Atorvastatin

Atorvastatin is a potent synthetic HMG-CoA reductase inhibitor with IC₅₀ values of 7.6nM against the rat liver enzyme and 14.3nM against the human enzyme prepared from HepG2 cells^[1]. Atorvastatin competitively inhibits HMG-CoA reductase, suppresses the mevalonate-cholesterol biosynthetic pathway, and thereby modulates downstream lipid, inflammatory, and cell-survival signaling^[1][3][4]. Atorvastatin is used in research on lipid metabolism, inflammatory responses, intervertebral-disc degeneration, and neuroprotection^{[2][3][4][5][6][7]}.

In vitro, HepG2 cells treated with Atorvastatin (0.5μM; 24h) showed a 42% reduction in apolipoprotein B secretion, associated with enhanced intracellular apolipoprotein B degradation^[2]. In PMA-differentiated THP-1 cells, Atorvastatin pretreatment (0-100μM; 24h), followed by lipopolysaccharide stimulation (0-100μg/mL; 24h), reduced interleukin-1β and tumor necrosis factor-α release and attenuated prostaglandin E₂, reactive oxygen species, and nitric oxide production; at 100μM, however, prostaglandin E₂ increased relative to lower-concentration responses^[3]. In primary rat nucleus pulposus cells, Atorvastatin (10 and 20μM; 1h pretreatment) followed by tumor necrosis factor-α (50ng/mL; 24h) reduced matrix-catabolic and inflammatory proteins, while Atorvastatin (20μM; 1h pretreatment) decreased NLRP3, cleaved caspase-1, and GSDMD-NT by 52%, 65%, and 48%, respectively, and increased autophagic flux^[4].

In vivo, rats received Atorvastatin (10mg/kg/day; oral administration once daily for 7 days) before intranasal MPTP exposure; Atorvastatin prevented short-term-memory impairment and depressive-like behavior and reduced motor deficits and substantia-nigra dopaminergic-neuron loss assessed on day21^[5]. In mice, Atorvastatin (0.1mg/kg; single oral administration; behavioral assessment 1h later) produced an antidepressant-like response that was abolished by serotonin depletion or blockade of 5-HT₁A or 5-HT₂A/₂C receptors^[6]. In a lipopolysaccharide-induced depressive-like behavior model, mice received Atorvastatin (1 and 10mg/kg/day; oral administration once daily for 7 days), followed by lipopolysaccharide (0.5mg/kg; single intraperitoneal injection; assessment 24h later). Atorvastatin prevented increased immobility without altering locomotor activity and prevented tumor necrosis factor-α elevation, brain-derived neurotrophic factor reduction, lipid peroxidation, and glutathione depletion in the hippocampus and prefrontal cortex^[7].

References:

[1] Bergstrom JD, Bostedor RG, Rew DJ, Geissler WM, Wright SD, Chao YS. Hepatic responses to inhibition of 3-hydroxy-3-methylglutaryl-CoA reductase: a comparison of atorvastatin and simvastatin. Biochim Biophys Acta. 1998;1389(3):213-221. doi:10.1016/S0005-2760(97)00182-3.

[2] Wilcox LJ, Barrett PHR, Huff MW. Differential regulation of apolipoprotein B secretion from HepG2 cells by two HMG-CoA reductase inhibitors, atorvastatin and simvastatin. J Lipid Res. 1999;40(6):1078-1089. PMID:10357840.

[3] McFarland AJ, Davey AK, McDermott CM, Grant GD, Lewohl J, Anoopkumar-Dukie S. 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.

[4] Chen J, Yan J, Li S, Zhu J, Zhou J, Li 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;20(20):2160-2173. doi:10.1080/15384101.2021.1973707.

[5] Castro AA, Wiemes BP, Matheus FC, Lapa FR, Viola GG, Santos AR, et al. Atorvastatin improves cognitive, emotional and motor impairments induced by intranasal 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine administration in rats, an experimental model of Parkinson's disease. Brain Res. 2013;1513:103-116. doi:10.1016/j.brainres.2013.03.029.

[6] Ludka FK, Constantino LC, Dal-Cim T, Binder LB, Zomkowski A, Rodrigues AL, Tasca CI. Atorvastatin evokes a serotonergic system-dependent antidepressant-like effect in mice. Pharmacol Biochem Behav. 2014;122:253-260. doi:10.1016/j.pbb.2014.04.005.

[7] Taniguti EH, Ferreira YS, Stupp IJV, Fraga-Junior EB, Mendonça CB, Rossi FL, et al. Atorvastatin prevents lipopolysaccharide-induced depressive-like behaviour in mice. Brain Res Bull. 2019;146:279-286. doi:10.1016/j.brainresbull.2019.01.018.