Skip to main content

Advertisement

SpringerLink
Log in

The potential therapeutic effect of statins in multiple sclerosis: beneficial or detrimental effects

  • Review
  • Published:
Inflammopharmacology Aims and scope Submit manuscript

Abstract

Multiple sclerosis (MS) is a chronic progressive disabling disease of the central nervous system (CNS) characterized by demyelination and neuronal injury. Dyslipidemia is observed as one of the imperative risk factors involved in MS neuropathology. Also, chronic inflammation in MS predisposes to the progress of dyslipidemia. Therefore, treatment of dyslipidemia in MS by statins may attenuate dyslipidemia-induced MS and avert MS-induced metabolic changes. Therefore, the present review aimed to elucidate the possible effects of statins on the pathogenesis and outcomes of MS. Statins adversely affect the cognitive function in MS by decreasing brain cholesterol CoQ10, which is necessary for the regulation of neuronal mitochondrial function. However, statins could be beneficial in MS by shifting the immune response from pro-inflammatory Th17 to an anti-inflammatory regulatory T cell (Treg). The protective effect of statins against MS is related to anti-inflammatory and immunomodulatory effects with modulation of fibrinogen and growth factors. In conclusion, the effects of statins on MS neuropathology seem to be conflicting, as statins seem to be protective in the acute phase of MS through anti-inflammatory and antioxidant effects. However, statins lead to detrimental effects in the chronic phase of MS by reducing brain cholesterol and inhibiting the remyelination process.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1

Created on BioRender.com

Fig. 2

Created on BioRender.com

Fig. 3

Created on BioRender.com

Similar content being viewed by others

Data availability

Not applicable.

References

  • Abdalla MA, Zakhary CM, Rushdi H, Hamdan JA, Youssef KN, Khan A, Khan S (2021) The effectiveness of statins as potential therapy for multiple sclerosis: a systematic review of randomized controlled trials. Cureus. https://doi.org/10.7759/cureus.18092

    Article  PubMed  PubMed Central  Google Scholar 

  • Adams AC, Cheng CC, Coskun T, Kharitonenkov A (2012) FGF21 requires βklotho to act in vivo. PLoS One 7:e49977

    CAS  PubMed  PubMed Central  Google Scholar 

  • Ahmad U, Frederiksen JL (2020) Fibrinogen: A potential biomarker for predicting disease severity in multiple sclerosis. Mult Scler Relat Disord 46:102509

    PubMed  Google Scholar 

  • Al-Kuraishy HM, Al-Gareeb AI, Hussien NR, Al-Naimi MS, Rasheed HA (2019) Statins an oft-prescribed drug is implicated in peripheral neuropathy: The time to know more. JPMA. J Pak Med Assoc 69:S108–S112

    Google Scholar 

  • Al-Kuraishy HM, Al-Gareeb AI, Naji MT (2021) Statin therapy associated with decreased neuronal injury measured by serum S100β levels in patients with acute ischemic stroke. Int J Crit Illn Inj Sci 11:246

    PubMed  PubMed Central  Google Scholar 

  • Al-kuraishy HM, Al-Gareeb AI, Alexiou A, Papadakis M, Alsayegh AA, Almohmadi NH, Saad HM, Batiha GE-S (2023) Pros and cons for statins use and risk of Parkinson’s disease: An updated perspective. Pharmacol Res Perspect 11:e01063

    PubMed  PubMed Central  Google Scholar 

  • Al-kuraishy HM, Al-Gareeb AI, Saad HM, Batiha GE-S (2022) Benzodiazepines in Alzheimer’s disease: beneficial or detrimental effects. Inflammopharmacology. https://doi.org/10.1007/s10787-023-01163-7

    Article  PubMed  PubMed Central  Google Scholar 

  • Alsubaie N, Al-kuraishy HM, Al-Gareeb AI, Alharbi B, De Waard M, Sabatier J-M, Saad HM, Batiha GE-S (2022) Statins use in Alzheimer disease: bane or boon from frantic search and narrative review. Brain Sci 12:1290

    CAS  PubMed  PubMed Central  Google Scholar 

  • Andaloro A, Russo M, Pastura C, Sessa E, Calatozzo P, Maggio MG, Bramanti P (2021) Is there a correlation between dyslipidemia and cognitive impairment in patients with multiple sclerosis? Int J Neurosci 132:201–206

    Google Scholar 

  • Balasa R, Barcutean L, Mosora O, Manu D (2021) Reviewing the significance of blood–brain barrier disruption in multiple sclerosis pathology and treatment. Int J Mol Sci 22:8370

    CAS  PubMed  PubMed Central  Google Scholar 

  • Bhardwaj S, Coleman CI, Sobieraj DM (2012) Efficacy of statins in combination with interferon therapy in multiple sclerosis: a meta-analysis. Am J Health Syst Pharm 69:1494–1499

    CAS  PubMed  Google Scholar 

  • Birnbaum G, Cree B, Altafullah I, Zinser M, Reder A (2008) Combining beta interferon and atorvastatin may increase disease activity in multiple sclerosis. Neurology 71:1390–1395

    CAS  PubMed  Google Scholar 

  • Black DM (1998) Statins and fibrinogen. The Lancet 351:1430

    CAS  Google Scholar 

  • Borghini I, Barja F, Pometta D, James RW (1995) Characterization of subpopulations of lipoprotein particles isolated from human cerebrospinal fluid. Biochimica et Biophysica Acta (BBA)-Lipids Lipid Metabol 1255:192–200

    Google Scholar 

  • Boshra H, Awad M, Hussein M, Elyamani E (2022) Vascular dysfunction and dyslipidemia in multiple sclerosis: are they correlated with disease duration and disability status? Egyptian Heart J 74:9

    Google Scholar 

  • Chen J, Zhang C, Jiang H, Li Y, Zhang L, Robin A, Katakowski M, Lu M, Chopp M (2005) Atorvastatin induction of VEGF and BDNF promotes brain plasticity after stroke in mice. J Cereb Blood Flow Metab 25:281–290

    PubMed  Google Scholar 

  • Chihara N (2018) Dysregulated T cells in multiple sclerosis. Clin Experim Neuroimmunol 9:20–29

    Google Scholar 

  • Ciurleo R, Bramanti P, Marino S (2014) Role of statins in the treatment of multiple sclerosis. Pharmacol Res 87:133–143

    CAS  PubMed  Google Scholar 

  • Conway DS, Thompson NR, Cohen JA (2017) Influence of hypertension, diabetes, hyperlipidemia, and obstructive lung disease on multiple sclerosis disease course. Mult Scler J 23:277–285

    Google Scholar 

  • Cucchiara B, Kasner SE (2001) Use of statins in CNS disorders. J Neurol Sci 187:81–89

    CAS  PubMed  Google Scholar 

  • D’haeseleer M, Cambron M, Vanopdenbosch L, De Keyser J (2011) Vascular aspects of multiple sclerosis. Lancet Neurol 10:657–666

    PubMed  Google Scholar 

  • de Oliveira FF, Bertolucci PHF, Chen ES, Smith MC (2022) Pharmacogenetic analyses of therapeutic effects of lipophilic statins on cognitive and functional changes in Alzheimer’s disease. J Alzheimers Dis 87:1–14

    Google Scholar 

  • Dobson R, Giovannoni G (2019) Multiple sclerosis–a review. Eur J Neurol 26:27–40

    CAS  PubMed  Google Scholar 

  • Dunn SE, Youssef S, Goldstein MJ, Prod’homme T, Weber MS, Zamvil SS, Steinman L (2006) Isoprenoids determine Th1/Th2 fate in pathogenic T cells, providing a mechanism of modulation of autoimmunity by atorvastatin. J Exp Med 203:401–412

    CAS  PubMed  PubMed Central  Google Scholar 

  • Dziedzic A, Miller E, Saluk-Bijak J, Bijak M (2020) The GPR17 receptor—a promising goal for therapy and a potential marker of the neurodegenerative process in multiple sclerosis. Int J Mol Sci 21:1852

    CAS  PubMed  PubMed Central  Google Scholar 

  • Edwards NC, Munsell M, Menzin J, Phillips AL (2018) Comorbidity in US patients with multiple sclerosis. Patient Relat Outcome Meas 9:97–102

    PubMed  PubMed Central  Google Scholar 

  • Eyal Leibovitz M, Neli Hazanov M, Angela Frieman M, Itzhak Elly M, Dov Gavish M (2004) Atorvastatin reduces fibrinogen levels in patients with severe hypercholesterolemia: additional evidence to support the anti-inflammatory effects of statins

  • Feng X, Vander Heyden N, Ratner L (2003) AlphaInterferon inhibits human T-cell leukemia virus type 1 assembly by preventing gag interaction withrafts. J Virol 77:13389–13395

    CAS  PubMed  PubMed Central  Google Scholar 

  • Feng X, Han D, Kilaru BK, Franek BS, Niewold TB, Reder AT (2012) Inhibition of interferon-beta responses in multiple sclerosis immune cells associated with high-dose statins. Arch Neurol 69:1303–1309

    PubMed  PubMed Central  Google Scholar 

  • Fessler MB, Parks JS (2011) Intracellular lipid flux and membrane microdomains as organizing principles in inflammatory cell signaling. J Immunol 187:1529–1535

    CAS  PubMed  Google Scholar 

  • Franklin RJ (2002) Why does remyelination fail in multiple sclerosis? Nat Rev Neurosci 3:705–714

    CAS  PubMed  Google Scholar 

  • Franklin RJ, Gallo V (2014) The translational biology of remyelination: past, present, and future. Glia 62:1905–1915

    PubMed  Google Scholar 

  • Frohman EM, Racke MK, Raine CS (2006) Multiple sclerosis—the plaque and its pathogenesis. N Engl J Med 354:942–955

    CAS  PubMed  Google Scholar 

  • Gao S, Yu R, Zhou X (2016) The role of geranylgeranyltransferase I-mediated protein prenylation in the brain. Mol Neurobiol 53:6925–6937

    CAS  PubMed  Google Scholar 

  • Gao Y-H, Li X (2023) Cholesterol metabolism: Towards a therapeutic approach for multiple sclerosis. Neurochem Int 164:105501

    CAS  PubMed  Google Scholar 

  • Ghittoni R, Napolitani G, Benati D, Uliveri C, Patrussi L, Laghi Pasini F, Lanzavecchia A, Baldari CT (2006) Simvastatin inhibits the MHC class II pathway of antigen presentation by impairing Ras superfamily GTPases. Eur J Immunol 36:2885–2893

    CAS  PubMed  Google Scholar 

  • Hardoňová M, Šiarnik P, Sivakova M, Sucha B, Vlček M, Imrich R, Turčáni P, Havranova A, Rádiková Ž (2021) Autonomic Nervous system function in newly diagnosed multiple sclerosis: association with lipid levels and insulin resistance. Physiol Res 70:875

    PubMed  PubMed Central  Google Scholar 

  • He W, Tian X, Yuan B, Chu B, Gao F, Wang H (2019) Rosuvastatin improves neurite extension in cortical neurons through the Notch 1/BDNF pathway. Neurol Res 41:658–664

    CAS  PubMed  Google Scholar 

  • Hinson ER, Joshi NS, Chen JH, Rahner C, Jung YW, Wang X, Kaech SM, Cresswell P (2010) Viperin is highly induced in neutrophils and macrophages during acute and chronic lymphocytic choriomeningitis virus infection. J Immunol 184:5723–5731

    CAS  PubMed  Google Scholar 

  • Hirrlinger J, Nave KA (2014) Adapting brain metabolism to myelination and long-range signal transduction. Glia 62:1749–1761

    PubMed  Google Scholar 

  • Höftberger R, Lassmann H, Berger T, Reindl M (2022) Pathogenic autoantibodies in multiple sclerosis—from a simple idea to a complex concept. Nat Rev Neurol 11:1–8

    Google Scholar 

  • Husain I, Akhtar M, Vohora D, Abdin MZ, Islamuddin M, Akhtar MJ, Najmi AK (2017) Rosuvastatin attenuates high-salt and cholesterol diet induced neuroinflammation and cognitive impairment via preventing nuclear factor KappaB pathway. Neurochem Res 42:2404–2416

    CAS  PubMed  Google Scholar 

  • Hussien NR, Al-Niemi MS, Al-Kuraishy HM, Al-Gareeb AI (2021) Statins and Covid-19: The neglected front of bidirectional effects. J Pak Med Assoc 71:133

    Google Scholar 

  • Ifergan I, Wosik K, Cayrol R, Kébir H, Auger C, Bernard M, Bouthillier A, Moumdjian R, Duquette P, Prat A (2006) Statins reduce human blood–brain barrier permeability and restrict leukocyte migration: relevance to multiple sclerosis. Ann Neurol 60:45–55

    CAS  PubMed  Google Scholar 

  • Kadhim SS, Al-Windy SA, Al-Nami MS, Al-kuraishy HM, Al-Gareeb AI (2019) Possible role of statins on the inflammatory biomarkers in patients with periodontal disease: a cross-sectional study. Dent Hypotheses 10:70

    CAS  Google Scholar 

  • Kadhim SS, Al-Windy SA, Al-Nami MS, Al Kuraishy HM, Al Gareeb AI (2020) Statins improve periodontal disease–induced inflammatory changes and associated lipid peroxidation in patients with dyslipidemia: Two birds by one stone. J Int Oral Health 12:66

    Google Scholar 

  • Kajinami K, Akao H, Polisecki E, Schaefer EJ (2005) Pharmacogenomics of statin responsiveness. Am J Cardiol 96:65–70

    Google Scholar 

  • Karimi N, Ashourizadeh H, Pasha BA, Haghshomar M, Jouzdani T, Shobeiri P, Teixeira AL, Rezaei N (2022) Blood levels of brain-derived neurotrophic factor (BDNF) in people with multiple sclerosis (MS): A systematic review and meta-analysis. Mult Scler Relat Disord 65:103984

    CAS  PubMed  Google Scholar 

  • Kata D, Földesi I, Feher L, Hackler L Jr, Puskas L, Gulya K (2016) Rosuvastatin enhances anti-inflammatory and inhibits pro-inflammatory functions in cultured microglial cells. Neuroscience 314:47–63

    CAS  PubMed  Google Scholar 

  • Katsiki N, Mantzoros C (2019) Fibroblast growth factor 21: A role in cardiometabolic disorders and cardiovascular risk prediction? Metabol Clin Exp 93:iii–v

    CAS  Google Scholar 

  • Kaur G, Saravana S, Banerjee P, Kumar M, Khurana D (2019) Influence of dyslipidemia on multiple sclerosis disease activity. J Neurol Sci 405:308

    Google Scholar 

  • Kendall A, Ekman S, Skiöldebrand E (2023) Nerve growth factor receptors in equine synovial membranes vary with osteoarthritic disease severity. J Orthop Res 41:316–324

    CAS  PubMed  Google Scholar 

  • Kennedy PG, George W, Yu X (2022) The possible role of neural cell apoptosis in multiple sclerosis. Int J Mol Sci 23:7584

    CAS  PubMed  PubMed Central  Google Scholar 

  • Khalilian B, Madadi S, Fattahi N, Abouhamzeh B (2021) Coenzyme Q10 enhances remyelination and regulate inflammation effects of cuprizone in corpus callosum of chronic model of multiple sclerosis. J Mol Histol 52:125–134

    CAS  PubMed  Google Scholar 

  • Kitzmiller JP, Mikulik EB, Dauki AM, Murkherjee C, Luzum JA (2016) Pharmacogenomics of statins: understanding susceptibility to adverse effects. Pharmgenom Pers Med 9:97–106

    CAS  Google Scholar 

  • Kumar DR, Aslinia F, Yale SH, Mazza JJ (2011) Jean-Martin Charcot: the father of neurology. Clin Med Res 9:46–49

    PubMed  PubMed Central  Google Scholar 

  • Kuroda M, Muramatsu R, Maedera N, Koyama Y, Hamaguchi M, Fujimura H, Yoshida M, Konishi M, Itoh N, Mochizuki H (2017) Peripherally derived FGF21 promotes remyelination in the central nervous system. J Clin Investig 127:3496–3509

    PubMed  PubMed Central  Google Scholar 

  • Kurosu H, Choi M, Ogawa Y, Dickson AS, Goetz R, Eliseenkova AV, Mohammadi M, Rosenblatt KP, Kliewer SA, Kuro-o M (2007) Tissue-specific expression of βKlotho and fibroblast growth factor (FGF) receptor isoforms determines metabolic activity of FGF19 and FGF21. J Biol Chem 282:26687–26695

    CAS  PubMed  Google Scholar 

  • Lanzillo R, Orefice G, Quarantelli M, Rinaldi C, Prinster A, Ventrella G, Spitaleri D, Lus G, Vacca G, Carotenuto B (2010) Atorvastatin combined to interferon to verify the efficacy (ACTIVE) in relapsing—remitting active multiple sclerosis patients: a longitudinal controlled trial of combination therapy. Mult Scler 16:450–454

    CAS  PubMed  Google Scholar 

  • Leoni V, Caccia C (2013) 24S-hydroxycholesterol in plasma: a marker of cholesterol turnover in neurodegenerative diseases. Biochimie 95:595–612

    CAS  PubMed  Google Scholar 

  • Li H, Kuwajima T, Oakley D, Nikulina E, Hou J, Yang WS, Lowry ER, Lamas NJ, Amoroso MW, Croft GF (2016) Protein prenylation constitutes an endogenous brake on axonal growth. Cell Rep 16:545–558

    CAS  PubMed  Google Scholar 

  • Mäkelä J, Tselykh TV, Maiorana F, Eriksson O, Do HT, Mudò G, Korhonen LT, Belluardo N, Lindholm D (2014) Fibroblast growth factor-21 enhances mitochondrial functions and increases the activity of PGC-1α in human dopaminergic neurons via Sirtuin-1. Springerplus 3:1–12

    Google Scholar 

  • Marik C, Felts PA, Bauer J, Lassmann H, Smith KJ (2007) Lesion genesis in a subset of patients with multiple sclerosis: a role for innate immunity? Brain 130:2800–2815

    PubMed  Google Scholar 

  • Marrie R, Rudick R, Horwitz R, Cutter G, Tyry T, Campagnolo D, Vollmer T (2010) Vascular comorbidity is associated with more rapid disability progression in multiple sclerosis. Neurology 74:1041–1047

    CAS  PubMed  PubMed Central  Google Scholar 

  • Massey J, Jackson K, Singh M, Hughes B, Withers B, Ford C, Khoo M, Hendrawan K, Zaunders J, Muylder C-D (2022) Haematopoietic stem cell transplantation results in extensive remodelling of the clonal T cell repertoire in multiple sclerosis. Front Immunol 13:232

    Google Scholar 

  • Melchor GS, Khan T, Reger JF, Huang JK (2019) Remyelination pharmacotherapy investigations highlight diverse mechanisms underlying multiple sclerosis progression. ACS Pharmacol Trans Sci 2:372–386

    CAS  Google Scholar 

  • Mincu RI, Magda LS, Florescu M, Velcea A, Mihaila S, Mihalcea D, Popescu BO, Chiru A, Tiu C, Cinteza M (2015) Cardiovascular dysfunction in multiple sclerosis. Maedica 10:364

    PubMed  PubMed Central  Google Scholar 

  • Miron VE, Zehntner SP, Kuhlmann T, Ludwin SK, Owens T, Kennedy TE, Bedell BJ, Antel JP (2009) Statin therapy inhibits remyelination in the central nervous system. Am J Pathol 174:1880–1890

    CAS  PubMed  PubMed Central  Google Scholar 

  • Mohammadhosayni M, Khosrojerdi A, Lorian K, Aslani S, Imani D, Razi B, Babaie F, Torkamandi S (2020) Matrix metalloproteinases (MMPs) family gene polymorphisms and the risk of multiple sclerosis: systematic review and meta-analysis. BMC Neurol 20:1–10

    Google Scholar 

  • Musabak U, Demirkaya S, Genç G, Ilikci RS, Odabasi Z (2011) Serum adiponectin, TNF-α, IL-12p70, and IL-13 levels in multiple sclerosis and the effects of different therapy regimens. NeuroImmunoModulation 18:57–66

    CAS  PubMed  Google Scholar 

  • Naegelin Y, Saeuberli K, Schaedelin S, Dingsdale H, Magon S, Baranzini S, Amann M, Parmar K, Tsagkas C, Calabrese P (2020) Levels of brain-derived neurotrophic factor in patients with multiple sclerosis. Ann Clin Trans Neurol 7:2251–2261

    CAS  Google Scholar 

  • Neuhaus O, Stüve O, Zarnvil SS, Hartung H-P (2004) Are statins a treatment option for multiple sclerosis? Lancet Neurol 3:369–371

    CAS  PubMed  Google Scholar 

  • Noori H, Gheini MR, Rezaeimanesh N, Saeedi R, Aliabadi HR, Sahraian MA, Moghadasi AN (2019) The correlation between dyslipidemia and cognitive impairment in multiple sclerosis patients. Mult Scler Relat Disord 36:101415

    PubMed  Google Scholar 

  • Ntolkeras G, Barba C, Mavropoulos A, Vasileiadis GK, Dardiotis E, Sakkas LI, Hadjigeorgiou G, Bogdanos DP (2019) On the immunoregulatory role of statins in multiple sclerosis: the effects on Th17 cells. Immunol Res 67:310–324

    CAS  PubMed  Google Scholar 

  • Okudan N, Belviranli M (2020) High dose simvastatin and rosuvastatin impair cognitive abilities of healthy rats via decreasing hippocampal neurotrophins and irisin. Brain Res Bull 165:81–89

    CAS  PubMed  Google Scholar 

  • Olsson T, Barcellos LF, Alfredsson L (2017) Interactions between genetic, lifestyle and environmental risk factors for multiple sclerosis. Nat Rev Neurol 13:25–36

    CAS  PubMed  Google Scholar 

  • Ortiz GG, Pacheco-Moisés FP, Macías-Islas MÁ, Flores-Alvarado LJ, Mireles-Ramírez MA, González-Renovato ED, Hernández-Navarro VE, Sánchez-López AL, Alatorre-Jiménez MA (2014) Role of the blood–brain barrier in multiple sclerosis. Arch Med Res 45:687–697

    CAS  PubMed  Google Scholar 

  • Paul F, Waiczies S, Wuerfel J, Bellmann-Strobl J, Dörr J, Waiczies H, Haertle M, Wernecke KD, Volk H-D, Aktas O (2008) Oral high-dose atorvastatin treatment in relapsing-remitting multiple sclerosis. PLoS One 3:e1928

    PubMed  PubMed Central  Google Scholar 

  • Paul R, Choudhury A, Boruah DC, Devi R, Bhattacharya P, Choudhury MD, Borah A (2017) Hypercholesterolemia causes psychomotor abnormalities in mice and alterations in cortico-striatal biogenic amine neurotransmitters: relevance to Parkinson’s disease. Neurochem Int 108:15–26

    CAS  PubMed  Google Scholar 

  • Penesova A, Vlcek M, Imrich R, Vernerova L, Marko A, Meskova M, Grunnerova L, Turcani P, Jezova D, Kollar B (2015) Hyperinsulinemia in newly diagnosed patients with multiple sclerosis. Metab Brain Dis 30:895–901

    CAS  PubMed  Google Scholar 

  • Petersen MA, Ryu JK, Akassoglou K (2018) Fibrinogen in neurological diseases: mechanisms, imaging and therapeutics. Nat Rev Neurosci 19:283–301

    CAS  PubMed  PubMed Central  Google Scholar 

  • Pieters M, Wolberg AS (2019) Fibrinogen and fibrin: An illustrated review. Res Pract Thromb Haemost 3:161–172

    PubMed  PubMed Central  Google Scholar 

  • Pihl-Jensen G, Tsakiri A, Frederiksen JL (2015) Statin treatment in multiple sclerosis: a systematic review and meta-analysis. CNS Drugs 29:277–291

    CAS  PubMed  Google Scholar 

  • Posvar EL, Radulovic LL, Cilla DD Jr, Whitfield LR, Sedman AJ (1996) Tolerance and pharmacokinetics of single-dose atorvastatin, a potent inhibitor of HMG-CoA reductase, in healthy subjects. J Clin Pharmacol 36:728–731

    CAS  PubMed  Google Scholar 

  • Radikova Z, Penesova A, Vlcek M, Havranova A, Sivakova M, Siarnik P, Zitnanova I, Imrich R, Kollar B, Turcani P (2018) LDL and HDL lipoprotein subfractions in multiple sclerosis patients with decreased insulin sensitivity. Endocr Regul 52:139–145

    PubMed  Google Scholar 

  • Restelli LM, Oettinghaus B, Halliday M, Agca C, Licci M, Sironi L, Savoia C, Hench J, Tolnay M, Neutzner A (2018) Neuronal mitochondrial dysfunction activates the integrated stress response to induce fibroblast growth factor 21. Cell Rep 24:1407–1414

    CAS  PubMed  PubMed Central  Google Scholar 

  • Rojas-Fernandez CH, Cameron J-CF (2012) Is statin-associated cognitive impairment clinically relevant? A narrative review and clinical recommendations. Ann Pharmacother 46:549–557

    PubMed  Google Scholar 

  • Sanoobar M, Eghtesadi S, Azimi A, Khalili M, Jazayeri S, Reza Gohari M (2013) Coenzyme Q10 supplementation reduces oxidative stress and increases antioxidant enzyme activity in patients with relapsing–remitting multiple sclerosis. Int J Neurosci 123:776–782

    CAS  PubMed  Google Scholar 

  • Sanoobar M, Dehghan P, Khalili M, Azimi A, Seifar F (2016) Coenzyme Q10 as a treatment for fatigue and depression in multiple sclerosis patients: A double blind randomized clinical trial. Nutr Neurosci 19:138–143

    CAS  PubMed  Google Scholar 

  • Schol-Gelok S, de Maat MP, Biedermann JS, van Gelder T, Leebeek FW, Lijfering WM, van der Meer FJ, Rijken DC, Versmissen J, Kruip MJ (2020) Rosuvastatin use increases plasma fibrinolytic potential: a randomised clinical trial. Br J Haematol 190:916–922

    CAS  PubMed  PubMed Central  Google Scholar 

  • Segatto M, Leboffe L, Trapani L, Pallottini V (2014) Cholesterol homeostasis failure in the brain: implications for synaptic dysfunction and cognitive decline. Curr Med Chem 21:2788–2802

    CAS  PubMed  Google Scholar 

  • Sellner J, Greeve I, Findling O, Kamm CP, Minten C, Engelhardt B, Grandgirard D, Leib SL, Mattle HP (2008) Effect of interferon-β and atorvastatin on Th1/Th2 cytokines in multiple sclerosis. Neurochem Int 53:17–21

    CAS  PubMed  Google Scholar 

  • Singhal G, Fisher FM, Chee MJ, Tan TG, El Ouaamari A, Adams AC, Najarian R, Kulkarni RN, Benoist C, Flier JS (2016) Fibroblast growth factor 21 (FGF21) protects against high fat diet induced inflammation and islet hyperplasia in pancreas. PLoS One 11:e0148252

    PubMed  PubMed Central  Google Scholar 

  • Sorensen PS, Lycke J, Erälinna J-P, Edland A, Wu X, Frederiksen JL, Oturai A, Malmeström C, Stenager E, Sellebjerg F (2011) Simvastatin as add-on therapy to interferon beta-1a for relapsing-remitting multiple sclerosis (SIMCOMBIN study): a placebo-controlled randomised phase 4 trial. Lancet Neurol 10:691–701

    CAS  PubMed  Google Scholar 

  • Stavroulopoulos A, Petras D, Kakavas I, Agroyannis I, Stamatelou K, Vyssoulis G, Papadakis IT, Stefanadis C (2010) Monocyte expression of adhesion molecules during low-and high-flux polysulfone hemodialysis and the effect of atorvastatin administration. Blood Purif 29:274–279

    CAS  PubMed  Google Scholar 

  • Stüve O, Prod’homme T, Slavin A, Youssef S, Dunn S, Steinman L, Zamvil SS (2003) Statins and their potential targets in multiple sclerosis therapy. Expert Opin Ther Targets 7:613–622

    PubMed  Google Scholar 

  • Stüve O, Youssef S, Weber MS, Nessler S, von Büdingen H-C, Hemmer B, Prodhomme T, Sobel RA, Zamvil SS (2006) Immunomodulatory synergy by combination of atorvastatin and glatiramer acetate in treatment of CNS autoimmunity. J Clin Investig 116:1037–1044

    PubMed  PubMed Central  Google Scholar 

  • Sun Y, Wang Y, Chen S-T, Chen Y-J, Shen J, Yao W-B, Gao X-D, Chen S (2020) Modulation of the astrocyte-neuron lactate shuttle system contributes to neuroprotective action of fibroblast growth factor 21. Theranostics 10:8430

    CAS  PubMed  PubMed Central  Google Scholar 

  • Taheri M, Ghafouri-Fard S, Sayad A, Arsang-Jang S, Mazdeh M, Toghi M, Omrani MD (2018) Assessment of protein prenylation pathway in multiple sclerosis patients. J Mol Neurosci 64:581–590

    CAS  PubMed  Google Scholar 

  • Tan W, Xue-bin C, Tian Z, Xiao-wu C, Pei-pei H, Zhi-bin C, Bei-sha T (2016) Effects of simvastatin on the expression of inducible nitric oxide synthase and brain-derived neurotrophic factor in a lipopolysaccharide-induced rat model of Parkinson disease. Int J Neurosci 126:278–286

    PubMed  Google Scholar 

  • Tettey P, Simpson S Jr, Taylor B, Blizzard L, Ponsonby A-L, Dwyer T, Kostner K, van der Mei I (2014) An adverse lipid profile is associated with disability and progression in disability, in people with MS. Mult Scler J 20:1737–1744

    CAS  Google Scholar 

  • Tettey P, Simpson S, Taylor B, Ponsonby A-L, Lucas RM, Dwyer T, Kostner K, van der Mei IA, group Ai (2017) An adverse lipid profile and increased levels of adiposity significantly predict clinical course after a first demyelinating event. J Neurol Neurosurg Psychiatry 88:395–401

    PubMed  Google Scholar 

  • Teunissen C, Dijkstra C, Polman C, Hoogervorst E, Von Bergmann K, Lütjohann D (2003) Decreased levels of the brain specific 24S-hydroxycholesterol and cholesterol precursors in serum of multiple sclerosis patients. Neurosci Lett 347:159–162

    CAS  PubMed  Google Scholar 

  • Togha M, Karvigh SA, Nabavi M, Moghadam NB, Harirchian MH, Sahraian MA, Enzevaei A, Nourian A, Ghanaati H, Firouznia K (2010) Simvastatin treatment in patients with relapsing-remitting multiple sclerosis receiving interferon beta 1a: a double-blind randomized controlled trial. Mult Scler J 16:848–854

    CAS  Google Scholar 

  • Vollmer T, Singh I (2004) Statins for multiple sclerosis. The Lancet 364:412–413

    Google Scholar 

  • Voskuhl RR, Itoh N, Tassoni A, Matsukawa MA, Ren E, Tse V, Jang E, Suen TT, Itoh Y (2019) Gene expression in oligodendrocytes during remyelination reveals cholesterol homeostasis as a therapeutic target in multiple sclerosis. Proc Natl Acad Sci 116:10130–10139

    CAS  PubMed  PubMed Central  Google Scholar 

  • Wagstaff LR, Mitton MW, Arvik BM, Doraiswamy PM (2003) Statin-associated memory loss: analysis of 60 case reports and review of the literature. Pharmacotherapy J Hum Pharmacol Drug Therapy 23:871–880

    Google Scholar 

  • Wang X-M, Xiao H, Liu L-L, Cheng D, Li X-J, Si L-Y (2016) FGF21 represses cerebrovascular aging via improving mitochondrial biogenesis and inhibiting p53 signaling pathway in an AMPK-dependent manner. Exp Cell Res 346:147–156

    CAS  PubMed  Google Scholar 

  • Wang J, Xiao Y, Luo M, Luo H (2011) Statins for multiple sclerosis. Cochrane Database System Rev

  • Weinstock-Guttman B, Zivadinov R, Mahfooz N, Carl E, Drake A, Schneider J, Teter B, Hussein S, Mehta B, Weiskopf M (2011) Serum lipid profiles are associated with disability and MRI outcomes in multiple sclerosis. J Neuroinflammation 8:1–7

    Google Scholar 

  • Wens I, Keytsman C, Deckx N, Cools N, Dalgas U, Eijnde B (2016) Brain derived neurotrophic factor in multiple sclerosis: effect of 24 weeks endurance and resistance training. Eur J Neurol 23:1028–1035

    CAS  PubMed  Google Scholar 

  • Woo Y, Xu A, Wang Y, Lam KS (2013) Fibroblast growth factor 21 as an emerging metabolic regulator: clinical perspectives. Clin Endocrinol (oxf) 78:489–496

    CAS  PubMed  Google Scholar 

  • Woodbury ME, Ikezu T (2014) Fibroblast growth factor-2 signaling in neurogenesis and neurodegeneration. J Neuroimmune Pharmacol 9:92–101

    Google Scholar 

  • Wu F, Luo T, Mei Y, Liu H, Dong J, Fang Y, Peng J, Guo Y (2018) Simvastatin alters M1/M2 polarization of murine BV2 microglia via Notch signaling. J Neuroimmunol 316:56–64

    CAS  PubMed  Google Scholar 

  • Xue-Shan Z, Qi W, Zhong R, Li-hong P, Zhi-han T, Zhi-sheng J, Gui-xue W, Lu-shan L (2016) Imbalanced cholesterol metabolism in Alzheimer’s disease. Clin Chim Acta 456:107–114

    PubMed  Google Scholar 

  • Yang D, Han Y, Zhang J, Chopp M, Seyfried DM (2012) Statins enhance expression of growth factors and activate the PI3K/Akt-mediated signaling pathway after experimental intracerebral hemorrhage. World J Neurosci. https://doi.org/10.4236/wjns.2012.22011

    Article  PubMed  PubMed Central  Google Scholar 

  • Yates RL, Esiri MM, Palace J, Jacobs B, Perera R, DeLuca GC (2017) Fibrin (ogen) and neurodegeneration in the progressive multiple sclerosis cortex. Ann Neurol 82:259–270

    CAS  PubMed  Google Scholar 

  • Youssef S, Stüve O, Patarroyo JC, Ruiz PJ, Radosevich JL, Hur EM, Bravo M, Mitchell DJ, Sobel RA, Steinman L (2002) The HMG-CoA reductase inhibitor, atorvastatin, promotes a Th2 bias and reverses paralysis in central nervous system autoimmune disease. Nature 420:78–84

    CAS  PubMed  Google Scholar 

  • Yu Y, He J, Li S, Song L, Guo X, Yao W, Zou D, Gao X, Liu Y, Bai F (2016) Fibroblast growth factor 21 (FGF21) inhibits macrophage-mediated inflammation by activating Nrf2 and suppressing the NF-κB signaling pathway. Int Immunopharmacol 38:144–152

    CAS  PubMed  Google Scholar 

  • Zambón D, Quintana M, Mata P, Alonso R, Benavent J, Cruz-Sánchez F, Gich J, Pocoví M, Civeira F, Capurro S (2010) Higher incidence of mild cognitive impairment in familial hypercholesterolemia. Am J Med 123:267–274

    PubMed  PubMed Central  Google Scholar 

  • Zamvil SS, Steinman L (2002) Cholesterol-lowering statins possess anti-inflammatory activity that might be useful for treatment of MS. AAN Enterprises 59:970–971

    Google Scholar 

  • Zhang X, Jin J, Peng X, Ramgolam VS, Markovic-Plese S (2008) Simvastatin inhibits IL-17 secretion by targeting multiple IL-17-regulatory cytokines and by inhibiting the expression of IL-17 transcription factor RORC in CD4+ lymphocytes. J Immunol 180:6988–6996

    CAS  PubMed  Google Scholar 

  • Zhornitsky S, McKay KA, Metz LM, Teunissen CE, Rangachari M (2016) Cholesterol and markers of cholesterol turnover in multiple sclerosis: relationship with disease outcomes. Mult Scler Relat Disord 5:53–65

    PubMed  Google Scholar 

  • Ziros P, Zagoriti Z, Lagoumintzis G, Kyriazopoulou V, Iskrenova RP, Habeos EI, Sykiotis GP, Chartoumpekis DV, Habeos IG (2016) Hepatic Fgf21 expression is repressed after simvastatin treatment in mice. PLoS One 11:e0162024

    PubMed  PubMed Central  Google Scholar 

Download references

Funding

Nil.

Author information

Authors and Affiliations

  1. Professor in Department of Clinical Pharmacology and Therapeutic Medicine, College of Medicine, ALmustansiriyiah University, M. B. Ch. B, FRCP, Box 14132, Baghdad, Iraq

    Hayder M. Al-Kuraishy & Ali I. Al-Gareeb

  2. Department of Pathology, Faculty of Veterinary Medicine, Matrouh University, Marsa Matrouh, 51744, Egypt

    Hebatallah M. Saad

  3. Department of Pharmacology and Therapeutics, Faculty of Veterinary Medicine, Damanhour University, Damanhour, 22511, AlBeheira, Egypt

    Gaber El-Saber Batiha

Authors
  1. Hayder M. Al-Kuraishy
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Ali I. Al-Gareeb
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Hebatallah M. Saad
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Gaber El-Saber Batiha
    View author publications

    You can also search for this author in PubMed Google Scholar

Contributions

HMA and AIA: conceptualization, data collection, and writing of the manuscript. HMS and GEB: writing, supervision, and editing of the manuscript. All authors read and approved the final version of the manuscript.

Corresponding authors

Correspondence to Hebatallah M. Saad or Gaber El-Saber Batiha.

Ethics declarations

Conflict of interest

Nil.

Ethics approval and consent to participate

Not applicable.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Springer Nature or its licensor (e.g. a society or other partner) holds exclusive rights to this article under a publishing agreement with the author(s) or other rightsholder(s); author self-archiving of the accepted manuscript version of this article is solely governed by the terms of such publishing agreement and applicable law.

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Al-Kuraishy, H.M., Al-Gareeb, A.I., Saad, H.M. et al. The potential therapeutic effect of statins in multiple sclerosis: beneficial or detrimental effects. Inflammopharmacol 31, 1671–1682 (2023). https://doi.org/10.1007/s10787-023-01240-x

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10787-023-01240-x

Keywords

Search

Navigation