红花黄色素对老年大鼠认知功能障碍的影响及机制
郑 诗 （ 广东省第二人民医院 ）
张 辉 （ 广东省第二人民医院 ）
梁 飞 （ 广东省第二人民医院 ）
https://doi.org/10.37155/2661-4766-0602-41Abstract
目的：探究红花黄色素对老年大鼠认知功能障碍的作用效果及机制，并探讨红花黄色素剂量高低与作用 效果之间关系，为认知功能障碍的防治提供了新方向。方法：我们选择25只15-16周SD大鼠，所有大鼠结束适应性饲 养后，均予D-半乳糖皮下注射构建大鼠衰老模型，随机分为5组（每组5只），分别是对照组、模型组、低剂量组、高 剂量组、高剂量 抑制剂组，其中低剂量组、高剂量组、高剂量＋抑制剂组分别由尾静脉注射1ml/kg、5ml/kg、5ml/kg 的红花黄色素注射液，而高剂量＋抑制剂组进行红花黄色素注射后一并完成腹腔注射1.5mg/kg LY294002，对照组、模 型组分别注射5ml/kg生理盐水。除对照组外，其他各组均进行七氟烷麻醉，七氟烷浓度3.2%，流量2L/min，持续6小 时。麻醉后进行水迷宫实验，检测各组大鼠潜伏期、穿越平台次数，采用ELISA检测大鼠血清TNF-α、IL-10水平，HE 染色大鼠脑组织，TUNEL染色检测海马区凋亡情况及计算凋亡率，采用Western Blot检测海马区组织PI3K、AKT蛋白 水平。结果：水迷宫结果显示麻醉后各时间点模型组潜伏期均比对照组明显延长（P < 0.05），高剂量组潜伏期较模 型组缩短（P < 0.05），而低剂量组在麻醉后第3-5天潜伏期与模型组相比稍缩短，但差异无统计学意义（P > 0.05）， 高剂量 抑制剂组与高剂量组相比，两组潜伏期未见明显差异（P > 0.05）；穿越平台次数结果显示，高剂量组和低剂 量组的穿越平台次数较模型组增多（P < 0.05），高、低剂量两组穿越平台次数相比差异无统计学意义（P > 0.05）， 高剂量 抑制剂组与高剂量组穿越平台次数相比差异无统计学意义（P > 0.05）；ELISA结果显示高剂量组和低剂量组 血清TNF-α含量均低于模型组，IL-10均高于模型组（P < 0.05）；低剂量组与高剂量组相比，两组TNF-α差异无统计学 意义（P > 0.05），而高剂量组IL-10较低剂量组升高更明显（P < 0.05）；HE染色结果提示模型组脑组织结构紊乱， 炎症细胞浸润，而低、高剂量组较模型组大鼠脑组织结构清晰，炎症浸润较少；TUNEL染色结果显示低、高剂量组海 马区神经元凋亡率较模型组减轻（P < 0.05），高剂量组与低剂量组相比，凋亡率无显著差异（P > 0.05）；脑海马取 组织Western blot结果提示高剂量组和低剂量组PI3K含量较模型组稍升高，但差异无统计学意义（P > 0.05），而高剂 量组、低剂量组AKT蛋白水平较明显模型组下降，且低剂量组AKT含量下降更明显（P < 0.05）。结论：红花黄色素 能有效改善老年大鼠麻醉后认知功能障碍，抑制炎症，抑制神经元凋亡，具有潜在的神经保护功效，为POCD的防治 提供了新方向，红花黄色素剂量高低与改善效果强弱并不完全一致，红花黄色素干预剂量仍需要后续研究，本研究结 果尚不支持红花黄色素改善认知功能障碍的机制与PI3K/AKT通路有关。
Keywords
红花黄色素；七氟烷；认知功能障碍；神经炎症；PI3K/AKT通路Full Text
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and anesthetic. Anesth Analg(S0003-2999).2011
May;112(5):1179-85.
[2] Monk TG, Weldon BC, Garvan CW, et al. Predictors
of cognitive dysfunction after major noncardiac surgery.
Anesthesiology(S0003-3022). 2008 Jan;108(1):18-30.
[3] Steinmetz J, Christensen KB, Lund T, et al. Long_x0002_term consequences
of postoperative cognitive dysfunction.
Anesthesiology(S0003-3022). 2009 Mar;110(3):548-55.
[4] Abildstrom H, Rasmussen LS, Rentowl P, et al.
Cognitive dysfunction 1-2 years after non-cardiac surgery
in the elderly. ISPOCD group. International Study of PostOperative
Cognitive Dysfunction. Acta Anaesthesiol
Scand(S0001-5172). 2000 Nov;44(10):1246-51.
[5] Moller JT, Cluitmans P, Rasmussen LS, et al. Longterm
postoperative cognitive dysfunction in the elderly:
ISPOCD1 study. Lancet(S0140-6736), 1998 Mar 21;
351(9106):857-61.
[6] Hudetz JA, Iqbal Z, Gandhi SD, et al. Postoperative
delirium and short-term cognitive dysfunction occur more
frequently in patients undergoing valve surgery with or
without coronary artery bypass graft surgery compared
with coronary artery bypass graft surgery alone: results of a
pilot study. J Cardiothorac Vasc Anesth(S 1053-0770). 2011
Oct;25(5):811-6.
[7] Hudetz JA, Patterson KM, Iqbal Z, et al. Metabolic
syndrome exacerbates short-term postoperative cognitive
dysfunction in patients undergoing cardiac surgery: results of
a pilot study. J Cardiothorac Vasc Anesth(S1053-0770). 2011
Apr;25(2):282-7.
[8] Dallmeier D, Larson MG, Vasan RS, et al.Metabolic
syndrome and inflammatory biomarkers: a communitybased
cross-sectional study at the Framingham Heart Study.
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flammation in Postoperative Cognitive Dysfunction: Moving
From Hypothesis to Treatment. Front Psychiatry(S 1664-
0640). 2019 Jan 17;9:752.
[10] Mahanna-Gabrielli E, Schenning KJ, Eriksson LI, et
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report from the American Society of Anesthesiologists Brain
Health Initiative Summit 2018. Br J Anaesth(S0007-0912).
2019 Oct;123(4):464-478.
[11] Terrando N, Monaco C, Ma D, et al. Tumor necrosis
factor-alpha triggers a cytokine cascade yielding postoperative
cognitive decline. Proc Natl Acad Sci USA(S 0027-8424).
2010 Nov 23;107(47):20518-22.
[12] Fidalgo AR, Cibelli M, White JPM, et al. Systemic
inflammation enhances surgery-induced cognitive dysfunction
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and neuroinflammation associated with cardiac surgery
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（S0003-2999）. 2019 Apr; 128（4）:781-788.
[15] Saxena S, Lai IK, Li R, et al. Neuroinflammation
is a putative target for prevention and treatment of
perioperative neurocognitive disorders. BRITISH MEDICAL
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[16] Berger M, Nadler JW, Friedman A, et al. The
effect of propofol versus isoflurane anesthesia on human
cerebrospinal fluid markers of alzheimer’s disease: results of
a randomized trial. J Alzheimers Dis(S1387-2877). 2016 Apr
15;52(4):1299-310.
[17] Hirsch J, Vacas S, Terrando N, et al. Perioperative
cerebrospinal fluid and plasma inflammatory markers after
orthopedic surgery. J Neuroinflammation(S1742-2094). 2016
Aug 30;13(1):211.
[18] Cianciulli A, Porro C, Calvello R, et al.Microglia
mediated neuroinflammation: focus on PI3K modulation.
Biomolecules(S2218-273X). 2020 Jan 14;10(1):137.
[19] Weichhart T, Saemann MD. The PI3K/Akt/mTOR
pathway in innate immune cells: emerging therapeutic
applications. Ann Rheum Dis(S0003-4967). 2008;67(Suppl
3):iii70–4.
[20] Hawkins PT, Stephens LR. PI3K signalling in
inflammation. Biochim Biophys Acta (S0006-3002). 2015
Jun;1851(6):882-97.
[21] Chu E, Mychasiuk R, Hibbs ML, et al. Dysregulated
phosphoinositide 3-kinase signaling in microglia: shaping
chronic neuroinflammation. J Neuroinflammation (S1742-
2094). 2021 Nov 27;18(1):276.
[22] Glumac S, Kardum G, Sodic L, et al. Longitudinal
assessment of preoperative dexamethasone administration on
cognitive function after cardiac surgery: a 4-year follow-up of
a randomized controlled trial. BMC Anesthesiol(S1471-2253).
2021 Apr 23;21(1):129.
[23] Oberman K, Hovens I, de Haan J, et al. Acute preoperative
ibuprofen improves cognition in a rat model for
postoperative cognitive dysfunction. J Neuroinflammation
（S1742-2094）. 2021 Jul 8;18（1）:156.
[24] Wang Y, Machizawa MG, Lisle T, et al. Suppression
of Neuroinflammation Attenuates Persistent Cognitive and
Neurogenic Deficits in a Rat Model of Cardiopulmonary
Bypass. Front Cell Neurosci(S1662-5102). 2022 Feb
24;16:780880.
[25] Hu J, Feng X, Valdearcos M, et al. Interleukin-6
is both necessary and sufficient to produce perioperative
neurocognitive disorder in mice. Br J Anaesth(S0007-0912).
2018 Mar;120(3):537-545.
[26] Delshad E, Yousefi M, Sasannezhad P, et al. Medical
uses of Carthamus tinctorius L. (Safflower): a comprehensive
review from Traditional Medicine to Modern Medicine.
Electron Physician(S2008-5842). 2018 Apr 25;10(4):6672-
6681.
[27] Lu QY, Ma JQ, Duan YY, et al. Carthamin Yellow
Protects the Heart Against Ischemia/Reperfusion Injury With
Reduced Reactive Oxygen Species Release and Inflammatory
Response. J Cardiovasc Pharmacol(S0160-2446). 2019
Sep;74(3):228-234.
[28] Kim JH , He MT , Kim MJ , et al. Safflower
(Carthamus tinctorius L.) seed attenuates memory impairment
induced by scopolamine in mice via regulation of cholinergic
dysfunction and oxidative stress. Food Funct(S2042-6496).
2019 Jun 19;10(6):3650-3659.
[29] Yu SY, Lee YJ, Kim JD, et al. Phenolic composition,
antioxidant activity and anti-adipogenic effect of hot water
extract from safflower (Carthamus tinctorius L.) seed.
Nutrients(S2072-6643). 2013 Nov 28;5(12):4894-907.
[30] Xuan J, Huang M, Lu Y, et al. Economic Evaluation
of Safflower Yellow Injection for the Treatment of Patients
with Stable Angina Pectoris in China: A Cost-Effectiveness
Analysis. J Altern Complement Med(S1075-5535). 2018
Jun;24(6):564-569.
[31] Jin X, Shi L, Chang F, et al. Efficacy and Safety of
Safflower Yellow in Early Diabetic Nephropathy: A MetaAnalysis.
Evid Based Complement Alternat Med(S 1741-
427X). 2019 Feb 14;2019:8065376.
[32] Azman KF, Zakaria R. D-Galactose-induced
accelerated aging model: an overview. Biogerontology
(S1389-5729). 2019 Dec;20(6):763-782.
[33] Cebe T, Atukeren P, Yanar K, et al. Oxidation
scrutiny in persuaded aging and chronological aging at
systemic redox homeostasis level. Exp Gerontol(S0531-5565).
2014 Sep;57:132-40.
[34] Yanar K, Aydın S, Cakatay U, et al. Protein
and DNA oxidation in different anatomic regions of rat
brain in a mimetic ageing model. Basic Clin Pharmacol
Toxicol(S1742-7835). 2011 Dec;109(6):423-33.
[35] Miller D, Lewis SR, Pritchard MW, et al.
Intravenous versus inhalational maintenance of anaesthesia
for postoperative cognitive outcomes in elderly people
undergoing non-cardiac surgery. Cochrane Database Syst
Rev(S1469-493X). 2018 Aug 21;8(8):CD012317.
[36] Purdon PL, Pavone KJ, Akeju O, et al. The ageing
brain: age-dependent changes in the electroencephalogram
during propofol and sevoflurane general anaesthesia. Br J
Anaesth(S0007-0912). 2015 Jul;115 Suppl 1(Suppl 1):i46-i57.
[37] Zhang L, Zhang J, Yang L, et al. Isoflurane
and sevoflurane increase interleukin-6 levels through the
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Publishing time:2024-04-30
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