Influence of salidroside, a neuroactive compound of Rhodiola rosea L., on alcohol tolerance development in rats

Open access


Introduction: In recent years, the search for potential neuroprotective properties of salidroside and its ability to influence the activity of nervous system become the subject of intense studies of many research groups. None of these studies, however, include an attempt to determine the effect of salidroside on the course of alcohol tolerance in vivo.

Objective: The aim of this study was to investigate the ability of salidroside to inhibit the development of alcohol tolerance in rats, determining whether the effect of its action may occur in a dose-dependent manner, reducing both metabolic and central tolerance without affecting body temperature in control rats.

Methods: Male Wistar rats were injected daily with ethanol at a dose of 3 g/kg for 9 consecutive days to produce ethanol tolerance. Salidroside in two doses (4.5 mg/kg and 45 mg/kg b.w.) or vehiculum was administered orally. On the 1st, 3rd, 5th and 8th day a hypothermic effect of ethanol was measured, while the loss of righting reflex procedure was performed on the 2nd, 4th, 6th and 7th day. On the 9th day rats were treated with salidroside, sacrificed 1 h after ethanol injections and blood was collected for blood-ethanol concentration measurement.

Results: Salidroside at a dose of 45 mg/kg inhibited the development of tolerance to hypothermic and sedative effects of ethanol, whereas insignificant elevation of blood-ethanol concentration was observed. The dose of 4.5 mg/kg b.w. had minimal effect, only small inhibition of tolerance to hypothermic action was observed. Salidroside affected neither body mass growth nor body temperature in non-alcoholic (control) rats.

Conclusions: Results of the study indicate that salidroside at a dose of 45 mg/kg inhibited the development of tolerance to the hypothermic effect of ethanol. Observed inhibition of tolerance to the sedative effect of ethanol seems to be associated with salidroside influence on the central nervous system. A comprehensive explanation of the abovementioned observations requires further pharmacological and pharmacodynamic studies.

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

  • 1. Spanagel R Kiefer F. Drugs for relapse prevention of alcoholism: ten years of progress. Trends Pharmacol Sci 2008; 29:109-115. doi:

  • 2. Keating GM. Nalmefene: a review of its use in the treatment of alcohol dependence. CNS Drugs 2013; 27(9):761-72. doi:

  • 3. Aubin HJ Reimer J Nutt DJ Bladström A Torup L François C Chick J. Clinical relevance of as-needed treatment with nalmefene in alcohol-dependent patients. Eur Addict Res 2015; 21(3):160-8. doi:

  • 4. Ferraguti G Pascale E Lucarelli M. Alcohol addiction: a molecular biology perspective. Curr Med Chem 2015; 22(6):670-84. doi:

  • 5. Xuan Z Naimi TS Kaplan MS Bagge CL Few LR Maisto S et al. Alcohol policies and suicide: a review of the literature. Alcohol Clin Exp Res 2016; 40(10):2043-2055. doi:

  • 6. Tomczyk M Zovko-Koncić M Chrostek L. Phytotherapy of alcoholism. Nat Prod Commun 2012; 7(2):273-80.

  • 7. Ożarowski M Mikołajczak PŁ Thiem B. Medicinal plants in the phytotherapy of alcohol or nicotine addiction. Implication for plants in vitro cultures. Przegl Lek 2013; 70(10):869-74.

  • 8. Colombo G Serra S Vacca G Orrù A Maccioni P Morazzoni P et al. Identification of miltirone as active ingredient of Salvia miltiorrhiza responsible for the reducing effect of root extracts on alcohol intake in rats. Alcohol Clin Exp Res 2006; 30(5):754-62.

  • 9. Abenavoli L Capasso F Addolorato G. Phytotherapeutic approach to alcohol dependence: new old way? Phytomedicine 2009; 16(6-7):638-644. doi:

  • 10. Mikołajczak PŁ Mrozikiewicz PM Mścisz A Bobkiewicz-Kozłowska T. Mechanisms of the antialcoholic activity of the Puerariae radix (kudzu root) extract. State of art. Herba Pol 2009; 2:78-87.

  • 11. Gryszczyńska A Mikołajczak PŁ Grządzielski P Zakowicz P Szulc M Kamińska E et al. Comparison of extracts from root of Rhodiola rosea and Rhodiola kirilowii inhibitory action on alcohol tolerance development in rats. Alcohol and Alcoholism 2015; 50(Suppl. 1):i44. doi:

  • 12. Mikołajczak PŁ Szulc M Kamińska E Dyr W Wyszogrodzka E Gryszczyńska A et al. Extract from root of Pueraria lobata inhibits an acute alcohol tolerance in high-preferring (WHP) and low-preferring (WLP) alcohol-drinking rats. Pharmacol Reports 2015; 67(Suppl. 1):14. doi:

  • 13. Krajewska-Patan A Gryszczyńska A Mielcarek S Furmanowa M Buchwald W Mikołajczak PŁ et al. Possible Rhodiola kirilowii use in modern phytotherapy. Post Fitoter 2013; 1:22-27.

  • 14. Chen SF Tsai HJ Hung TH Chen CC Lee CY Wu CH et al. Salidroside improves behavioral and histological outcomes and reduces apoptosis via PI3K/Akt signaling after experimental traumatic brain injury. PLoS One 2012; 7(9):e45763. doi:

  • 15. Han T. Effects of salidroside pretreatment on expression of tumor necrosis factor-alpha and permeability of blood brain barrier in rat model of focal cerebralischemia-reperfusion injury. Asian Pacific J Trop Med 2013; 6(2)156-158. doi:

  • 16. Zhang J Zhen YF Pu-Bu-Ci-Ren Song LG Kong WN Shao TM et al. Salidroside attenuates beta amyloid-induced cognitive deficits via modulating oxidative stress and inflammatory mediators in rat hippocampus. Behav Brain Res 2013; 244:70-81. doi:

  • 17. Zhang B Wang Y Li H Xiong R Zhao Z Chu X et al. Neuroprotective effects of salidroside through PI3K/Akt pathway activation in Alzheimer's disease models. Drug Des Devel Ther 2016; 10:1335-1343.

  • 18. Guo N Zhu M Han X Sui D Wang Y Yang Q. The metabolism of salidroside to its aglycone p-tyrosol in rats following the administration of salidroside. PLoS One 2014; 9(8):e103648.

  • 19. Panossian A Hamm R Wikman G Efferth T. Mechanism of action of Rhodiola salidroside tyrosol and triandrin in isolated neuroglial cells: an interactive pathway analysis of the downstream effects using RNA microarray data. Phytomedicine 2014; 21(11):1325-1348. doi:

  • 20. Atochin DN Chernysheva GA Smolyakova VI Osipenko AN Logvinov SV Zhdankina AA et al. Neuroprotective effects of p-tyrosol after the global cerebral ischemia in rats. Phytomedicine 2016; 23(7):784-792. doi:

  • 21. Naavi SF Braidy N Orhan IE Badiee A Daglia M Nabavi SM. Rhodiola rosea L. and Alzheimer's disease: from farm to pharmacy. Phytother Res 2016; 30(4):532-539. doi:

  • 22. Tao K Wang B Feng D Zhang W Lu F Lai J et al. Salidroside protects against 6-hydroxydopamine-induced cytotoxicity by attenuating ER stress. Neurosci Bull 2016; 32(1):61-69. doi:

  • 23. Gao J Zhou R You X Luo F He H Chang X et al. Salidroside suppresses inflammation in a D-galactose-induced rat model of Alzheimer's disease via SIRT1/NF-κB pathway. Metab Brain Dis 2016; 31(4):771-778. doi:

  • 24. Dey A Bhattacharya R Mukherjee A Pandey DK. Natural products against Alzheimer's disease: Pharmaco-therapeutics and biotechnological interventions. Biotechnol Adv 2017; 35:178-216. doi:

  • 25. Crabbe JC Janowsky JS Young ER Kosobud A Stack J Rigter H. Tolerance to ethanol hypothermia in inbred mice: genotypic correlations with behavioral responses. Alcohol Clin Exp 1982; 6:446-458.

  • 26. Szulc M Mikołajczak PŁ Geppert B Wachowiak R Dyr W Bobkiewicz-Kozłowska T. Ethanol affects acylated and total ghrelin levels in peripheral blood of alcohol-dependent rats. Addict Biol 2013; 18:689-701. doi:

  • 27. Lopez MF Griffin WC Melendez RI Becker HC. Repeated cycles of chronic intermittent ethanol exposure leads to the development of tolerance to aversive effects of ethanol in C57BL/6J mice. Alcohol Clin Exp Res 2012; 36:1180-1187. doi:

  • 28. Crabbe JC. Use of animal models of alcohol-related behavior. Handbook of clinical neurology 2014; 125:71-86. doi:

  • 29. World Health Organization (WHO). International classification of diseases and related health problems 10th revision. Geneva World Health Organization 2007.

  • 30. Okulicz-Kozaryn I Mikołajczak PŁ Kamińska E. Tolerance to hypothermia and hypnotic action of ethanol in 3 and 14 months old rats. 3rd Joint Meeting of Hungarian Italian and Polish Pharmacological Societies. Modena (Italy) June 8-10 1992 Pharmacol Res. 1992 25 Suppl. II: 63-64.

  • 31. Wu SX Guo YD Guo SL Liangchao L Wang BX Ma T. Study of the chemical constituents of ethanol extracts of Rhodiola crenulata H. Mod Food Sci Technol 2008; 4.

  • 32. Chiang HM Chen HC Wu CS Wu PY Wen KC. Wu SX et al. Study of the chemical constituents of ethanol extracts of Rhodiola crenulata H. J Food Drug Anal 2015; 23(3) 359-369.

  • 33. Szulc M Mularczyk P Kamińska E Kujawski R Gryszczyńska A Krajewska-Patan A et al. Effect of salidroside on the development of alcohol tolerance in rats. In: XXIII Naukowy Zjazd Polskiego Towarzystwa Farmaceutycznego „Pharmacy in Poland – perspectives of science and profession”; 2017 Sep 19-22; Kraków Poland 2017:138.

  • 34. Mattioli L Titomanlio F Perfumi M. Effects of a Rhodiola rosea L. extract on the acquisition expression extinction and reinstatement of morphine-induced conditioned place preference in mice. Psychopharmacology 2012; 221:183-193. doi:

  • 35. Titomanlio F Perfumi M Mattioli L. Rhodiola rosea L. extract and its active compound salidroside antagonized both induction and reinstatement of nicotine place preference in mice. Psychopharmacology 2014; 231:2077-2086. doi:

  • 36. Zhao HB Ma H Ha XQ Zheng P Li XY Zhang M et al. Salidroside induces rat mesenchymal stem cells to differentiate into dopaminergic neurons. Cell Biol Int 2014; 38(4):462-471. doi:

  • 37. Zhang L Yu H Sun Y Lin X Chen B Tan C et al. Protective effects of salidroside on hydrogen peroxide-induced apoptosis in SH-SY5Y human neuroblastoma cells. Eur J Pharmacol 2007; 564(1-3):18-25. doi:

  • 38. Palmeri A Mammana L Tropea M Gulisano W Puzzo D. Salidroside a bioactive compound of Rhodiola rosea ameliorates memory and emotional behavior in adult mice. J Alzheimers Dis 2016; 52(1): 65-75. doi:

  • 39. Jin H Pei L Shu X Yang X Yan T Wu Y et al. Therapeutic intervention of learning and memory decays by salidroside stimulation of neurogenesis in aging. Mol Neurobiol 2016; 53(2):851-866. doi:

  • 40. Dewapriya P Himaya SWA Li YX Kim SK. Tyrosol exerts a protective effect against dopaminergic neuronal cell death in in vitro model of Parkinson's disease. Food Chem 2013; 141(2):1147-1157. doi:

  • 41. Keung WM. Anti-dipsotropic isoflavones: The potential therapeutic agents for alcohol dependence. Med Res Rev 2003; 23:669-696. doi:

  • 42. Addolorato G Capristo E Greco AV Stefanini GF Gasbarrini G. Influence of chronic alcohol abuse on body weight and energy metabolism: is excess ethanol consumption a risk factor for obesity or malnutrition?. J Intern Med 1998; 244: 387-395. doi:

  • 43. Li T Xu G Wu L Sun C. Pharmacological studies on the sedative and hypnotic effect of salidroside from the Chinese medicinal plant Rhodiola sachalinensis. Phytomedicine 2007; 14(9):601-604. doi:

  • 44. Le AD Khanna JM Kalant H Grossi F. Tolerance to and cross-tolerance among ethanol pentobarbital and chlordiazepoxide. Pharmacol Biochem Behav 1986; 24(1):93-98.

Journal information
Cited By
All Time Past Year Past 30 Days
Abstract Views 0 0 0
Full Text Views 457 208 11
PDF Downloads 211 109 6