Spruce Needle Polyprenols Protect Against Atorvastatin-Induced Muscle Weakness and do not Influence Central Nervous System Functions in Rats

Baiba Jansone 1 , Zane Dzirkale 1 , Kaspars Jekabsons 1 , Vladimirs Pilipenko 1 , Ulrika Beitnere 1 , Ingrīda Māgure 1 , Raimonds Skumbiņš 1 , Uģis Klētnieks 2 , Ilona Vanaga 3 , Ruta Muceniece 1 ,  and Vija Kluša 1
  • 1 Faculty of Medicine, University of Latvia, Raiņa bulv. 19, Rīga, LV-1586, LATVIA
  • 2 Silvanols Ltd., Kurbada iela 2A, Rīga, LV-1009, LATVIA
  • 3 Pharma and Chemistry Competence Centre of Latvia Ltd., Dzirnavu iela 93-27, Rīga, LV-1006, LATVIA


Polyprenols (PPs) have been identified in almost all living organisms. The richest source of PPs is the needles of conifer trees. Endogenously, PPs, similarly to cholesterol, are synthesised in human and animal cells via the mevalonate pathway. Previous studies have demonstrated the anti-oxidant properties of PPs. To our knowledge, no studies have been published on the influence of PPs on muscle strength. We hypothesised that administration of PPs could prevent changes in muscle functioning caused by statins (weakness, etc.). In the present study, atorvastatin (80 mg/kg) was used as a model compound. PPs at doses 1, 10 and 20 mg/kg were administered. Both drugs were given per os for 16 days. The influence of atorvastatin, PPs and their combination on behaviour, muscle strength, plasma cholesterol and creatine kinase activity was assessed in female Wistar rats. Our data demonstrated that atorvastatin considerably impaired muscle strength, whereas PPs protected that effect. Neither PPs, nor atorvastatin influenced plasma cholesterol levels, whereas PPs at dose 20 mg/kg elevated creatine kinase activity by about 25%. PPs at the tested doses did not alter behaviour, indicating safety of central nervous system functions. The obtained data suggest usefulness of PPs as a complement in statin therapy to reduce muscle-related side effects.

If the inline PDF is not rendering correctly, you can download the PDF file here.

  • Abdelbaset, M., Safar, M. M., Mahmoud, S. S., Negm, S. A., Agha, A. M. (2014). Red yeast rice and coenzyme Q10 as safe alternatives to surmount atorvastatin-induced myopathy in hyperlipidemic rats. Can. J. Physiol. Pharmacol., 92 (6), 481–489.

  • Abourjaily, H. M., Alsheikh-Ali, A. A., Karas, R. H. (2003). Comparison of the frequency of adverse events in patients treated with atorvastatin or simvastatin. Amer. J. Cardiol., 91 (8), 999–1002.

  • Baker, S. K. (2005). Molecular clues into the pathogenesis of statin-mediated muscle toxicity. Muscle Nerve, 31 (5), 572–580.

  • Ballard, K. D., Parker, B. A., Capizzi, J. A., Grimaldi, A. S., Clarkson, P. M., Cole, S. M., Keadle, J., Chipkin, S., Pescatello, L. S., Simpson, K., White, C. M., Thompson, P. D. (2013). Increases in creatine kinase with atorvastatin treatment are not associated with decreases in muscular performance. Atherosclerosis, 230 (1), 121–124.

  • Bays, H. (2006). Statin safety: An overview and assessment of the data-2005. Amer. J. Cardiol., 97 (8A), 6C–26C.

  • Bitzur, R., Cohen, H., Kamari, Y., Harats, D. (2013). Intolerance to statins: Mechanisms and management. Diabetes Care, 36 (2), S325–S330.

  • Bizzarri, R., Cerbai, B., Signori, F. (2003). New perspectives for (S)-dolichol and (S)-nor dolichol synthesis and biological functions. Biogerontology, 4 (6), 353–363.

  • Buhaescu, I., Izzedine, H. (2007). Mevalonate pathway: a review of clinical and therapeutical implications. Clin. Biochem., 40 (9–10), 575–584.

  • Camerino, G. M., Pellegrino, M. A., Brocca, L. (2011). Statin or fibrate chronic treatment modifies the proteomic profile of rat skeletal muscle. Biochem. Pharm., 81 (8), 1054–1064.

  • Cantagrel, V., Lefeber, D. J. (2011). From glycosylation disorders to dolichol biosynthesis defects: A new class of metabolic diseases. J. Inherit. Metab. Dis., 34 (4), 859–867.

  • Chojnacki, T., Dallner, G. (1983). The uptake of dietary polyprenols and their modification to active dolichols by the rat liver. J. Biol. Chem., 258 (2), 916–922.

  • Chojnacki, T., Dallner, G. (1988). The biological role of dolichol. Biochem. J., 251 (1), 1–9.

  • Dwajani, S., Kumar, V. S., Keerthi, D. (2012). Atorvastatin and simvastatin as analgesic agents in experimental models. J. Basic Clin. Pharm., 3 (4), 332–335.

  • Fedotova, J. O., Sultanov, V. S., Kuznetsova, N. N. (2010). Effect of new polyprenol drug ropren on anxiety-depressive-like behavior in rats with experimental Alzheimer disease. Eksp. Klin. Farmakol., 73 (9), 2–5.

  • Fedotova, J., Soultanov, V., Nikitina, T. (2012). Ropren® is a polyprenol preparation from coniferous plants that ameliorates cognitive deficiency in a rat model of beta-amyloid peptide-(25-35)-induced amnesia. Phytomedicine, 19 (5), 451–456.

  • Garcia, G. G., Miranda, H. F., Noriega, V. (2011). Antinociception induced by atorvastatin in different pain models. Pharmacol. Biochem. Behav., 100 (1), 125–129.

  • Hartley, M. D., Imperiali, B. (2012). At the membrane frontier: a prospectus on the remarkable evolutionary conservation of polyprenols and polyprenyl-phosphates. Arch. Biochem. Biophys., 517 (2), 83–97.

  • Jaiswal, S. R., Sontakke, S. D. (2012). Experimental evaluation of analgesic and anti-inflammatory activity of simvastatin and atorvastatin. Indian J. Pharmacol., 44 (4), 475–479.

  • Jakobsson, A., Swiezewska, E., Chojnacki, T. (1989). Uptake and modification of dietary polyprenols and dolichols in rat liver. FEBS Lett, 255 (1), 32–36.

  • Laaksonen, R. (2013). STOMPing forward: Statins, muscle complaints and CK. Atherosclerosis, 230 (2), 256–257.

  • Madsen, C. S., Janovitz, E., Zhang, R. (2008). The Guinea pig as a preclinical model for demonstrating the efficacy and safety of statins. J. Pharmacol. Exp. Ther., 324 (2), 576–586.

  • Mazroa, S. A., Asker, S. A. (2010). Myotoxic effects of atorvastatin drug (Lipitor) on the skeletal muscles of adult Mmale albino rats and the effect of L-carnitine co-administration light microscopical, immunohistochemical and biochemical Study. Egypt. J. Histol., 33 (3), 520–531.

  • Manoukian, A. A., Bhagavan, N. V., Hayashi, T. (1990). Rhabdomyolysis secondary to lovastatin therapy. Clin. Chem., 36 (12), 2145–2147.

  • Milenkovic, D., Jude, B., Morand, C. (2013). miRNA as molecular target of polyphenols underlying their biological effects. Free Radic. Biol. Med., 64, 40–51.

  • Pronin, A. V., Danilov, L. L., Narovlyansky, A. N. (2014). Plant polyisoprenoids and control of cholesterol level. Arch. Immunol. Ther. Exp. (Warsz), 62 (1), 31–39.

  • Rosenson, R. S., Baker, S. K., Jacobson, T. A. (2014). An assessment by the Statin Muscle Safety Task Force: 2014 update. J. Clin. Lipidol., 8 (3), S58–S71.

  • Sathasivam, S., Lecky, B. (2008). Statin induced myopathy. British Medical Journal (BMJ), 337, a2286.

  • Sierra, S., Ramos, M. C., Molina, P. (2011). Statins as neuroprotectants:A comparative in vitro study of lipophilicity, blood-brain-barrier penetration, lowering of brain cholesterol, and decrease of neuron cell death. J. Alzheimers Dis., 23 (2), 307–318.

  • Soner, B. C., Inan, S. Y., Güven, U. (2013). Combined treatment with resveratrol prevents the atorvastatin-induced myopathy in rat skeletal muscle. Afr. J. Pharm. Pharmacol., 7 (18), 1114–1118.

  • Surmacz, L., Swiezewska, E. (2011). Polyisoprenoids — secondary metabolites or physiologically important superlipids? Biochem. Biophys. Res. Commun., 407 (4), 627–632.

  • Tuccori, M., Montagnani, S., Mantarro, S. (2014). Neuropsychiatric adverse events associated with statins: Epidemiology, pathophysiology, prevention and management. Central Nervous System Drugs, 28 (3), 249–272.

  • van der Most, P. J., Dolga, A. M., Nijholt, I. M. (2009). Statins: Mechanisms of neuroprotection. Prog. Neurobiol., 88 (1), 64–75.

  • Wagstaff, L. R, Mitton, M. W., Arvik, B. M. (2003). Statin-associated memory loss: Analysis of 60 case reports and review of the literature. Pharmacother, 23 (7), 871–880.

  • Wang, C. Z., Wang, W. L., Ye, J. Z. (2008). Studies on separation of polyprenols from leaves of Ginkgo biloba L. by molecular short distillation. Chemistry and Industry of Forest Products, 28 (3), 23–27.

  • Wang, C., He, L., Yan, M. (2014). Effects of polyprenols from needles of Pinus massoniana on ameliorating cognitive impairment in a d-galactose-induced mouse model. Age (Dordr), 36 (4), 9676.

  • Werner, M., Sacher, J., Hohenegger, M. (2004). Mutual amplification of apoptosis by statin-induced mitochondrial stress and doxorubicin toxicity in human rhabdomyosarcoma cells. Brit. J. Pharmacol., 143 (6), 715–724.

  • Wilkinson, M. J., Laffin, L. J., Davidson, M. H. (2014). Overcoming toxicity and side-effects of lipid-lowering therapies. Best Pract. Res. Clin. Endocrinol. Metab., 28 (3), 439–452.


Journal + Issues