Atorvastatin is an orally active HMG-CoA reductase inhibitor, has the ability to effectively decrease blood lipids[1]. Atorvastatin inhibits human SV-SMC proliferation and invasion with IC50s of 0.39 μM and 2.39 mM.
PMA-differentiated THP-1 cells were used as surrogate microglial cells, and LPS was used to induce inflammatory conditions. Pretreatment with atorvastatin was able to significantly reduce LPS-induced interleukin (IL)-1β and tumour necrosis factor (TNF)-α release, as well as decrease LPS-induced prostaglandin E2 (PGE2). Similarly, global reactive oxygen species (ROS) and nitric oxide (NO) production were decreased following pretreatment with atorvastatin[5]. In rat NP cells, Atorvastatin might suppress matrix degradation induced by TNF-α by suppressing NLRP3 inflammasome activity and inducing autophagic flux. Moreover, atorvastatin suppressed NF-κB signaling induced by TNF-α. NF-κB signaling inhibition suppressed NLRP3 inflammasome activity, and NLRP3 inhibition suppressed NF-κB signaling activation induced by TNF-α. NLRP3 inhibition or NLRP3 knockdown induced autophagic flux in the presence of TNF-α[7].
In mice, Atorvastatin pretreatment promoted increased cell viability after OGD and reoxygenation of hippocampal slices. Atorvastatin-induced neuroprotection may be related to diminished oxidative stress, since it prevented OGD-induced decrement of non-proteic thiols (NPSH) levels and increase in the production of reactive oxygen species (ROS)[3]. The oral treatment with atorvastatin (10mg/kg/day)was able to prevent short-term memory impairments and depressive-like behavior of rats assessed in the social recognition and forced swimming tests at 7 and 14 days, respectively, after a single intranasal administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) (1mg/nostril)[4].The effects of atorvastatin antidepressants are related to the regulation of serotonergic transmission, the inhibition of NMDA receptor and NO-CGMP synthesis, and the activation of receptor γ dependent on peroxisome proliferators[6]. Atorvastatin treatment exerted neuroprotective effects against LPS-induced depressive-like behaviour which may be related to reduction of TNF-α release, oxidative stress and modulation of BDNF expression[2].
参考文献:
[1]: Taciak PP, Lysenko N, et,al. Drugs which influence serotonin transporter and serotonergic receptors: Pharmacological and clinical properties in the treatment of depression. Pharmacol Rep. 2018 Feb;70(1):37-46. doi: 10.1016/j.pharep.2017.07.011. Epub 2017 Jul 16. PMID: 29309998.
[2]: Taniguti EH, Ferreira YS, et,al. Atorvastatin prevents lipopolysaccharide-induced depressive-like behaviour in mice. Brain Res Bull. 2019 Mar;146:279-286. doi: 10.1016/j.brainresbull.2019.01.018. Epub 2019 Jan 25. PMID: 30690060.
[3]: Vandresen-Filho S, Martins WC, et,al. Atorvastatin prevents cell damage via modulation of oxidative stress, glutamate uptake and glutamine synthetase activity in hippocampal slices subjected to oxygen/glucose deprivation. Neurochem Int. 2013 Jun;62(7):948-55. doi: 10.1016/j.neuint.2013.03.002. Epub 2013 Mar 14. PMID: 23500607.
[4]: Castro AA, Wiemes BP, et,al. Atorvastatin improves cognitive, emotional and motor impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration in rats, an experimental model of Parkinson's disease. Brain Res. 2013 Jun 4;1513:103-16. doi: 10.1016/j.brainres.2013.03.029. Epub 2013 Mar 30. PMID: 23548600.
[5]: McFarland AJ, Davey AK, et,al. Statins Reduce Lipopolysaccharide-Induced Cytokine and Inflammatory Mediator Release in an In Vitro Model of Microglial-Like Cells. Mediators Inflamm. 2017;2017:2582745. doi: 10.1155/2017/2582745. Epub 2017 May 4. PMID: 28546657; PMCID: PMC5435995.
[6]: Ludka FK, Constantino LC, et,al. Atorvastatin evokes a serotonergic system-dependent antidepressant-like effect in mice. Pharmacol Biochem Behav. 2014 Jul;122:253-60. doi: 10.1016/j.pbb.2014.04.005. Epub 2014 Apr 21. PMID: 24769309.
[7]: Chen J, Yan J, et,al.Atorvastatin inhibited TNF-α induced matrix degradation in rat nucleus pulposus cells by suppressing NLRP3 inflammasome activity and inducing autophagy through NF-κB signaling. Cell Cycle. 2021 Oct;20(20):2160-2173. doi: 10.1080/15384101.2021.1973707. Epub 2021 Sep 8. PMID: 34494933; PMCID: PMC8565837.
阿托伐他汀是一种具有口服活性的 HMG-CoA 还原酶抑制剂，具有有效降低血脂的能力[1]。阿托伐他汀抑制人 SV-SMC 增殖和侵袭，IC50 分别为 0.39 μM 和 2.39 mM。
PMA 分化的 THP-1 细胞用作替代小胶质细胞，LPS 用于诱导炎症条件。阿托伐他汀预处理能够显着降低 LPS 诱导的白细胞介素 (IL)-1β；和肿瘤坏死因子（TNF）-α；释放，以及减少 LPS 诱导的前列腺素 E2 (PGE2)。类似地，在用阿托伐他汀[5] 预处理后，总体活性氧 (ROS) 和一氧化氮 (NO) 的产生减少。在大鼠 NP 细胞中，阿托伐他汀可能抑制 TNF-α 诱导的基质降解；通过抑制 NLRP3 炎性体活性和诱导自噬通量。此外，阿托伐他汀抑制 NF-κB 信号由 TNF-α 诱导。 NF-κB 信号抑制抑制 NLRP3 炎性体活性，NLRP3 抑制抑制 NF-κTNF-α 诱导的 B 信号激活;。在 TNF-α 存在的情况下，NLRP3 抑制或 NLRP3 敲低诱导自噬通量；[7]。
在小鼠中，阿托伐他汀预处理促进 OGD 后细胞活力增加和海马切片复氧.阿托伐他汀诱导的神经保护作用可能与氧化应激减弱有关，因为它阻止了 OGD 诱导的非蛋白硫醇 (NPSH) 水平下降和活性氧 (ROS) 产生的增加[3] .口服阿托伐他汀（10mg/kg/天）能够预防大鼠在单次鼻内给药后分别在第 7 天和第 14 天的社会认知和强迫游泳测试中评估的短期记忆障碍和抑郁样行为1-甲基-4-苯基-1,2,3,6-四氢吡啶 (MPTP)（1 毫克/鼻孔）[4]。阿托伐他汀抗抑郁药的作用与血清素能传递的调节有关, NMDA受体和NO-CGMP合成的抑制，以及受体γ的激活；依赖于过氧化物酶体增殖物[6]。阿托伐他汀治疗对 LPS 诱导的抑郁样行为具有神经保护作用，这可能与 TNF-α 的减少有关； BDNF表达的释放、氧化应激和调控[2].
| Cell experiment [1]: | |
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Cell lines |
Differentiated THP-1 human monocytes |
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Preparation Method |
Following differentiation, cells were treated with either vehicle control or one of the six statins (atorvastatin;0-100 μM) and incubated at 37 ?栩n 5% CO2 for 60 minutes. |
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Reaction Conditions |
0-100uM atorvastatin at 37 ?栦or 60 minutes |
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Applications |
Pretreatment with atorvastatin was able to significantly reduce LPS-induced interleukin (IL)-1β and tumour necrosis factor (TNF)-α release, as well as decrease LPS-induced prostaglandin E2 (PGE2). Similarly, global reactive oxygen species (ROS) and nitric oxide (NO) production were decreased following pretreatment with atorvastatin. |
| Animal experiment [2]: | |
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Animal models |
Male adult Swiss albino mice (30-50 g) |
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Preparation Method |
Animals were pretreated with 10 mg/kg/day of atorvastatin, orally or vehicle (saline, 0.9%) once a day for 7 days before preparing hippocampal slices for ex vivo OGD induction and measurement of cellular viability, oxidative stress and glutamatergic transmission parameters. |
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Dosage form |
10 mg/kg atorvastatin, orally once a day for 7 days |
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Applications |
Atorvastatin pretreatment promoted increased cell viability after OGD and reoxygenation of hippocampal slices. Atorvastatin-induced neuroprotection may be related to diminished oxidative stress, since it prevented OGD-induced decrement of non-proteic thiols (NPSH) levels and increase in the production of reactive oxygen species (ROS). |
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参考文献: [1]. McFarland AJ, Davey AK, et,al. Statins Reduce Lipopolysaccharide-Induced Cytokine and Inflammatory Mediator Release in an In Vitro Model of Microglial-Like Cells. Mediators Inflamm. 2017;2017:2582745. doi: 10.1155/2017/2582745. Epub 2017 May 4. PMID: 28546657; PMCID: PMC5435995. |
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