Atorvastatin

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].

References:
[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.