Abstract
Salvia splendens is a species of the genus Salvia that is known for its neuro-therapeutic properties. The present study aimed to investigate the effect of two fractions from the methanolic extract of the aerial parts of S. splendens cultivated in Egypt, the petroleum ether-soluble (PES) and n-butanol-soluble (BS) fractions, against AlCl3-induced Alzheimer’s disease (AD) in rats. Rats treated with AlCl3 (100 mg/kg b.wt. p.o.) for 4 weeks developed behavioral, biochemical and histological changes similar to that of AD. Behavioral deficits were assessed by T-maze test and percentage changes in oxidative stress and AD markers in brain. Extent of DNA damage and histopathological changes were also evaluated. Results revealed that both fractions; PES and BS (at dose of 500 mg/kg b.wt), significantly attenuated AlCl3-induced behavioral impairment in rats. This effect was accompanied by acetylcholinesterase (AChE) activity inhibition (53.18% and 68.66%, respectively), and Aβ deposition reduction (33.3% and 34.3%, respectively). Both fractions markedly decreased oxidative stress markers level (lipid peroxide, protein carbonyl, reduced glutathione and nitric oxide), and inhibited catalase and caspase-3 activities. Also, the content of noradrenaline, adrenaline, 5-HT and dopamine were significantly increased. The fractions preserved the histo-architecture pattern of the hippocampus and cortex from the AlCl3-induced damage. Bioactivity-guided fractionation led to the isolation of two sterols; β-sitosterol and β-sitosterolpalmitate from PES fraction, and 6 phenolic compounds (acacetin, chrysoeriol, apigenin, luteolin, rosmarinic acid and caffeic acid) from BS fraction. Rosmarinic acid and caffeic acid significantly inhibited AChE in vitro (IC50 values of 0.398 mg/mL and 0.327 mg/mL, respectively) compared to physostigmine (IC50 0.227 mg/mL). The BS fraction is standardized (HPLC–DAD) to contain not less than 0.0254% (w/w)of rosmarinic acid and 0.0129% (w/w) of caffeic acid. These findings suggest that S. splendens is beneficial in attenuating AlCl3-induced neurotoxicity in rats.
This is a preview of subscription content, log in via an institution to check access.
Similar content being viewed by others
Abbreviations
- ME:
-
Methanolic extract
- PES:
-
Petroleum ether-soluble fraction
- BS:
-
n-Butanol-soluble fraction
- VLC:
-
Vacuum liquid chromatography
- MAO:
-
Monoamine oxidase
- GSH:
-
Glutathione
- HPLC:
-
High pressure liquid chromatography
- ECD:
-
Electrochemical detector
- ESI:
-
Electrospray ionization
- ELISA:
-
Enzyme linked immunosorbent assay
- DAD:
-
Diode array detector
- AChE:
-
Acetylcholinesterase
- AD:
-
Alzheimer’s disease
- CE:
-
Catechin equivalent
- GAE:
-
Gallic acid equivalent
References
Adolfsson R, Gottfries C, Roos B, Winblad B (1979) Changes in the brain catecholamines in patients with dementia of Alzheimer type. Br J Psychiatry 135:216–223
Al-Jubory SY (2013) Lethal dose (LD 50) and acute toxicity, histopathological effects of glycosides extract of Lawsonia inermis (Henna) leaves in mice. J Babylon Univ Pure Appl Sci 21:1093–1099
Alleva E, Rankin J, Santucci D (1998) Neurobehavioral alteration in rodents following developmental exposure to aluminum. Toxicol Ind Health 14:209–221. https://doi.org/10.1177/074823379801400113
Bondy S, Liu D, Guo-Ross S (1998) Aluminum treatment induces nitric oxide synthase in the rat brain. Neurochem Int 33:51–54. https://doi.org/10.1016/S0197-0186(98)00009-6
Chaturvedula VSP, Prakash I (2012) Isolation of Stigmasterol and β-Sitosterol from the dichloromethane extract of Rubus suavissimus. Int Curr Pharm J 1:239–242
Chaurasiya ND et al (2016) Isolation of Acacetin from Calea urticifolia with inhibitory properties against human monoamine oxidase-A and-B. J Nat Prod 79:2538–2544. https://doi.org/10.1021/acs.jnatprod.6b00440
Deacon RM, Rawlins JNP (2006) T-maze alternation in the rodent. Nat Protoc 1:7. https://doi.org/10.1038/nprot.2006.2
Drury R, Wallington E (1980) Preparation and fixation of tissues. In: Carleton HM (ed) Carleton’s histological technique, vol 5, 5th edn. Oxford University Press, Oxford, New York, pp 41–54
Edward F, Teresa H (1999) Salvia splendens. University of Florida, Gainesville, p 528
Eikelenboom P, Van Exel E, Hoozemans JJ, Veerhuis R, Rozemuller AJ, Van Gool WA (2010) Neuroinflammation—an early event in both the history and pathogenesis of Alzheimer’s disease. Neurodegen Dis 7:38–41. https://doi.org/10.1159/000283480
Ellman GL, Courtney KD, Andres V, Featherstone RM (1961) A new and rapid colorimetric determination of acetylcholinesterase activity. Biochem Pharmacol 7:88IN191-9095
Gomes RA, Ramirez RR, Maciel JKdS, Agra MdF, Souza MdFVd, Falcão-Silva VS, Siqueira-Junior JP (2011) Phenolic compounds from Sidastrum micranthum (A. St.-Hil.) fryxell and evaluation of acacetin and 7, 4′-Di-O-methylisoscutellarein as motulator of bacterial drug resistence. Quim Nova 34:1385–1388. https://doi.org/10.1590/S0100-40422011000800016
Ha SK, Moon E, Lee P, Ryu JH, Oh MS, Kim SY (2012) Acacetin attenuates neuroinflammation via regulation the response to LPS stimuli in vitro and in vivo. Neurochem Res 37:1560–1567. https://doi.org/10.1007/s11064-012-0751-z
Iuvone T, De Filippis D, Esposito G, D’Amico A, Izzo AA (2006) The spice sage and its active ingredient rosmarinic acid protect PC12 cells from amyloid-β peptide-induced neurotoxicity. J Pharmacol Exp Ther 317:1143–1149. https://doi.org/10.1124/jpet.105.099317
Jeong C-H, Jeong HR, Choi GN, Kim D-O, Lee U, Heo HJ (2011) Neuroprotective and anti-oxidant effects of caffeic acid isolated from Erigeron annuus leaf. Chin Med 6:25. https://doi.org/10.1186/1749-8546-6-25
Julka D, Gill KD (1996) Altered calcium homeostasis: a possible mechanism of aluminium-induced neurotoxicity. Biochim Biophys Acta (BBA)-Mol Basis Dis 1315:47–54. https://doi.org/10.1016/0925-4439(95)00100-x
Katyal R, Desigan B, Sodhi CP, Ojha S (1997) Oral aluminum administration and oxidative injury. Biol Trace Elem Res 57:125–130. https://doi.org/10.1007/BF02778195
Kumar V, Bal A, Gill KD (2009) Aluminium-induced oxidative DNA damage recognition and cell-cycle disruption in different regions of rat brain. Toxicology 264:137–144. https://doi.org/10.1016/j.tox.2009.05.011
Kumar A, Prakash A, Dogra S (2011) Neuroprotective effect of carvedilol against aluminium induced toxicity: possible behavioral and biochemical alterations in rats. Pharmacol Rep 63:915–923
Lee TS et al (2011) BglBrick vectors and datasheets: a synthetic biology platform for gene expression. J Biol Eng 5:12. https://doi.org/10.1186/1754-1611-5-12
Lin L-C, Pai Y-F, Tsai T-H (2015) Isolation of luteolin and luteolin-7-O-glucoside from Dendranthema morifolium Ramat Tzvel and their pharmacokinetics in rats. J Agric Food Chem 63:7700–7706. https://doi.org/10.1021/jf505848z
Lowell C (1997) Salvia splendens-scarlet sage Flower seed trials: Michigan state trials. Michigan State University, East Lansing
Lu Y, Foo LY (1999) Rosmarinic acid derivatives from Salvia officinalis. Phytochemistry 51:91–94. https://doi.org/10.1016/S0031-9422(98)00730-4
Lucca G et al (2009) Effects of chronic mild stress on the oxidative parameters in the rat brain. Neurochem Int 54:358–362. https://doi.org/10.1016/j.neuint.2009.01.001
Marinova D, Ribarova F, Atanassova M (2005) Total phenolics and total flavonoids in Bulgarian fruits and vegetables. J Univ Chem Technol Metall 40:255–260
McDermott JR, Smith AI, Iqbal K, Wisniewski HM (1979) Brain aluminum in aging and Alzheimer disease. Neurology 29:809–814
Moharram FA, Marzouk MS, El-Shenawy SM, Gaara AH, El Kady WM (2012) Polyphenolic profile and biological activity of Salvia splendens leaves. J Pharm Pharmacol 64:1678–1687
Novak E (1999) Method of preventing and delaying onset of Alzheimer’s disease and composition therefor, US Patent 5,985,936. Forbes Medi-Tech, Inc
Park Y, Moon BH, Yang H, Lee Y, Lee E, Lim Y (2007) Complete assignments of NMR data of 13 hydroxymethoxy flavones. Magn Reson Chem 45:1072–1075. https://doi.org/10.1002/mrc.2063
Peters A (2002) The effects of normal aging on myelin and nerve fibers: a review. J Neurocytol 31:581–593. https://doi.org/10.1023/A:1025731309829
Praticò D, Uryu K, Sung S, Tang S, Trojanowski JQ, Lee VM-Y (2002) Aluminum modulates brain amyloidosis through oxidative stress in APP transgenic mice. FASEB J 16:1138–1140. https://doi.org/10.1096/fj.02-0012fje
Ravi S, Prabhu B, Raju T, Bindu P (2000) Long-term effects of postnatal aluminium exposure on acetylcholinesterase activity and biogenic amine neurotransmitters in rat brain. Indian J Physiol Pharmacol 44:473–478
Rezai-Zadeh K, Ehrhart J, Bai Y, Sanberg PR, Bickford P, Tan J, Shytle RD (2008) Apigenin and luteolin modulate microglial activation via inhibition of STAT1-induced CD40 expression. J Neuroinflamm 5:41. https://doi.org/10.1186/1742-2094-5-41
Shati A, Elsaid F, Hafez E (2011) Biochemical and molecular aspects of aluminium chloride-induced neurotoxicity in mice and the protective role of Crocus sativus L. extraction and honey syrup. Neuroscience 175:66–74. https://doi.org/10.1016/j.neuroscience.2010.11.043
Singh NP, McCoy MT, Tice RR, Schneider EL (1988) A simple technique for quantitation of low levels of DNA damage in individual cells. Exp Cell Res 175:184–191
Sonkusare S, Kaul C, Ramarao P (2005) Dementia of Alzheimer’s disease and other neurodegenerative disorders—memantine, a new hope. Pharmacol Res 51:1–17. https://doi.org/10.1016/j.phrs.2004.05.005
Sul D, Kim H-S, Lee D, Joo SS, Hwang KW, Park S-Y (2009) Protective effect of caffeic acid against beta-amyloid-induced neurotoxicity by the inhibition of calcium influx and tau phosphorylation. Life Sci 84:257–262. https://doi.org/10.1016/j.lfs.2008.12.001
Sumathi T, Shobana C, Mahalakshmi V, Sureka R, Subathra M, Vishali A, Rekha K (2013) Oxidative stress in brains of male rats intoxicated with aluminium and neuromodulating effect of Celastrus paniculatus alcoholic seed extract. Asian J Pharm Clin Res 6:80–90
Sun H, Zhang J, Ye Y, Pan Y, Shen Y (2003) Cytotoxic pentacyclic triterpenoids from the rhizome of Astilbe chinensis. Helv Chim Acta 86:2414–2423. https://doi.org/10.1002/hlca.200390194
Van Loo P, De Bruyn A, Buděšínský M (1986) Reinvestigation of the structural assignment of signals in the 1H and 13C NMR spectra of the flavone apigenin. Magn Res Chem 24:879–882. https://doi.org/10.1002/mrc.1260241007
Vladimir-Knežević S, Blažeković B, Kindl M, Vladić J, Lower-Nedza AD, Brantner AH (2014) Acetylcholinesterase inhibitory, antioxidant and phytochemical properties of selected medicinal plants of the Lamiaceae family. Molecules 19:767–782. https://doi.org/10.3390/molecules19010767
Wang X, Perumalsamy H, Kwon HW, Na Y-E, Ahn Y-J (2015) Effects and possible mechanisms of action of acacetin on the behavior and eye morphology of Drosophila models of Alzheimer’s disease. Sci Rep 5:16127. https://doi.org/10.1038/srep16127
Yassin N, El-Shenawy S, Mahdy KA, Gouda N, Marrie A, Farrag A, Ibrahim BM (2013) Effect of Boswellia serrata on Alzheimer’s disease induced in rats. J Arab Soc Med Res 8:1–11. https://doi.org/10.7123/01.JASMR.0000429323.25743.cc
Yokel RA (2000) The toxicology of aluminum in the brain: a review. Neurotoxicology 21:813–828
Zagrodzka J, Romaniuk A, Wieczorek M, Boguszewski P (2000) Bicuculline administration into ventromedial hypothalamus: effects on fear and regional brain monoamines and GABA concentrations in rats. Acta Neurobiol Exp 60:333–344
Zhao L, Wang J-l, Wang Y-r, Fa X-z (2013) Apigenin attenuates copper-mediated β-amyloid neurotoxicity through antioxidation, mitochondrion protection and MAPK signal inactivation in an AD cell model. Brain Res 1492:33–45. https://doi.org/10.1016/j.brainres.2012.11.019
Zhu X, Raina AK, Lee H-g, Casadesus G, Smith MA, Perry G (2004) Oxidative stress signalling in Alzheimer’s disease. Brain Res 1000:32–39. https://doi.org/10.1016/j.brainres.2004.01.012
Zusterzeel PL, Visser W, Peters WH, Merkus HW, Nelen WL, Steegers EA (2000) Polymorphism in the glutathione S-transferase P1 gene and risk for preeclampsia. Obstet Gynecol 96:50–54. https://doi.org/10.1016/S0029-7844(00)00845-0
Acknowledgements
This work was supported by the National Research Centre (NRC), Egypt [Grant No. 12/5/2].
Author information
Authors and Affiliations
Corresponding author
Ethics declarations
Ethical statement
All procedures and handling of animals were performed in accordance with the ethical guidelines of Medical Ethical Committee of National Research Centre in Egypt (Approval No. 15122).
Conflict of interest
Salma Ahmed El Sawi has no conflict of interest. Shahira Mohamed Ezzat has no conflict of interest. Hanan Farouk Aly has no conflict of interest. Rana Merghany Merghany has no conflict of interest. Meselhy Ragab Meselhy has no conflict of interest.
Additional information
Publisher's Note
Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Electronic supplementary material
Below is the link to the electronic supplementary material.
Rights and permissions
About this article
Cite this article
El-Sawi, S.A., Ezzat, S.M., Aly, H.F. et al. Neuroprotective effect of Salvia splendens extract and its constituents against AlCl3-induced Alzheimer’s disease in rats. ADV TRADIT MED (ADTM) 20, 381–393 (2020). https://doi.org/10.1007/s13596-019-00421-w
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1007/s13596-019-00421-w