{"title":"阿托伐他汀降低小鼠四氧嘧啶诱导的厌恶刺激记忆损伤。","authors":"Osman Kukula, Caner Günaydın","doi":"10.2478/abm-2022-0009","DOIUrl":null,"url":null,"abstract":"<p><strong>Background: </strong>An association between dysregulated glucose levels in patients with diabetes mellitus and detrimental effects on the central nervous system, particularly in Alzheimer disease, has been recognized. Atorvastatin treatment has improved memory and cognition in some patients with diabetes mellitus and Alzheimer disease.</p><p><strong>Objectives: </strong>To determine possible neuroprotective effects of atorvastatin on memory and cognition by measuring changes in an adverse stimulus avoidance learning deficit induced by alloxan in a murine model of diabetes mellitus and impaired memory and cognition.</p><p><strong>Methods: </strong>We administered 150 mg/kg and 100 mg/kg alloxan in saline (intraperitoneally, i.p.) at a 48 h interval to produce a model of diabetes mellitus in male BALB/c mice. An oral glucose tolerance test (OGTT) was used to assess blood glucose regulation. After demonstrating hyperglycemia in mice (n = 7 per group) we administered vehicle (saline, i.p.), atorvastatin (10 mg/kg, i.p.), or liraglutide (200 μg/kg, i.p.) for 28 d except for those in a negative control group, which were given saline instead of alloxan, and a group administered atorvastatin alone, which were given saline instead of alloxan followed by atorvastatin (10 mg/kg, i.p.) for 28 d. Locomotor activity was measured 24 h after the final drug treatments, and subsequently their learned behavioral response to an adverse electrical stimulus to their plantar paw surface in a dark compartment was measured using a passive avoidance apparatus (Ugo Basile) in a model of impaired memory and cognition associated with Alzheimer disease. To determine any deficit in their learned avoidance of the adverse stimulus, we measured the initial latency or time mice spent in an illuminated white compartment before entering the dark compartment in the learning trial, and on the day after learning to avoid the adverse stimulus, the retention period latency in the light compartment and time spent in the dark compartment.</p><p><strong>Results: </strong>Atorvastatin alone produced no significant change in blood glucose levels (<i>F</i><sub>4,10</sub> = 0.80, <i>P</i> = 0.55) within 2 h. Liraglutide decreased blood glucose levels after 0.5 h (<i>F</i><sub>4,10</sub> = 11.7, <i>P</i> < 0.001). We found no significant change in locomotor activity in any group. In mice with alloxan-induced diabetes, atorvastatin significantly attenuated the decreased avoidance associated with the diabetes (<i>F</i><sub>4,30</sub> = 38.0, <i>P</i> = 0.02) and liraglutide also significantly attenuated the decreased avoidance (<i>F</i><sub>4,30</sub> = 38.0, <i>P</i> < 0.001). Atorvastatin alone had no significant effect on the adversive learned response compared with vehicle treatment (<i>F</i><sub>4,30</sub> = 38.0, <i>P</i> > 0.05). Atorvastatin significantly decreased the time mice with alloxan-induced diabetes spent in the dark compartment compared with mice in the diabetes group without atorvastatin treatment (<i>F</i><sub>4,30</sub> = 53.9, <i>P</i> = 0.046). Liraglutide also significantly reduced the time mice with alloxan-induced diabetes spent in the dark compartment compared with vehicle-treated mice with alloxan-induced diabetes (<i>F</i><sub>4,30</sub> = 53.9, <i>P</i> < 0.001). Atorvastatin treatment alone had no significant effect on the time mice spent in dark compartment compared with the control group (<i>F</i><sub>4,30</sub> = 53.9, <i>P</i> > 0.05).</p><p><strong>Conclusion: </strong>Atorvastatin significantly attenuated the adverse stimulus avoidance learning deficit in the alloxan-induced murine model of diabetes suggesting decreased impairment of memory and cognition.</p>","PeriodicalId":8501,"journal":{"name":"Asian Biomedicine","volume":null,"pages":null},"PeriodicalIF":0.4000,"publicationDate":"2022-04-01","publicationTypes":"Journal Article","fieldsOfStudy":null,"isOpenAccess":false,"openAccessPdf":"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10321169/pdf/","citationCount":"0","resultStr":"{\"title\":\"Atorvastatin reduces alloxan-induced impairment of aversive stimulus memory in mice.\",\"authors\":\"Osman Kukula, Caner Günaydın\",\"doi\":\"10.2478/abm-2022-0009\",\"DOIUrl\":null,\"url\":null,\"abstract\":\"<p><strong>Background: </strong>An association between dysregulated glucose levels in patients with diabetes mellitus and detrimental effects on the central nervous system, particularly in Alzheimer disease, has been recognized. Atorvastatin treatment has improved memory and cognition in some patients with diabetes mellitus and Alzheimer disease.</p><p><strong>Objectives: </strong>To determine possible neuroprotective effects of atorvastatin on memory and cognition by measuring changes in an adverse stimulus avoidance learning deficit induced by alloxan in a murine model of diabetes mellitus and impaired memory and cognition.</p><p><strong>Methods: </strong>We administered 150 mg/kg and 100 mg/kg alloxan in saline (intraperitoneally, i.p.) at a 48 h interval to produce a model of diabetes mellitus in male BALB/c mice. An oral glucose tolerance test (OGTT) was used to assess blood glucose regulation. After demonstrating hyperglycemia in mice (n = 7 per group) we administered vehicle (saline, i.p.), atorvastatin (10 mg/kg, i.p.), or liraglutide (200 μg/kg, i.p.) for 28 d except for those in a negative control group, which were given saline instead of alloxan, and a group administered atorvastatin alone, which were given saline instead of alloxan followed by atorvastatin (10 mg/kg, i.p.) for 28 d. Locomotor activity was measured 24 h after the final drug treatments, and subsequently their learned behavioral response to an adverse electrical stimulus to their plantar paw surface in a dark compartment was measured using a passive avoidance apparatus (Ugo Basile) in a model of impaired memory and cognition associated with Alzheimer disease. To determine any deficit in their learned avoidance of the adverse stimulus, we measured the initial latency or time mice spent in an illuminated white compartment before entering the dark compartment in the learning trial, and on the day after learning to avoid the adverse stimulus, the retention period latency in the light compartment and time spent in the dark compartment.</p><p><strong>Results: </strong>Atorvastatin alone produced no significant change in blood glucose levels (<i>F</i><sub>4,10</sub> = 0.80, <i>P</i> = 0.55) within 2 h. Liraglutide decreased blood glucose levels after 0.5 h (<i>F</i><sub>4,10</sub> = 11.7, <i>P</i> < 0.001). We found no significant change in locomotor activity in any group. In mice with alloxan-induced diabetes, atorvastatin significantly attenuated the decreased avoidance associated with the diabetes (<i>F</i><sub>4,30</sub> = 38.0, <i>P</i> = 0.02) and liraglutide also significantly attenuated the decreased avoidance (<i>F</i><sub>4,30</sub> = 38.0, <i>P</i> < 0.001). Atorvastatin alone had no significant effect on the adversive learned response compared with vehicle treatment (<i>F</i><sub>4,30</sub> = 38.0, <i>P</i> > 0.05). Atorvastatin significantly decreased the time mice with alloxan-induced diabetes spent in the dark compartment compared with mice in the diabetes group without atorvastatin treatment (<i>F</i><sub>4,30</sub> = 53.9, <i>P</i> = 0.046). Liraglutide also significantly reduced the time mice with alloxan-induced diabetes spent in the dark compartment compared with vehicle-treated mice with alloxan-induced diabetes (<i>F</i><sub>4,30</sub> = 53.9, <i>P</i> < 0.001). Atorvastatin treatment alone had no significant effect on the time mice spent in dark compartment compared with the control group (<i>F</i><sub>4,30</sub> = 53.9, <i>P</i> > 0.05).</p><p><strong>Conclusion: </strong>Atorvastatin significantly attenuated the adverse stimulus avoidance learning deficit in the alloxan-induced murine model of diabetes suggesting decreased impairment of memory and cognition.</p>\",\"PeriodicalId\":8501,\"journal\":{\"name\":\"Asian Biomedicine\",\"volume\":null,\"pages\":null},\"PeriodicalIF\":0.4000,\"publicationDate\":\"2022-04-01\",\"publicationTypes\":\"Journal Article\",\"fieldsOfStudy\":null,\"isOpenAccess\":false,\"openAccessPdf\":\"https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10321169/pdf/\",\"citationCount\":\"0\",\"resultStr\":null,\"platform\":\"Semanticscholar\",\"paperid\":null,\"PeriodicalName\":\"Asian Biomedicine\",\"FirstCategoryId\":\"3\",\"ListUrlMain\":\"https://doi.org/10.2478/abm-2022-0009\",\"RegionNum\":4,\"RegionCategory\":\"医学\",\"ArticlePicture\":[],\"TitleCN\":null,\"AbstractTextCN\":null,\"PMCID\":null,\"EPubDate\":\"\",\"PubModel\":\"\",\"JCR\":\"Q4\",\"JCRName\":\"MEDICINE, RESEARCH & EXPERIMENTAL\",\"Score\":null,\"Total\":0}","platform":"Semanticscholar","paperid":null,"PeriodicalName":"Asian Biomedicine","FirstCategoryId":"3","ListUrlMain":"https://doi.org/10.2478/abm-2022-0009","RegionNum":4,"RegionCategory":"医学","ArticlePicture":[],"TitleCN":null,"AbstractTextCN":null,"PMCID":null,"EPubDate":"","PubModel":"","JCR":"Q4","JCRName":"MEDICINE, RESEARCH & EXPERIMENTAL","Score":null,"Total":0}
引用次数: 0
摘要
背景:糖尿病患者的血糖水平失调与中枢神经系统,特别是阿尔茨海默病的有害影响之间的关联已经被认识到。阿托伐他汀治疗可改善部分糖尿病和阿尔茨海默病患者的记忆和认知能力。目的:通过测量四氧嘧啶引起的糖尿病小鼠记忆和认知障碍的不良刺激回避学习缺陷的变化,探讨阿托伐他汀对记忆和认知可能的神经保护作用。方法:每隔48 h分别给药150 mg/kg和100 mg/kg的四氧嘧啶生理盐水(腹腔灌胃)制造雄性BALB/c小鼠糖尿病模型。口服葡萄糖耐量试验(OGTT)评估血糖调节。在小鼠出现高血糖后(每组7只),我们分别给药(生理盐水,i.p)、阿托伐他汀(10 mg/kg, i.p)或利拉鲁肽(200 μg/kg, i.p) 28 d,阴性对照组给予生理盐水代替四氧嘧啶,单独给药组给予阿托伐他汀(10 mg/kg, i.p) 28 d。在药物治疗结束后24 h测量运动活动。随后,在与阿尔茨海默病相关的记忆和认知受损模型中,使用被动回避装置(Ugo Basile)测量了他们在黑暗隔间中对足底掌表面的不良电刺激的习得行为反应。为了确定它们在学习回避不利刺激方面的缺陷,我们测量了小鼠在学习试验中进入黑暗隔间之前在明亮白色隔间中度过的初始潜伏期或时间,以及在学习避免不利刺激后的第二天,在明亮隔间中的保留期潜伏期和在黑暗隔间中度过的时间。结果:单独使用阿托伐他汀治疗2 h内血糖水平无明显变化(F4,10 = 0.80, P = 0.55),利拉鲁肽治疗0.5 h后血糖水平降低(F4,10 = 11.7, P < 0.001)。我们发现各组的运动活动没有明显变化。阿托伐他汀和利拉鲁肽均能显著降低四氧胺诱导的糖尿病小鼠的避鼠能力(F4,30 = 38.0, P = 0.02),利拉鲁肽也能显著降低四氧胺诱导的糖尿病小鼠避鼠能力(F4,30 = 38.0, P < 0.001)。与载体治疗相比,阿托伐他汀单独治疗对不良学习反应无显著影响(F4,30 = 38.0, P > 0.05)。与未给予阿托伐他汀治疗的糖尿病组小鼠相比,阿托伐他汀显著减少了四氧烷诱导的糖尿病小鼠在暗室中的时间(F4,30 = 53.9, P = 0.046)。与四氧嘧啶诱导的糖尿病小鼠相比,利拉鲁肽还显著减少了四氧嘧啶诱导的糖尿病小鼠在暗室中的时间(F4,30 = 53.9, P < 0.001)。与对照组相比,单独使用阿托伐他汀对小鼠黑暗室停留时间无显著影响(F4,30 = 53.9, P > 0.05)。结论:阿托伐他汀可显著减轻四氧嘧啶诱导的糖尿病小鼠的不良刺激回避学习缺陷,提示其记忆和认知功能受损。
Atorvastatin reduces alloxan-induced impairment of aversive stimulus memory in mice.
Background: An association between dysregulated glucose levels in patients with diabetes mellitus and detrimental effects on the central nervous system, particularly in Alzheimer disease, has been recognized. Atorvastatin treatment has improved memory and cognition in some patients with diabetes mellitus and Alzheimer disease.
Objectives: To determine possible neuroprotective effects of atorvastatin on memory and cognition by measuring changes in an adverse stimulus avoidance learning deficit induced by alloxan in a murine model of diabetes mellitus and impaired memory and cognition.
Methods: We administered 150 mg/kg and 100 mg/kg alloxan in saline (intraperitoneally, i.p.) at a 48 h interval to produce a model of diabetes mellitus in male BALB/c mice. An oral glucose tolerance test (OGTT) was used to assess blood glucose regulation. After demonstrating hyperglycemia in mice (n = 7 per group) we administered vehicle (saline, i.p.), atorvastatin (10 mg/kg, i.p.), or liraglutide (200 μg/kg, i.p.) for 28 d except for those in a negative control group, which were given saline instead of alloxan, and a group administered atorvastatin alone, which were given saline instead of alloxan followed by atorvastatin (10 mg/kg, i.p.) for 28 d. Locomotor activity was measured 24 h after the final drug treatments, and subsequently their learned behavioral response to an adverse electrical stimulus to their plantar paw surface in a dark compartment was measured using a passive avoidance apparatus (Ugo Basile) in a model of impaired memory and cognition associated with Alzheimer disease. To determine any deficit in their learned avoidance of the adverse stimulus, we measured the initial latency or time mice spent in an illuminated white compartment before entering the dark compartment in the learning trial, and on the day after learning to avoid the adverse stimulus, the retention period latency in the light compartment and time spent in the dark compartment.
Results: Atorvastatin alone produced no significant change in blood glucose levels (F4,10 = 0.80, P = 0.55) within 2 h. Liraglutide decreased blood glucose levels after 0.5 h (F4,10 = 11.7, P < 0.001). We found no significant change in locomotor activity in any group. In mice with alloxan-induced diabetes, atorvastatin significantly attenuated the decreased avoidance associated with the diabetes (F4,30 = 38.0, P = 0.02) and liraglutide also significantly attenuated the decreased avoidance (F4,30 = 38.0, P < 0.001). Atorvastatin alone had no significant effect on the adversive learned response compared with vehicle treatment (F4,30 = 38.0, P > 0.05). Atorvastatin significantly decreased the time mice with alloxan-induced diabetes spent in the dark compartment compared with mice in the diabetes group without atorvastatin treatment (F4,30 = 53.9, P = 0.046). Liraglutide also significantly reduced the time mice with alloxan-induced diabetes spent in the dark compartment compared with vehicle-treated mice with alloxan-induced diabetes (F4,30 = 53.9, P < 0.001). Atorvastatin treatment alone had no significant effect on the time mice spent in dark compartment compared with the control group (F4,30 = 53.9, P > 0.05).
Conclusion: Atorvastatin significantly attenuated the adverse stimulus avoidance learning deficit in the alloxan-induced murine model of diabetes suggesting decreased impairment of memory and cognition.
期刊介绍:
Asian Biomedicine: Research, Reviews and News (ISSN 1905-7415 print; 1875-855X online) is published in one volume (of 6 bimonthly issues) a year since 2007. [...]Asian Biomedicine is an international, general medical and biomedical journal that aims to publish original peer-reviewed contributions dealing with various topics in the biomedical and health sciences from basic experimental to clinical aspects. The work and authorship must be strongly affiliated with a country in Asia, or with specific importance and relevance to the Asian region. The Journal will publish reviews, original experimental studies, observational studies, technical and clinical (case) reports, practice guidelines, historical perspectives of Asian biomedicine, clinicopathological conferences, and commentaries
Asian biomedicine is intended for a broad and international audience, primarily those in the health professions including researchers, physician practitioners, basic medical scientists, dentists, educators, administrators, those in the assistive professions, such as nurses, and the many types of allied health professionals in research and health care delivery systems including those in training.