Glutamate Toxicity to Differentiated Neuroblastoma N2a Cells Is Prevented by the Sesquiterpene Lactone Achillolide A and the Flavonoid 3,5,4′-Trihydroxy-6,7,3′-Trimethoxyflavone from Achillea fragrantissima
Glutamate toxicity is a major contributor to the pathophysiology of numerous neurodegenerative diseases including amyotrophic lateral sclerosis and Alzheimer’s disease. Therefore, protecting neuronal cells against glutamate-induced cytotoxicity might be an effective approach for the treatment of these diseases. We have previously purified from the medicinal plant Achillea fragrantissima two bioactive compounds which were not studied before: the sesquiterpene lactone achillolide A and the flavonoid 3,5,4′-trihydroxy-6,7,3′-trimethoxyflavone (TTF). We have shown that these compounds protect astrocytes from oxidative stress-induced cell death and inhibit microglial activation. The current study examined for the first time their effects on differentiated mouse neuroblastoma N2a cells and on glutamate toxicity. We have found that, although these compounds belong to different chemical families, they protect neuronal cells from glutamate toxicity. We further demonstrate that this protective effect might be, at least partially, due to inhibitory effects of these compounds on the levels of reactive oxygen species produced following treatment with glutamate.
This is a preview of subscription content, log in to check access.
This research was supported by research grant no. IS-4473-11 from BARD, the US–Israel Binational Agricultural Research and Development Fund. The authors wish to thank Yardena Abudi (TAU), Miriam Rindner (ARO), and Sigrid Penno-Winters (Arava-Dead Sea Science Center) for their technical assistance. This is publication 773/17 from the Agricultural Research Organization.
Compliance with Ethical Standards
Conflict of Interest
The authors declare that they have no conflict of interest.
Afanas’ev IB, Dorozhko AI, Brodskii AV, Kostyuk VA, Potapovitch AI (1989) Chelating and free radical scavenging mechanisms of inhibitory action of rutin and quercetin in lipid peroxidation. Biochem Pharmacol 38:1763–1769CrossRefPubMedGoogle Scholar
Albright TD, Jessell TM, Kandel ER, Posner MI (2000) Neural science: a century of progress and the mysteries that remain. Cell 100(Suppl):S1–55CrossRefPubMedGoogle Scholar
Chen J, Chua KW, Chua CC, Yu HL, Pei AJ, Chua BHL, Hamdy RC, Xu XS, Liu CF (2011) Antioxidant activity of 7,8-dihydroxyflavone provides neuroprotection against glutamate-induced toxicity. Neurosci Lett 499:181–185CrossRefPubMedGoogle Scholar
Choi EM, Kim GH, Lee YS (2009) Protective effects of dehydrocostus lactone against hydrogen peroxide-induced dysfunction and oxidative stress in osteoblastic MC3T3-E1 cells. Toxicol in Vitro 23:862–867CrossRefPubMedGoogle Scholar
Eissa TAF, Palomino OM, Carretero ME, Gomez-Serranillos MP (2014) Ethnopharmacological study of medicinal plants used in the treatment of CNS disorders in Sinai Peninsula, Egypt. J Ethnopharmacol 151:317–332CrossRefPubMedGoogle Scholar
Elmann A, Mordechay S, Erlank H, Telerman A, Rindner M, Ofir R (2011a) Anti-neuroinflammatory effects of the extract of Achillea fragrantissima. BMC Complement Altern Med 11:98CrossRefPubMedPubMedCentralGoogle Scholar
Elmann A, Telerman A, Mordechay S, Erlank H, Rindner M, Ofir , Beit-Yannai, E. (2011b). Extract of Achillea fragrantissima downregulates ROS production and protects astrocytes from oxidative-stress-induced cell death. In: Chang R C-C (ed) Neurodegenerative diseases—processes, prevention, protection and monitoringGoogle Scholar
Elmann A, Telerman A, Mordechay S, Erlank H, Rindner M, Ofir R, Kashman Y (2014) 3,5,4′-Trihydroxy-6,7,3′-trimethoxyflavone protects astrocytes against oxidative stress via interference with cell signaling and by reducing the levels of intracellular reactive oxygen species. Neurochem Int 78:67–75CrossRefPubMedGoogle Scholar
Elmann A, Telerman A, Mordechay S, Erlank H, Rindner M, Kashman Y, Ofir R (2015) Downregulation of microglial activation by achillolide A. Planta Med 81:215–221CrossRefPubMedGoogle Scholar
Elmann A, Telerman A, Erlank H, Ofir R, Kashman Y, Beit-Yannai E (2016) Achillolide A protects astrocytes against oxidative stress by reducing intracellular reactive oxygen species and interfering with cell signaling. Molecules 2016(21):301. doi:10.3390/molecules21030301CrossRefGoogle Scholar
Gach K, Dlugosz A, Janecka A (2015) The role of oxidative stress in anticancer activity of sesquiterpene lactones. Naunyn Schmiedeberg’s Arch Pharmacol 388:477–486CrossRefGoogle Scholar
Hamdan I, Afifi FU (2004) Studies on the in vitro and in vivo hypoglycemic activities of some medicinal plants used in treatment of diabetes in Jordanian traditional medicine. J Ethnopharmacol 93:117–121CrossRefPubMedGoogle Scholar
Kim SK, Cho SB, Moon HI (2010) Neuroprotective effects of a sesquiterpene lactone and flavanones from Paulownia tomentosa Steud. against glutamate-induced neurotoxicity in primary cultured rat cortical cells. Phytother Res 24:1898–1900CrossRefPubMedGoogle Scholar
Lee KY, Hwang L, Jeong EJ, Kim SH, Kim YC, Sung SH (2010) Effect of neuroprotective flavonoids of Agrimonia eupatoria on glutamate-induced oxidative injury to HT22 hippocampal cells. Biosci Biotechnol Biochem 74:1704–1706CrossRefPubMedGoogle Scholar
Mandour MA, Al-Shami SA, Al-Eknah MM, Hussein YA, El-Ashmawy IM (2013) The acute and long-term safety evaluation of aqueous, methanolic and ethanolic extracts of Achillea fragrantissima. Afr J Pharm Pharmacol 7:2282–2290CrossRefGoogle Scholar
Merfort I (2011) Perspectives on sesquiterpene lactones in inflammation and cancer. Curr Drug Targets 12:1560–1573CrossRefPubMedGoogle Scholar
Mustafa EH, Abu Zarga M, Abdalla S (1992) Effects of cirsiliol, a flavone isolated from Achillea fragrantissima, on rat isolated ileum. Gen Pharmacol 23:555–560CrossRefPubMedGoogle Scholar
Segal R, Dor A (1987) The sesquiterpene lactones from achillea fragrantissima, I. Achillolide A and B, two novel germacranolides. Tetrahedron 43:4125–4132CrossRefGoogle Scholar
Serafini M, Peluso I, Raguzzini A (2010) Session 1: antioxidants and the immune system flavonoids as anti-inflammatory agents. Proc Nutr Soc 69:273–278CrossRefPubMedGoogle Scholar
Shimmyo Y, Kihara T, Akaike A, Niidome T, Sugimoto H (2008) Three distinct neuroprotective functions of myricetin against glutamate-induced neuronal cell death: involvement of direct inhibition of caspase-3. J Neurosci Res 86:1836–1845CrossRefPubMedGoogle Scholar
Song JX, Sze SC, Ng TB, Lee CK, Leung GP, Shaw PC, Tong Y, Zhang YB (2012) Anti-Parkinsonian drug discovery from herbal medicines: what have we got from neurotoxic models? J Ethnopharmacol 139:698–711CrossRefPubMedGoogle Scholar
Vergun O, Sobolevsky AI, Yelshansky MV, Keelan J, Khodorov BI, Duchen MR (2001) Exploration of the role of reactive oxygen species in glutamate neurotoxicity in rat hippocampal neurones in culture. J Physiol 531:147–163CrossRefPubMedPubMedCentralGoogle Scholar
Wang YP, Wang ZF, Zhang YC, Tian Q, Wang JZ (2004) Effect of amyloid peptides on serum withdrawal-induced cell differentiation and cell viability. Cell Res 14:467–472CrossRefPubMedGoogle Scholar
Williams RJ, Spencer JP (2012) Flavonoids, cognition, and dementia: actions, mechanisms, and potential therapeutic utility for Alzheimer disease. Free Radic Biol Med 52:35–45CrossRefPubMedGoogle Scholar
Youdim KA, Qaiser MZ, Begley DJ, Rice-Evans CA, Abbott NJ (2004) Flavonoid permeability across an in situ model of the blood-brain barrier. Free Radic Biol Med 36:592–604CrossRefPubMedGoogle Scholar