and frequency cross to the central area in the D + C group( P > 0. 05),and the time ratio exploring new location in D + C group( P < 0. 01),D group( P < 0. 05),5-FU group( P < 0. 05) were obviously decreased. Nissl staining demonstrated that,compared with the Control group,the neurons in the hippocampus CA1 and CA3 regions of the D + C group were significantly reduced( P < 0. 01),in addition to the neurons were sparse; while the D group( P < 0. 01) and 5-FU group( P < 0. 05) showed a decrease only in the hippocampus CA3 region. Comparing with D + C group,the cell numbers in hippocampus CA1 region of the D group was significantly increased( P < 0. 05).Conclusion: Comparing with using single Doxorubicin or 5-Fluorouracil,Combined Doxorubicin with Cyclophosphamide treatment mice has displayed serious cognitive damage in a short time.
引文
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[16]Welbat JU,Chaisawang P,Pannangrong W,et al. Neuroprotective properties of asiatic acid against 5-Fluorouracil chemotherapy in the hippocampus in an adult rat model[J]. Nutrients,2018,10. DOI:10. 3390/nu10081053.
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[19]Philpot RM,Ficken M,Wecker L. Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female,but not male mice[J]. Behav Brain Res,2016,307:165-175.DOI:10. 1016/j. bbr. 2016. 04. 017.
[20] Flanigan TJ,Anderson JE,Elayan I,et al. Effects of cyclophosphamide and/or doxorubicin in a murine model of postchemotherapy cognitive impairment[J]. Toxicol Sci,2018,162:462-474.DOI:10. 1093/toxsci/kfx267.
[21]Shi DD,Huang YH,Lai C,et al. Chemotherapy-induced cognitive impairment is associated with cytokine dysregulation and disruptions in neuroplasticity[J]. Mol Neurobiol,2018. DOI:10. 1007/s12035-018-1224-4.
[22]Christie LA,Acharya MM,Parihar VK,et al. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy[J]. Clin Cancer Res,2012,18:1954-1965. DOI:10.1158/1078-0432. CCR-11-2000.
[23]Kim ES,Jang H,Chang SY,et al. Total synthesis and biological evaluation of sericetin for protection against cisplatin-induced acute kidney injury[J]. J Nat Prod,2018. DOI:10. 1021/acs. jnatprod. 8b00434.
[24]Koppen C,Reifschneider O,Castanheira I,et al. Quantitative imaging of platinum based on laser ablation-inductively coupled plasmamass spectrometry to investigate toxic side effects of cisplatin[J].Metallomics,2015,7:1595-1603. DOI:10. 1039/c5mt00226e.
[25]Lomeli N,Di K,Czerniawski J,et al. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats[J]. Free Radic Biol Med,2017,102:274-286. DOI:10.1016/j. freeradbiomed. 2016. 11. 046.
[26] Abdel-Raheem IT,Khedr NF. Renoprotective effects of montelukast,a cysteinyl leukotriene receptor antagonist,against methotrexate-induced kidney damage in rats[J]. Naunyn Schmiedebergs Arch Pharmacol,2014,387:341-353. DOI:10. 1007/s00210-013-0949-x.
[27]Yang M,Kim JS,Kim J,et al. Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer[J]. Brain Res Bull,2012,89:50-56. DOI:10. 1016/j. brainresbull. 2012. 07. 003.
[28]An JM,Kim SS,Rhie JH,et al. Carmustine induces ERK-and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species[J]. Toxicol In Vitro,2011,25:1359-1365. DOI:10. 1016/j. tiv. 2011. 05. 006.
[2]Horowitz TS,Suls J,Trevino M. A call for a neuroscience approach to cancer-related cognitive impairment[J]. Trends Neurosci,2018,41:493-496. DOI:10. 1016/j. tins. 2018. 05. 001.
[3]Ren X,St Clair DK,Butterfield DA. Dysregulation of cytokine mediated chemotherapy induced cognitive impairment[J]. Pharmacol Res,2017,117:267-273. DOI:10. 1016/j. phrs. 2017. 01.001.
[4]Hardy SJ,Krull KR,Wefel JS,et al. Cognitive changes in cancer survivors[J]. Am Soc Clin Oncol Educ Book,2018(38):795-806. DOI:10. 1200/EDBK_201179.
[5]Sleight A. Coping with cancer-related cognitive dysfunction:a scoping review of the literature[J]. Disabil Rehabil,2016,38:400-408. DOI:10. 3109/09638288. 2015. 1038364.
[6]Zordoky BN,Anwar-Mohamed A,Aboutabl ME,et al. Acute doxorubicin toxicity differentially alters cytochrome P450 expression and arachidonic acid metabolism in rat kidney and liver[J]. Drug Metab Dispos,2011,39:1440-1450. DOI:10. 1124/dmd. 111.039123.
[7] Hermelink K. Acute and late onset cognitive dysfunction associated with chemotherapy in women with breast cancer[J]. Cancer,2011,117:1103,1103-1104. DOI:10. 1002/cncr. 25708.
[8]Barcenas CH,Niu J,Zhang N,et al. Risk of hospitalization according to chemotherapy regimen in early-stage breast cancer[J]. J Clin Oncol,2014,32:2010-2017. DOI:10. 1200/JCO. 2013. 49.3676.
[9]Kitamura Y,Kanemoto E,Sugimoto M,et al. Influence of nicotine on doxorubicin and cyclophosphamide combination treatment-induced spatial cognitive impairment and anxiety-like behavior in rats[J]. Naunyn Schmiedebergs Arch Pharmacol,2017,390:369-378. DOI:10. 1007/s00210-016-1338-z.
[10]Janelsins MC,Heckler CE,Thompson BD,et al. A clinically relevant dose of cyclophosphamide chemotherapy impairs memory performance on the delayed spatial alternation task that is sustained over time as mice age[J]. Neurotoxicology,2016,56:287-293.DOI:10. 1016/j. neuro. 2016. 06. 013.
[11]Keeney JT,Swomley AM,Forster S,et al. Apolipoprotein A-I:insights from redox proteomics for its role in neurodegeneration[J].Proteomics Clin Appl,2013,7:109-122. DOI:10. 1002/prca.201200087.
[12]Gaman AM,Uzoni A,Popa-Wagner A,et al. The role of oxidative stress in etiopathogenesis of chemotherapy induced cognitive impairment(CICI)-“chemobrain”[J]. Aging Dis,2016,7:307-317.DOI:10. 14336/AD. 2015. 1022.
[13]Cruzado JA,Lopez-Santiago S,Martinez-Marin V,et al. Longitudinal study of cognitive dysfunctions induced by adjuvant chemotherapy in colon cancer patients[J]. Support Care Cancer,2014,22:1815-1823. DOI:10. 1007/s00520-014-2147-x.
[14]Ince S,Kucukkurt I,Demirel HH,et al. Protective effects of boron on cyclophosphamide induced lipid peroxidation and genotoxicity in rats[J]. Chemosphere,2014,108:197-204. DOI:10. 1016/j.chemosphere. 2014. 01. 038.
[15] El-Agamy SE,Abdel-Aziz AK,Wahdan S,et al. Astaxanthin ameliorates doxorubicin-induced cognitive impairment(chemobrain)in experimental rat model:impact on oxidative,inflammatory,and apoptotic machineries[J]. Mol Neurobiol,2018,55:5727-5740. DOI:10. 1007/s12035-017-0797-7.
[16]Welbat JU,Chaisawang P,Pannangrong W,et al. Neuroprotective properties of asiatic acid against 5-Fluorouracil chemotherapy in the hippocampus in an adult rat model[J]. Nutrients,2018,10. DOI:10. 3390/nu10081053.
[17]Andryszak P,Wilkosc M,Zurawski B,et al. Verbal memory in breast cancer patients treated with chemotherapy with doxorubicin and cyclophosphamide[J]. Eur J Cancer Care(Engl),2018,27.DOI:10. 1111/ecc. 12749.
[18] Kang S,Lee S,Kim J,et al. Chronic treatment with combined chemotherapeutic agents affects hippocampal micromorphometry and function in mice,independently of neuroinflammation[J]. Exp Neurobiol,2018,27:419-436. DOI:10. 5607/en. 2018. 27. 5.419.
[19]Philpot RM,Ficken M,Wecker L. Doxorubicin and cyclophosphamide lead to long-lasting impairment of spatial memory in female,but not male mice[J]. Behav Brain Res,2016,307:165-175.DOI:10. 1016/j. bbr. 2016. 04. 017.
[20] Flanigan TJ,Anderson JE,Elayan I,et al. Effects of cyclophosphamide and/or doxorubicin in a murine model of postchemotherapy cognitive impairment[J]. Toxicol Sci,2018,162:462-474.DOI:10. 1093/toxsci/kfx267.
[21]Shi DD,Huang YH,Lai C,et al. Chemotherapy-induced cognitive impairment is associated with cytokine dysregulation and disruptions in neuroplasticity[J]. Mol Neurobiol,2018. DOI:10. 1007/s12035-018-1224-4.
[22]Christie LA,Acharya MM,Parihar VK,et al. Impaired cognitive function and hippocampal neurogenesis following cancer chemotherapy[J]. Clin Cancer Res,2012,18:1954-1965. DOI:10.1158/1078-0432. CCR-11-2000.
[23]Kim ES,Jang H,Chang SY,et al. Total synthesis and biological evaluation of sericetin for protection against cisplatin-induced acute kidney injury[J]. J Nat Prod,2018. DOI:10. 1021/acs. jnatprod. 8b00434.
[24]Koppen C,Reifschneider O,Castanheira I,et al. Quantitative imaging of platinum based on laser ablation-inductively coupled plasmamass spectrometry to investigate toxic side effects of cisplatin[J].Metallomics,2015,7:1595-1603. DOI:10. 1039/c5mt00226e.
[25]Lomeli N,Di K,Czerniawski J,et al. Cisplatin-induced mitochondrial dysfunction is associated with impaired cognitive function in rats[J]. Free Radic Biol Med,2017,102:274-286. DOI:10.1016/j. freeradbiomed. 2016. 11. 046.
[26] Abdel-Raheem IT,Khedr NF. Renoprotective effects of montelukast,a cysteinyl leukotriene receptor antagonist,against methotrexate-induced kidney damage in rats[J]. Naunyn Schmiedebergs Arch Pharmacol,2014,387:341-353. DOI:10. 1007/s00210-013-0949-x.
[27]Yang M,Kim JS,Kim J,et al. Acute treatment with methotrexate induces hippocampal dysfunction in a mouse model of breast cancer[J]. Brain Res Bull,2012,89:50-56. DOI:10. 1016/j. brainresbull. 2012. 07. 003.
[28]An JM,Kim SS,Rhie JH,et al. Carmustine induces ERK-and JNK-dependent cell death of neuronally-differentiated PC12 cells via generation of reactive oxygen species[J]. Toxicol In Vitro,2011,25:1359-1365. DOI:10. 1016/j. tiv. 2011. 05. 006.