A Close Look at Echium amoenum Processing, Neuroactive Components, and Effects on Neuropsychiatric Disorders
DOI:
https://doi.org/10.31661/gmj.v8i.1559Keywords:
Echium amoenum, Rosmarinic Acid, Phenolic Compound, Antioxidant, Anti-inflammatory, Neuropsychiatric Disorders, Persian MedicineAbstract
Pharmacological researches in the area of herbal medicine have considerably increased over the last two centuries. Echium amoenum (known as Gol-e-Gavzaban in Persian) is a medicinal plant that has been widely used in Iranian folk medicine. In this review, databases including PubMed, Scopus, and Google Scholar were searched up. Data collecting was completed by January 2019 and available scientific reports regarding the processing methods, main chemical constituents, and effects of E. amoenum on different neuropsychiatric disorders are summarized. Thirteen five studies met the inclusion criteria. According to results, the important phytochemicals of the plant was phenolic compounds, fatty acids, rosmarinic acid, anthocyanidins, and flavonoids. Also, experimental and clinical studies demonstrated the effectiveness of E. amoenum in the treatment of several neuropsychiatric disorders such as anxiety, depression, ischemic stroke, seizure, Alzheimer’s disease, and pain. Many of these effects are, at least in part, due to its rosmarinic acid or polyphenolic compounds such as flavonoids and natural pigments such as anthocyanins. Also, fatty acids such as gamma-linolenic acid play critical role in neuroactive properties of this herb. Among these effects, only the antidepressant and anxiolytic properties of the plant extract have been examined both experimentally and clinically. There was some controversy over its toxicity effects. It seems that E. amoenum protects neurons via attenuation of oxidative stress and inflammation as well as blocking of apoptosis in the nervous system. However, more studies are necessary for assessing exact mechanisms of action in neuropsychiatric disorders, finding of bioactive ingredients, and processing methods of this plant. [GMJ.2019;8:e1559]
References
Sadigh-Eteghad S, Tayefi-Nasrabadi H, Aghdam Z, Zarredar H, Shanehbandi D, Khayyat L et al. Rosa canina L. fruit hydro-alcoholic extract effects on some immunological and biochemical parameters in rats. BioImpacts: BI. 2011;1(4):219. Zhang X. WHO Guide lines on Safety Monitoring of Herbal Medicines in Pharmacovigilance Systems. Geneva, Switzerland: World Health Organization; 2004. Sadigh-Eteghad S, Abadi N, Ghavami S, Golabi M, Shanebandi D. Synergetic effects of oral administration of levamisole and Echinacea purpurea on immune response in Wistar rat. Res Vet Sci. 2011;91(1):82-5. https://doi.org/10.1016/j.rvsc.2010.07.027PMid:20797737 Zargari A. Medicinal plants. Tehran: Tehran University Press; 1993. Gupta M, Singh S. Borago officinalis Linn. An important medicinal plant of mediterranean region: a review. Int J Pharm Sci Rev Res. 2010;5(1):27-34. Mehrabani M, Ghassemi N, Ghannadi ESA, Shams-Ardakani M. Main phenolic compound of petals of Echium amoenum Fisch. and CA Mey., a famous medicinal plant of Iran. Daru. 2005;13(2):65-9. Azizi H, Ghafari S, Ghods R, Shojaii A, Salmanian M, Ghafarzadeh J. A review study on pharmacological activities, chemical constituents, and traditional uses of Echium amoenum. Pharmacogn Rev. 2018;12(24):208. https://doi.org/10.4103/phrev.phrev_13_18 Ghoreishi S, Mardani E, Ghaziaskar H. Separation of γâ€linolenic and other polyunsaturated fatty acids from Boraginaceae via supercritical CO2. J Sep Sci. 2011;34(2):233-40. https://doi.org/10.1002/jssc.201000716PMid:21246730 Erdemoglu N, Kusmenoglu S, Vural M. γâ€Linolenic acid content and fatty acid composition of Boraginaceae seed oils. Eur J Lipid Sci Technol. 2004;106(3):160-4. https://doi.org/10.1002/ejlt.200300910 Hajghanbari L, Alizadeh A, Honarvar M. Essential oil constituents and fatty acids in Echium amoenum grown wild in Iran. Int J Biosci. 2015;6(1):156-61. https://doi.org/10.12692/ijb/6.1.156-161 Pilerood SA, Prakash J. Evaluation of nutritional composition and antioxidant activity of Borage (Echium amoenum) and Valerian (Valerian officinalis). J Food Sci Technol. 2014;51(5):845-54. https://doi.org/10.1007/s13197-011-0573-zPMid:24803690 PMCid:PMC4008743 Grieve M. A modern herbal. New York: Dover Publications; 1971. Moemen M. Tohfat-Al-Hakim Moemen. 2nd ed. Tehran: Mahmoodi Press; 1967. Avicenna_(980-1037_AD). Canon of Medicine. Translated into English by Hameed HA. S. Waris Nawab. New Delhi: Senior Press Superintendent, Jamia Hamdard Printing Press; 1998. Ghafouri RR, Araj-Khodaei M, Targhi ST, Varshochi M, Parsian Z, Yarani R et al. First report of a disease by rhazes 10 centuries ago. International Journal of Preventive Medicine. 2019;10. Khodaei MA, Noorbala AA, Parsian Z, Targhi ST, Emadi F, Alijaniha F et al. Avicenna (980-1032CE): The pioneer in treatment of depression. Transylvanian Review. 2017. Taheri-Targhi S, Gjedde A, Araj-Khodaei M, Rikhtegar R, Parsian Z, Zarrintan S et al. Avicenna (980-1037 CE) and his Early Description and Classification of Dementia. Journal of Alzheimer's Disease. (Preprint):1-6. https://doi.org/10.3233/JAD-190345PMid:31524162 Abed A, Vaseghi G, Jafari E, Fattahian E, Babhadiashar N, Abed M. Echium Amoenum Fisch. Et Mey: A review on its pharmacological and medicinal properties. Asian J Med Pharm Res. 2014;4:21-3. https://doi.org/10.1016/j.pnpbp.2009.08.021https://doi.org/10.1016/j.pnpbp.2009.08.021PMid:19737592 https://doi.org/10.1016/j.pnpbp.2005.10.005https://doi.org/10.1016/j.pnpbp.2005.10.005PMid:16309809 Sayyah M, Siahpoosh A, Khalili H, Malayeri A, Samaee H. A double-blind, placebo-controlled study of the aqueous extract of Echium amoenum for patients with general anxiety disorder. Iran J Pharm Res. 2012;11(2):697. Sadeghi L, Yousefi Babadi V, Tanwir F. Improving effects of Echium amoenum aqueous extract on rat model of Alzheimer's disease. J Integr Neurosci. 2018(Preprint):1-9. Heidari MR, Azad EM, Mehrabani M. Evaluation of the analgesic effect of Echium amoenum Fisch & CA Mey. extract in mice: possible mechanism involved. J Ethnopharmacol. 2006;103(3):345-9. https://doi.org/10.1016/j.jep.2005.08.027PMid:16185831 Heidari MR, Mandegary A, Hosseini A, Vahedian M. Anticonvulsant effect of methanolic extract of Echium amoenum Fisch and C.A. Mey. Against seizure induced by picrotoxin in mice. Pak J Biol Sci. 2006;9:772-6. https://doi.org/10.3923/pjbs.2006.772.776 Ranjbar A, Khorami S, Safarabadi M, Shahmoradi A, Malekirad AA, Vakilian K et al. Antioxidant activity of Iranian Echium amoenum Fisch & CA Mey flower decoction in humans: a cross-sectional before/after clinical trial. Evid Based Complement Alternat Med. 2006;3(4):469-73. https://doi.org/10.1093/ecam/nel031PMid:17173110 PMCid:PMC1697746 Naseri N, Kalantar K, Amirghofran Z. Anti-inflammatory activity of Echium amoenum extract on macrophages mediated by inhibition of inflammatory mediators and cytokines expression. Res Pharm Sci. 2018;13(1):73. https://doi.org/10.4103/1735-5362.220970PMid:29387114 PMCid:PMC5772084 Hemmati K, Omidbiagi R, Bashirisadre Z, Ebrahemi Y. Effect of climate and harvesting time in quantities and qualities flavonoids certain in Citrus cultivars: Ph. D. Thesis. Modarres University Publisher; 2003. Abbaszadeh S, Radjabian T, Taghizadeh M. Antioxidant Activity, Phenolic and Flavonoid Contents of Echium Species from Different Geographical Locations of Iran. Journal of Medicinal Plants and By-Products. 2013;2(1):23-31. Sajirani EB, Hadian J, Abdossi V, Larijani K. Evaluation content of flavonoids and anthocyanins in Iranian borage (Echium amoenum fisch & mey) subjected in eshkevari accessions affected by different habitats in North of Iran. J Biodivers Environ Sci 2014;4(2):364-8. Safavi S, Khajehpour M. Effects of salinity on Na, K and Ca contents of borage (Borago officinalis L.) and echium (Echium amoenum Fisch. & Mey.). Res Pharm Sci. 2008;2(1):23-7. Tanko H, Carrier DJ, Duan L, Clausen E. Pre-and post-harvest processing of medicinal plants. Plant Genet Resour Newsl. 2005;3(2):304-13. https://doi.org/10.1079/PGR200569 Saeedi A, Asadi-Gharneh HA. Effect of Different Drying Methods on Some Biochemical Properties of Iranian Ox-tongue (Echium amoenum Fisch. & Mey.). Journal of Herbal Drugs 2017;8(2):87-92. https://doi.org/10.18869/jhd.8.2.87 Santana ACMd, Pereira GS, Boaventura CM, Uetenabaro APT, Costa LCdB, Oliveira RAd. Rupture of glandular trichomes in Ocimum gratissimum leaves influences the content of essential oil during the drying method. Rev Bras Farmacogn. 2014;24(5):524-30. https://doi.org/10.1016/j.bjp.2014.10.006 Nadi F. Bioactive compound retention in Echium amoenum Fisch. & CA Mey. petals: Effect of fluidized bed drying conditions. Int J Food Prop. 2017;20(10):2249-60. https://doi.org/10.1080/10942912.2016.1233436 Bekhradnia S, Ebrahimzadeh MA. Antioxidant activity of Echium amoenum. Rev Chim J. 2016;67(2):223-6. Asghari B, Mafakheri S, Zarrabi M, Erdem S, Orhan I, Bahadori M. Therapeutic target enzymes inhibitory potential, antioxidant activity, and rosmarinic acid content of Echium amoenum. S Afr J Bot. 2018. https://doi.org/10.1016/j.sajb.2018.05.017 Shekarchi M, Hajimehdipoor H, Saeidnia S, Gohari AR, Hamedani MP. Comparative study of rosmarinic acid content in some plants of Labiatae family. Pharmacogn Mag. 2012;8(29):37. https://doi.org/10.4103/0973-1296.93316PMid:22438661 PMCid:PMC3307200 Qiao S, Li W, Tsubouchi R, Haneda M, Murakami K, Takeuchi F et al. Rosmarinic acid inhibits the formation of reactive oxygen and nitrogen species in RAW264. 7 macrophages. Free Radic Res. 2005;39(9):995-1003. https://doi.org/10.1080/10715760500231836PMid:16087481 Swarup V, Ghosh J, Ghosh S, Saxena A, Basu A. Antiviral and anti-inflammatory effects of rosmarinic acid in an experimental murine model of Japanese encephalitis. Antimicrob Agents Chemother. 2007;51(9):3367-70. https://doi.org/10.1128/AAC.00041-07PMid:17576830 PMCid:PMC2043228 Mushtaq N, Schmatz R, Pereira LB, Ahmad M, Stefanello N, Vieira JM et al. Rosmarinic acid prevents lipid peroxidation and increase in acetylcholinesterase activity in brain of streptozotocinâ€induced diabetic rats. Cell Biochem Funct. 2014;32(3):287-93. https://doi.org/10.1002/cbf.3014PMid:24301255 Boonyarikpunchai W, Sukrong S, Towiwat P. Antinociceptive and anti-inflammatory effects of rosmarinic acid isolated from Thunbergia laurifolia Lindl. Pharmacol Biochem Behav. 2014;124:67-73. https://doi.org/10.1016/j.pbb.2014.05.004PMid:24836183 Hasanein P, Mohammad Zaheri L. Effects of rosmarinic acid on an experimental model of painful diabetic neuropathy in rats. Pharm Biol. 2014;52(11):1398-402. https://doi.org/10.3109/13880209.2014.894090PMid:25026351 Friedman T. The effect of rosmarinic acid on immunological and neurological systems: a basic science and clinical review. J Restor Med. 2015;4(1):50-9. https://doi.org/10.14200/jrm.2015.4.0105 Rampart M, Beetens JR, Bult H, Herman AG, Parnham MJ, Winkelmann J. Complement-dependent stimulation of prostacyclin biosynthesis: inhibition by rosmarinic acid. Biochem Pharmacol. 1986;35(8):1397-400. https://doi.org/10.1016/0006-2952(86)90289-3 Frankel EN, Huang S-W, Aeschbach R, Prior E. Antioxidant activity of a rosemary extract and its constituents, carnosic acid, carnosol, and rosmarinic acid, in bulk oil and oil-in-water emulsion. J Agric Food Chem. 1996;44(1):131-5. https://doi.org/10.1021/jf950374p https://doi.org/10.1016/j.tox.2008.06.010https://doi.org/10.1016/j.tox.2008.06.010PMid:18644421 Shimojo Y, Kosaka K, Noda Y, Shimizu T, Shirasawa T. Effect of rosmarinic acid in motor dysfunction and life span in a mouse model of familial amyotrophic lateral sclerosis. J Neurosci Res. 2010;88(4):896-904. https://doi.org/10.1002/jnr.22242PMid:19798750 https://doi.org/10.1016/j.fitote.2010.03.010https://doi.org/10.1016/j.fitote.2010.03.010PMid:20230877 Iuvone T, De Filippis D, Esposito G, D'Amico A, Izzo AA. The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-β peptide-induced neurotoxicity. J Pharmacol Exp Ther. 2006;317(3):1143-9. https://doi.org/10.1124/jpet.105.099317PMid:16495207 Alkam T, Nitta A, Mizoguchi H, Itoh A, Nabeshima T. A natural scavenger of peroxynitrites, rosmarinic acid, protects against impairment of memory induced by Aβ25-35. Behav Brain Res. 2007;180(2):139-45. https://doi.org/10.1016/j.bbr.2007.03.001PMid:17420060 Falé PL, Madeira PJA, Florêncio MH, Ascensão L, Serralheiro MLM. Function of Plectranthus barbatus herbal tea as neuronal acetylcholinesterase inhibitor. Food Funct. 2011;2(2):130-6. https://doi.org/10.1039/C0FO00070APMid:21779558 Nijveldt RJ, Van Nood E, Van Hoorn DE, Boelens PG, Van Norren K, Van Leeuwen PA. Flavonoids: a review of probable mechanisms of action and potential applications. Am J Clin Nutr. 2001;74(4):418-25. https://doi.org/10.1093/ajcn/74.4.418PMid:11566638 https://doi.org/10.1016/j.fitote.2011.01.018https://doi.org/10.1016/j.fitote.2011.01.018PMid:21277359 https://doi.org/10.1016/j.neuint.2016.01.009https://doi.org/10.1016/j.neuint.2016.01.009PMid:26845377 Van Acker SA, Tromp MN, Griffioen DH, Van Bennekom WP, Van Der Vijgh WJ, Bast A. Structural aspects of antioxidant activity of flavonoids. Free Radic Biol Med. 1996;20(3):331-42. https://doi.org/10.1016/0891-5849(95)02047-0 Banjarnahor SD, Artanti N. Antioxidant properties of flavonoids. Medical Journal of Indonesia. 2015;23(4):239-44. https://doi.org/10.13181/mji.v23i4.1015 Farooqui AA. Beneficial Effects of Flavonoids on Neurological Disorders. Phytochemicals, Signal Transduction, and Neurological Disorders. Springer; 2013. p. 83-115. https://doi.org/10.1007/978-1-4614-3804-5_4 Serafini M, Peluso I, Raguzzini A. Flavonoids as anti-inflammatory agents. Proc Nutr Soc. 2010;69(3):273-8. doi:10.1017/S002966511000162X. https://doi.org/10.1017/S002966511000162XPMid:20569521 Grosso C, Valentão P, Ferreres F, B Andrade P. The use of flavonoids in central nervous system disorders. Curr Med Chem. 2013;20(37):4694-719. https://doi.org/10.2174/09298673113209990155PMid:23834189 Guan L-P, Liu B-Y. Antidepressant-like effects and mechanisms of flavonoids and related analogues. Eur J Med Chem. 2016;121:47-57. https://doi.org/10.1016/j.ejmech.2016.05.026PMid:27214511 Telerman A, Ofir R, Kashman Y, Elmann A. 3,5,4′-trihydroxy-6,7,3′-trimethoxyflavone protects against beta amyloid-induced neurotoxicity through antioxidative activity and interference with cell signaling. BMC Complement Altern Med. 2017;17(1):332. doi:10.1186/s12906-017-1840-y. https://doi.org/10.1186/s12906-017-1840-yPMid:28645294 PMCid:PMC5481959 Khan H, Amin S, Kamal MA, Patel S. Flavonoids as acetylcholinesterase inhibitors: Current therapeutic standing and future prospects. Biomed Pharmacother. 2018;101:860-70. https://doi.org/10.1016/j.biopha.2018.03.007PMid:29635895 Rendeiro C, Vauzour D, Kean RJ, Butler LT, Rattray M, Spencer JP et al. Blueberry supplementation induces spatial memory improvements and region-specific regulation of hippocampal BDNF mRNA expression in young rats. Psychopharmacol. 2012;223(3):319-30. https://doi.org/10.1007/s00213-012-2719-8PMid:22569815 Williams CM, El Mohsen MA, Vauzour D, Rendeiro C, Butler LT, Ellis JA et al. Blueberry-induced changes in spatial working memory correlate with changes in hippocampal CREB phosphorylation and brain-derived neurotrophic factor (BDNF) levels. Free Radic Biol Med. 2008;45(3):295-305. https://doi.org/10.1016/j.freeradbiomed.2008.04.008PMid:18457678 Citraro R, Navarra M, Leo A, Donato Di Paola E, Santangelo E, Lippiello P et al. The anticonvulsant activity of a flavonoid-rich extract from orange juice involves both NMDA and GABA-benzodiazepine receptor complexes. Molecules. 2016;21(9):1261. https://doi.org/10.3390/molecules21091261PMid:27657037 PMCid:PMC6273133 Choudhary N, Bijjem KRV, Kalia AN. Antiepileptic potential of flavonoids fraction from the leaves of Anisomeles malabarica. J Ethnopharmacol. 2011;135(2):238-42. https://doi.org/10.1016/j.jep.2011.02.019PMid:21354295 Putta S, Yarla NS, Peluso I, Tiwari DK, Reddy GV, Giri PV et al. Anthocyanins: Multi-Target Agents for Prevention and Therapy of Chronic Diseases. Curr Pharm Des. 2017;23(41):6321-46. https://doi.org/10.2174/1381612823666170519151801PMid:28741457 Kim K-T, Nam T-K, Park Y-S, Kim Y-B, Park S-W. Neuroprotective effect of anthocyanin on experimental traumatic spinal cord injury. J Korean Neurosurg Soc. 2011;49(4):205. https://doi.org/10.3340/jkns.2011.49.4.205PMid:21607177 PMCid:PMC3098422 Ye J, Meng X, Yan C, Wang C. Effect of purple sweet potato anthocyanins on β-amyloid-mediated PC-12 cells death by inhibition of oxidative stress. Neurochem Res. 2010;35(3):357-65. https://doi.org/10.1007/s11064-009-0063-0PMid:19771514 Wallace TC, Giusti MM. Anthocyanins in health and disease. CRC Press; 2013. https://doi.org/10.1201/b15554 Kelsey N, Hulick W, Winter A, Ross E, Linseman D. Neuroprotective effects of anthocyanins on apoptosis induced by mitochondrial oxidative stress. Nutr Neurosci. 2011;14(6):249-59. https://doi.org/10.1179/1476830511Y.0000000020PMid:22053756 Strathearn KE, Yousef GG, Grace MH, Roy SL, Tambe MA, Ferruzzi MG et al. Neuroprotective effects of anthocyanin-and proanthocyanidin-rich extracts in cellular models of Parkinson׳ s disease. Brain Res. 2014;1555:60-77. https://doi.org/10.1016/j.brainres.2014.01.047PMid:24502982 PMCid:PMC4024464 Bertuglia S, Malandrino S, Colantuoni A. Effect of Vaccinium myrtillus anthocyanosides on ischaemia reperfusion injury in hamster cheek pouch microcirculation. Pharmacol Res. 1995;31(3-4):183-7. https://doi.org/10.1016/1043-6618(95)80016-6 Andres-Lacueva C, Shukitt-Hale B, Galli RL, Jauregui O, Lamuela-Raventos RM, Joseph JA. Anthocyanins in aged blueberry-fed rats are found centrally and may enhance memory. Nutr Neurosci. 2005;8(2):111-20. https://doi.org/10.1080/10284150500078117PMid:16053243 Gutierres JM, Carvalho FB, Schetinger MRC, Agostinho P, Marisco PC, Vieira JM et al. Neuroprotective effect of anthocyanins on acetylcholinesterase activity and attenuation of scopolamine-induced amnesia in rats. Int J Dev Neurosci. 2014;33:88-97. https://doi.org/10.1016/j.ijdevneu.2013.12.006PMid:24374256 https://doi.org/10.1016/j.lfs.2005.12.033https://doi.org/10.1016/j.lfs.2005.12.033PMid:16442129 https://doi.org/10.1016/j.neulet.2011.05.048https://doi.org/10.1016/j.neulet.2011.05.048PMid:21651957 Hwang MK, Kang NJ, Heo Y-S, Lee KW, Lee HJ. Fyn kinase is a direct molecular target of delphinidin for the inhibition of cyclooxygenase-2 expression induced by tumor necrosis factor-α. Biochem Pharmacol. 2009;77(7):1213-22. https://doi.org/10.1016/j.bcp.2008.12.021PMid:19174152 Scarabelli TM, Mariotto S, Abdel-Azeim S, Shoji K, Darra E, Stephanou A et al. Targeting STAT1 by myricetin and delphinidin provides efficient protection of the heart from ischemia/reperfusionâ€induced injury. FEBS Lett. 2009;583(3):531-41. https://doi.org/10.1016/j.febslet.2008.12.037PMid:19116149 Safaeian L, Javanmard SH, Ghanadian M, Seifabadi S. Cytoprotective and antioxidant effects of Echium amoenum anthocyanin-rich extract in human endothelial cells (HUVECs). Avicenna J Phytomed. 2015;5(2):157. Sergeant S, Rahbar E, Chilton FH. Gamma-linolenic acid, Dihommo-gamma linolenic, Eicosanoids and Inflammatory Processes. Eur J Pharmacol. 2016;785:77-86. doi:10.1016/j.ejphar.2016.04.020. https://doi.org/10.1016/j.ejphar.2016.04.020PMid:27083549 PMCid:PMC4975646 Belch JJ, Hill A. Evening primrose oil and borage oil in rheumatologic conditions. Am J Clin Nutr. 2000;71(1):352s-6s. https://doi.org/10.1093/ajcn/71.1.352sPMid:10617996 Chang C-S, Sun H-L, Lii C-K, Chen H-W, Chen P-Y, Liu K-L. Gamma-linolenic acid inhibits inflammatory responses by regulating nf-κB and AP-1 activation in lipopolysaccharide-induced RAW 264.7 macrophages. Inflammation. 2010;33(1):46-57. https://doi.org/10.1007/s10753-009-9157-8PMid:19842026 Puri B. The safety of evening primrose oil in epilepsy. Prostaglandins, Leukotrienes and Essential Fatty Acids. 2007;77(2):101-3. https://doi.org/10.1016/j.plefa.2007.07.003PMid:17764919 Wagner W, Nootbaarâ€Wagner U. Prophylactic treatment of migraine with gammaâ€linolenic and alphaâ€linolenic acids. Cephalalgia. 1997;17(2):127-30. https://doi.org/10.1046/j.1468-2982.1997.1702127.xPMid:9137851 Hounsom L, Horrobin D, Tritschler H, Corder R, Tomlinson D. A lipoic acid-gamma linolenic acid conjugate is effective against multiple indices of experimental diabetic neuropathy. Diabetologia. 1998;41(7):839-43. https://doi.org/10.1007/s001250050996PMid:9686927 Jamal G, Carmichael H. The Effect of γâ€Linolenic Acid on Human Diabetic Peripheral Neuropathy: A Doubleâ€blind Placeboâ€controlled Trial. Diabet Med. 1990;7(4):319-23. https://doi.org/10.1111/j.1464-5491.1990.tb01397.xPMid:2159860 Craske MG, Rauch SL, Ursano R, Prenoveau J, Pine DS, Zinbarg RE. What is an anxiety disorder? Focus. 2011;9(3):369-88. https://doi.org/10.1176/foc.9.3.foc369 Reeves JW, Fisher AJ, Newman MG, Granger DA. Sympathetic and hypothalamicâ€pituitaryâ€adrenal asymmetry in generalized anxiety disorder. Psychophysiology. 2016;53(6):951-7. https://doi.org/10.1111/psyp.12634PMid:26934635 Bandelow B, Michaelis S, Wedekind D. Treatment of anxiety disorders. Dialogues Clin Neurosci. 2017;19(2):93. Saki K, Bahmani M, Rafieian-Kopaei M. The effect of most important medicinal plants on two importnt psychiatric disorders (anxiety and depression)-a review. Asian Pac J Trop Med. 2014;7:S34-S42. https://doi.org/10.1016/S1995-7645(14)60201-7 Shafaghi B, Naderi N, Tahmasb L, Kamalinejad M. Anxiolytic effect of Echium amoenum L. in mice. Iran J Pharm Res. 2002:37-41. Rabbani M, Sajjadi S, Vaseghi G, Jafarian A. Anxiolytic effects of Echium amoenum on the elevated plus-maze model of anxiety in mice. Fitoterapia. 2004;75(5):457-64. https://doi.org/10.1016/j.fitote.2004.04.004PMid:15261383 Gholamzadeh S, Zare S, Ilkhanipoor M. Evaluation of the anxiolytic effect of Echium amoenum petals extract, during chronic treatment in rat. Res Pharm Sci. 2009;2(2):91-5. Rabbani M, Sajjadi S, Khalili S. A Lack of tolerance to the anxiolytic action of Echium amoenum. Res Pharm Sci. 2011;6(2):101. Yousefi M. Comparison of Anxiolytic-like effects of Echium amoenum in the male and female rats Der Pharma Chemica. 2016;8(18):35-9 Nguyen TT. The cholesterol-lowering action of plant stanol esters. J Nutr. 1999;129(12):2109-12. https://doi.org/10.1093/jn/129.12.2109PMid:10573535 Trautwein EA, Duchateau GS, Lin Y, Mel'nikov SM, Molhuizen HO, Ntanios FY. Proposed mechanisms of cholesterolâ€lowering action of plant sterols. Eur J Lipid Sci Technol. 2003;105(3â€4):171-85. https://doi.org/10.1002/ejlt.200390033 Awad AB, Hartati MS, Fink CS. Phytosterol feeding induces alteration in testosterone metabolism in rat tissues. J Nutr Biochem. 1998;9(12):712-7. https://doi.org/10.1016/S0955-2863(98)00076-X Javid Z, Hosseini S. Comparison of the Effect of Echium amoenum with Buspironeon the Anxiety of Cruciate Maze in Adult Male Rats. Health Horiz. 2016;22(1):51-6. https://doi.org/10.18869/acadpub.hms.22.1.51 Medina JH, Viola H, Wolfman C, Marder M, Wasowski C, Calvo D et al. Overview-flavonoids: a new family of benzodiazepine receptor ligands. Neurochem Res. 1997;22(4):419-25. https://doi.org/10.1023/A:1027303609517PMid:9130252 Duman RS. Pathophysiology of depression and innovative treatments: remodeling glutamatergic synaptic connections. Dialogues Clin Neurosci. 2014;16(1):11. Smaga I, Niedzielska E, Gawlik M, Moniczewski A, Krzek J, PrzegaliÅ„ski E et al. Oxidative stress as an etiological factor and a potential treatment target of psychiatric disorders. Part 2. Depression, anxiety, schizophrenia and autism. Pharmacol Rep. 2015;67(3):569-80. https://doi.org/10.1016/j.pharep.2014.12.015PMid:25933971 Zafir A, Banu N. Modulation of in vivo oxidative status by exogenous corticosterone and restraint stress in rats. Stress. 2009;12(2):167-77. https://doi.org/10.1080/10253890802234168PMid:18850490 de Souza Balk R, Bridi JC, de Lima Portella R, Carvalho NR, Dobrachinski F, Da Silva MH et al. Clomipramine treatment and repeated restraint stress alter parameters of oxidative stress in brain regions of male rats. Neurochem Res. 2010;35(11):1761-70. https://doi.org/10.1007/s11064-010-0240-1PMid:20694755 Maria Michel T, Pulschen D, Thome J. The role of oxidative stress in depressive disorders. Curr Pharm Des. 2012;18(36):5890-9. https://doi.org/10.2174/138161212803523554PMid:22681168 Lee S-Y, Lee S-J, Han C, Patkar AA, Masand PS, Pae C-U. Oxidative/nitrosative stress and antidepressants: targets for novel antidepressants. Prog Neuropsychopharmacol Biol Psychiatry. 2013;46:224-35. https://doi.org/10.1016/j.pnpbp.2012.09.008PMid:23022673 Weizman R, Laor N, Podliszewski E, Notti I, Djaldetti M, Bessler H. Cytokine production in major depressed patients before and after clomipramine treatment. Biol Psychiatry. 1994;35(1):42-7. https://doi.org/10.1016/0006-3223(94)91166-5 Al-Harbi KS. Treatment-resistant depression: therapeutic trends, challenges, and future directions. Patient Prefer Adherence. 2012;6:369. https://doi.org/10.2147/PPA.S29716PMid:22654508 PMCid:PMC3363299 Lee G, Bae H. Therapeutic effects of phytochemicals and medicinal herbs on depression. Biomed Res Int. 2017;2017. https://doi.org/10.1155/2017/6596241PMid:28503571 PMCid:PMC5414506 Anjaneyulu M, Chopra K, Kaur I. Antidepressant activity of quercetin, a bioflavonoid, in streptozotocin-induced diabetic mice. J Med Food. 2003;6(4):391-5. https://doi.org/10.1089/109662003772519976PMid:14977450 Butterweck V, Hegger M, Winterhoff H. Flavonoids of St. John's Wort reduce HPA axis function in the rat. Planta Med. 2004;70(10):1008-11. https://doi.org/10.1055/s-2004-832631PMid:15490333 Faryadian S, Sydmohammadi A, Khosravi A, Kashiri M, Faryadayn P, Abasi N. Aqueous Extract of Echium amoenum Elevate CSF Serotonin and Dopamine Level in Depression rat. Biomed Pharmacol J. 2014;7(1):137-42. https://doi.org/10.13005/bpj/463 Sadegh L, Tanwir F, Yousefi Babadi V. Physiological and Biochemical Effects of Echium Amoenum Extract on Mn2+-Imposed Parkinson Like Disorder in Rats. Adv Pharm Bull. 2018;8:705-13. https://doi.org/10.15171/apb.2018.079PMid:30607343 PMCid:PMC6311646 Anushiravani M, Manteghi A, Taghipur A, Eslami M. Comparing effectiveness of a combined herbal drug based on Echium amoenum with Citalopram in the treatment of Major Depressive Disorder. Curr Drug Discov Technol. 2018. https://doi.org/10.2174/1570163815666180219115844PMid:29468978 Wylie T, Murr N. Seizure, Status Epilepticus. StatPearls. StatPearls Publishing; 2018. Voskuyl RA, Vreugdenhil M, Kang JX, Leaf A. Anticonvulsant effect of polyunsaturated fatty acids in rats, using the cortical stimulation model. Eur J Pharmacol. 1998;341(2-3):145-52. https://doi.org/10.1016/S0014-2999(97)01467-2 Taha AY, Filo E, Ma DW, McIntyre Burnham W. Doseâ€dependent anticonvulsant effects of linoleic and αâ€linolenic polyunsaturated fatty acids on pentylenetetrazol induced seizures in rats. Epilepsia. 2009;50(1):72-82. https://doi.org/10.1111/j.1528-1167.2008.01731.xPMid:18657173 Du XM, Sun NY, Takizawa N, Guo YT, Shoyama Y. Sedative and anticonvulsant activities of goodyerin, a flavonol glycoside from Goodyera schlechtendaliana. Phytother Res. 2002;16(3):261-3. https://doi.org/10.1002/ptr.862PMid:12164273 Liu Z, Lindemeyer AK, Liang J, Wallner M, Shao XM, Shao Y et al. Flavonoids isolated from Tibetan medicines, binding to GABAA receptor and the anticonvulsant activity. Phytomed. 2018;50:1-7. https://doi.org/10.1016/j.phymed.2018.09.198PMid:30466968 Patel NB. Physiology of pain. Guide to pain management in low-resource settings. IASP; 2010. p. 13. Council NR. Recognition and alleviation of pain in laboratory animals. National Academies Press; 2010. Mills S, Bone K. Principles and practice of phytotherapy. Modern herbal medicine. Churchill Livingstone; 2000. Rahbardar MG, Amin B, Mehri S, Mirnajafi-Zadeh SJ, Hosseinzadeh H. Anti-inflammatory effects of ethanolic extract of Rosmarinus officinalis L. and rosmarinic acid in a rat model of neuropathic pain. Biomed Pharmacother. 2017;86:441-9. https://doi.org/10.1016/j.biopha.2016.12.049PMid:28012923 Kanyal N. The science of ischemic stroke: pathophysiology & pharmacological treatment. Int J Pharma Res Rev. 2015;4:65-84. Safaeian L, Tameh AA, Ghannadi A, Naghani EA, Tavazoei H, Alavi SS. Protective effects of Echium amoenum Fisch. and CA Mey. against cerebral ischemia in the rats. Adv Biomed Res. 2015;4. Behnammanesh G. Evaluation of Neuroprotective Properties of Ecchium Amoenum L. Ethanolic Extract: Universiti Sains Malaysia; 2015. Rudy CC, Hunsberger HC, Weitzner DS, Reed MN. The role of the tripartite glutamatergic synapse in the pathophysiology of Alzheimer's disease. Aging Dis. 2015;6(2):131-48. https://doi.org/10.14336/AD.2014.0423PMid:25821641 PMCid:PMC4365957 Morales I, Guzmán-MartÃnez L, Cerda-Troncoso C, FarÃas GA, Maccioni RB. Neuroinflammation in the pathogenesis of Alzheimer's disease. A rational framework for the search of novel therapeutic approaches. Front Cell Neurosci. 2014;8:112. doi:10.3389/fncel.2014.00112. https://doi.org/10.3389/fncel.2014.00112 Farajdokht F, Amani M, Bavil FM, Alihemmati A, Mohaddes G, Babri S. Troxerutin protects hippocampal neurons against amyloid beta-induced oxidative stress and apoptosis. EXCLI J. 2017;16:1081. Hampel H, Mesulam M-M, Cuello AC, Farlow MR, Giacobini E, Grossberg GT et al. The cholinergic system in the pathophysiology and treatment of Alzheimer's disease. Brain. 2018;141(7):1917-33. https://doi.org/10.1093/brain/awy132PMid:29850777 PMCid:PMC6022632 Sadigh-Eteghad S, Sabermarouf B, Majdi A, Talebi M, Farhoudi M, Mahmoudi J. Amyloid-beta: a crucial factor in Alzheimer's disease. Med Princ Pract. 2015;24(1):1-10. https://doi.org/10.1159/000369101PMid:25471398 PMCid:PMC5588216 Wang X, Wang W, Li L, Perry G, Lee H-g, Zhu X. Oxidative stress and mitochondrial dysfunction in Alzheimer's disease. Biochim Biophys Acta. 2014;1842(8):1240-7. https://doi.org/10.1016/j.bbadis.2013.10.015PMid:24189435 PMCid:PMC4007397 http://dx.doi.org/10.1016/j.nbd.2015.06.013https://doi.org/10.1016/j.nbd.2015.06.013PMid:26102023 PMCid:PMC4684986 https://doi.org/10.1016/j.bbadis.2009.10.006https://doi.org/10.1016/j.bbadis.2009.10.006PMid:19853658 Orhan IE, Senol FS, Ercetin T, Kahraman A, Celep F, Akaydin G et al. Assessment of anticholinesterase and antioxidant properties of selected sage (Salvia) species with their total phenol and flavonoid contents. Ind Crops Prod. 2013;41:21-30. https://doi.org/10.1016/j.indcrop.2012.04.002 Bahadori MB, Asghari B, Dinparast L, Zengin G, Sarikurkcu C, Abbas-Mohammadi M et al. Salvia nemorosa L.: A novel source of bioactive agents with functional connections. Food Sci Technol. 2017;75:42-50. https://doi.org/10.1016/j.lwt.2016.08.048 Rahimi F, Sadigh-Eteghad S, Dehnad A, Mahmoudi J, Baradaran L. The effects of Rosa canina fruit hydro alcoholic extract on oxidative stress, total antioxidant capacity and haematological parameters in diabetic mice. J Kerman Uni Med Sci. 2017;24(2):132-40. Barnes J, Anderson LA, Phillipson JD. Herbal medicines. vol 3rd Edition. Pharmaceutical Press; 2007. Zahedi MJ, Heidari M, Mohajeri M. Study the effect of Valeriana Officinalis and Echium Amoenum on the liver and renal function tests in rats. J Kerman Uni Med Sci. 2004;10(1):22-7. Etebari M, Zolfaghari B, Jafarian-Dehkordi A, Rakian R. Evaluation of DNA damage of hydro-alcoholic and aqueous extract of Echium amoenum and Nardostachys jatamansi. J Res Med Sci. 2012;17(8):782. Mehrabani M, Ghannadi A, Sajjadi E, Ghassemi N, Shams-Ardakani M. Toxic pyrrolizidine alkaloids of echium amoenum fisch. & mey. . Daru. 2006;14(3):122-7. Timothy S, Richard L. Herbal products, toxicology and clinical pharmacology. New Jersey: Humana Press; 2007. Mehrabani M, Mehrabani M. Evaluation of Hepatotoxicity of Common Doses of Decoction of Echium Amoenum Fisch and CA Mey in Rats. J Kerman Uni Med Sci. 2014(1). Zamansoltani F, Nassiri-Asl M, Karimi R, Mamaghani-Rad P. Hepatotoxicity effects of aqueous extract of Echium amoenum in rats. Pharmacologyonline. 2008;1:432-8.