Download PDF
Planta Med 2020; 86(06): 434-441
DOI: 10.1055/a-1107-9337
Biological and Pharmacological Activity
Original Papers
Georg Thieme Verlag KG Stuttgart · New York

11-Keto-β-Boswellic Acid Attenuates Glutamate Release and Kainic Acid-Induced Excitotoxicity in the Rat Hippocampus

Cheng Wei Lu
1   Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City, Taiwan
3   Department of Mechanical Engineering, Yuan Ze University, Taoyuan City, Taiwan
,
Tzu Yu Lin
1   Department of Anesthesiology, Far-Eastern Memorial Hospital, New Taipei City, Taiwan
3   Department of Mechanical Engineering, Yuan Ze University, Taoyuan City, Taiwan
,
Su Jane Wang
2   School of Medicine, Fu Jen Catholic University, New Taipei City, Taiwan
4   Research Center for Chinese Herbal Medicine, College of Human Ecology, Chang Gung University of Science and Technology, Taoyuan City, Taiwan
› Author AffiliationsSupported by: the Ministry of Science and Technology Taiwan MOST 107-2314-B-418-005; MOST 106-2320-B-030-002
Further Information

Publication History

received 29 October 2019
revised 20 January 2020

accepted 28 January 2020

Publication Date:
25 February 2020 (online)

Also available at
    Permissions and Reprints

Abstract

Excessive glutamate concentration induces neuronal death in acute brain injuries and chronic neurodegenerative diseases. Natural compounds from medicinal plants have attracted considerable attention for their use in the prevention and treatment of neurological disorders. 11-Keto-β-boswellic acid, a triterpenoid found in the medicinal plant Boswellia serrata, has neuroprotective potential. The present study investigated the effect of 11-keto-β-boswellic acid on glutamate release in vitro and kainic acid-induced glutamate excitotoxicity in vivo in the rat hippocampus. In rat hippocampal nerve terminals (synaptosomes), 11-keto-β-boswellic acid dose-dependently inhibited 4-aminopyridine-stimulated glutamate release. This effect was dependent on extracellular calcium, persisted in the presence of the glutamate transporter inhibitor DL-threo-β-benzyloxyaspartate, and was blocked by the vesicular transporter inhibitor bafilomycin A1. In addition, 11-keto-β-boswellic acid reduced the 4-aminopyridine-induced increase in intrasynaptosomal Ca2+ levels. The N- and P/Q-type channel blocker ω-conotoxin MVIIC and the protein kinase A inhibitor H89 significantly suppressed the 11-keto-β-boswellic acid-mediated inhibition of glutamate release, whereas the intracellular Ca2+-releasing inhibitors dantrolene, CGP37157, and xestospongin C, mitogen-activated protein kinase inhibitor PD98059, as well as protein kinase C inhibitor calphostin C had no effect. In a rat model of excitotoxicity induced by intraperitoneal kainic acid injection (15 mg/kg), intraperitoneal 11-keto-β-boswellic acid administration (10 or 50 mg/kg) 30 min before kainic acid injection considerably ameliorated kainic acid-induced glutamate concentration elevation and CA3 neuronal death. These data suggested that 11-keto-β-boswellic acid inhibits glutamate release from the rat hippocampal synaptosomes by suppressing N- and P/Q-type Ca2+ channels and protein kinase A activity, as well as exerts protective effects against kainic acid-induced excitotoxicity in vivo.

Key words

Burseraceae - Boswellia serrata - KBA - presynaptic glutamate release - kainic acid - neuroprotection - hippocampus
 

  • References

  • 1 Zhou Y, Danbolt NC. Glutamate as a neurotransmitter in the healthy brain. J Neural Transm 2014; 121: 799-817
    CrossrefPubMedSearch in Google Scholar
  • 2 Bano D, Ankarcrona M. Beyond the critical point: an overview of excitotoxicity, calcium overload and the downstream consequences. Neurosci Lett 2018; 663: 79-85
    CrossrefPubMedSearch in Google Scholar
  • 3 Choi DW. Glutamate neurotoxicity and diseases of the nervous system. Neuron 1988; 1: 623-634
    CrossrefPubMedSearch in Google Scholar
  • 4 Lewerenz J, Maher P. Chronic glutamate toxicity in neurodegenerative diseases – What is the evidence?. Front Neurosci 2015; 9: 469
    CrossrefPubMedSearch in Google Scholar
  • 5 Danysz W, Parsons CG. Glycine and N-methyl-D-aspartate receptors: physiological significance and possible therapeutic applications. Pharmacol Rev 1998; 50: 597-664
    PubMedSearch in Google Scholar
  • 6 Ikonomidou C, Turski L. Why did NMDA receptor antagonists fail clinical trials for stroke and traumatic brain injury?. Lancet Neurol 2002; 1: 383-386
    CrossrefPubMedSearch in Google Scholar
  • 7 Wu PF, Zhang Z, Wang F, Chen JG. Natural compounds from traditional medicinal herbs in the treatment of cerebral ischemia/reperfusion injury. Acta Pharmacol Sin 2010; 31: 1523-1531
    CrossrefPubMedSearch in Google Scholar
  • 8 Kim MH, Kim SH, Yang WM. Mechanisms of action of phytochemicals from medicinal herbs in the treatment of Alzheimerʼs disease. Planta Med 2014; 80: 1249-1258
    Thieme ConnectPubMedSearch in Google Scholar
  • 9 Russo P, Frustaci A, Del Bufalo A, Fini M, Cesario A. From traditional European medicine to discovery of new drug candidates for the treatment of dementia and Alzheimerʼs disease: acetylcholinesterase inhibitors. Curr Med Chem 2013; 20: 976-983
    PubMedSearch in Google Scholar
  • 10 Siddiqui M. Boswellia serrata, a potential antiinflammatory agent: an overview. Indian J Pharm Sci 2011; 73: 255
    PubMedSearch in Google Scholar
  • 11 Abdel-Tawab M, Werz O, Schubert-Zsilavecz M. Boswellia serrata: an overall assessment of in vitro, preclinical, pharmacokinetic and clinical data. Clin Pharmacokinet 2011; 50: 349-369
    CrossrefPubMedSearch in Google Scholar
  • 12 Ammon HP. Boswellic acids in chronic inflammatory diseases. Planta Med 2006; 72: 1100-1116
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Beghelli D, Isani G, Roncada P, Andreani G, Bistoni O, Bertocchi M, Lupidi G, Alunno A. Antioxidant and Ex vivo immune system regulatory properties of Boswellia serrata extracts. Oxid Med Cell Longev 2017; 2017: 7468064
    PubMedSearch in Google Scholar
  • 14 Roy NK, Parama D, Banik K, Bordoloi D, Devi AK, Thakur KK, Padmavathi G, Shakibaei M, Fan L, Sethi G, Kunnumakkara AB. An update on pharmacological potential of boswellic acids against chronic diseases. Int J Mol Sci 2019; 20: 4101
    CrossrefPubMedSearch in Google Scholar
  • 15 Rajabian A, Boroushaki MT, Hayatdavoudi P, Sadeghnia HR. Boswellia serrata protects against glutamate-induced oxidative stress and apoptosis in PC12 and N2a cells. DNA Cell Biol 2016; 35: 666-679
    CrossrefPubMedSearch in Google Scholar
  • 16 Sadeghnia HR, Arjmand F, Ghorbani A. Neuroprotective effect of Boswellia serrata and its active constituent acetyl 11-keto-β-boswellic acid against oxygen-glucose-serum deprivation-induced cell injury. Acta Pol Pharm 2017; 74: 911-920
    PubMedSearch in Google Scholar
  • 17 Ding Y, Chen M, Wang M, Wang M, Zhang T, Park J, Zhu Y, Guo C, Jia Y, Li Y, Wen A. Neuroprotection by acetyl-11-keto-β-Boswellic acid, in ischemic brain injury involves the Nrf2/HO-1 defense pathway. Sci Rep 2014; 4: 7002
    PubMedSearch in Google Scholar
  • 18 Forouzanfar F, Hosseinzadeh H, Ebrahimzadeh Bideskan A, Sadeghnia HR. Aqueous and ethanolic extracts of Boswellia serrata protect against focal cerebral ischemia and reperfusion injury in rats. Phytother Res 2016; 30: 1954-1967
    CrossrefPubMedSearch in Google Scholar
  • 19 Doaee P, Rajaei Z, Roghani M, Alaei H, Kamalinejad M. Effects of Boswellia serrata resin extract on motor dysfunction and brain oxidative stress in an experimental model of Parkinsonʼs disease. Avicenna J Phytomed 2019; 9: 281-290
    PubMedSearch in Google Scholar
  • 20 Gomaa AA, Makboul RM, Al-Mokhtar MA, Nicola MA. Polyphenol-rich Boswellia serrata gum prevents cognitive impairment and insulin resistance of diabetic rats through inhibition of GSK3β activity, oxidative stress and pro-inflammatory cytokines. Biomed Pharmacother 2019; 109: 281-292
    CrossrefPubMedSearch in Google Scholar
  • 21 Hosseini-Sharifabad M, Kamali-Ardakani R, Hosseini-Sharifabad A. Beneficial effect of Boswellia serrata gum resin on spatial learning and the dendritic tree of dentate gyrus granule cells in aged rats. Avicenna J Phytomed 2016; 6: 189-197
    PubMedSearch in Google Scholar
  • 22 Reising K, Meins J, Bastian B, Eckert G, Mueller WE, Schubert-Zsilavecz M, Abdel-Tawab M. Determination of boswellic acids in brain and plasma by high-performance liquid chromatography/tandem mass spectrometry. Anal Chem 2005; 77: 6640-6645
    CrossrefPubMedSearch in Google Scholar
  • 23 Ding Y, Chen M, Wang M, Li Y, Wen A. Posttreatment with 11-keto-β-boswellic acid ameliorates cerebral ischemia-reperfusion injury: Nrf2/HO-1 pathway as a potential mechanism. Mol Neurobiol 2015; 52: 1430-1439
    CrossrefPubMedSearch in Google Scholar
  • 24 Dohare P, Hyzinski-García MC, Vipani A, Bowens NH, Nalwalk JW, Feustel PJ, Keller jr. RW, Jourdʼheuil D, Mongin AA. The neuroprotective properties of the superoxide dismutase mimetic tempol correlate with its ability to reduce pathological glutamate release in a rodent model of stroke. Free Radic Biol Med 2014; 77: 168-182
    CrossrefPubMedSearch in Google Scholar
  • 25 Wong SB, Cheng SJ, Hung WC, Lee WT, Min MY. Rosiglitazone suppresses in vitro seizures in hippocampal slice by inhibiting presynaptic glutamate release in a model of temporal lobe epilepsy. PLoS One 2015; 10: e0144806
    CrossrefPubMedSearch in Google Scholar
  • 26 McMahon HT, Nicholls DG. Transmitter glutamate release from isolated nerve terminals: evidence for biphasic release and triggering by localized Ca2+ . J Neurochem 1991; 56: 86-94
    CrossrefPubMedSearch in Google Scholar
  • 27 Nicholls DG, Sihra TS, Sanchez-Prieto J. Calcium dependent and -independent release of glutamate from synaptosomes monitored by continuous fluorometry. J Neurochem 1987; 49: 50-57
    CrossrefPubMedSearch in Google Scholar
  • 28 Millán C, Sánchez-Prieto J. Differential coupling of N-and P/Q-type calcium channels to glutamate exocytosis in the rat cerebral cortex. Neurosci Lett 2002; 330: 29-32
    CrossrefPubMedSearch in Google Scholar
  • 29 Berridge MJ. Neuronal calcium signaling. Neuron 1998; 21: 13-26
    CrossrefPubMedSearch in Google Scholar
  • 30 Millán C, Torres M, Sánchez-Prieto J. Co-activation of PKA and PKC in cerebrocortical nerve terminals synergistically facilitates glutamate release. J Neurochem 2003; 87: 1101-1111
    CrossrefPubMedSearch in Google Scholar
  • 31 Pereira DB, Carvalho AP, Duarte CB. Non-specific effects of the MEK inhibitors PD98059 and U0126 on glutamate release from hippocampal synaptosomes. Neuropharmacology 2002; 42: 9-19
    CrossrefPubMedSearch in Google Scholar
  • 32 Lin TY, Lu CW, Wang SJ. Luteolin protects the hippocampus against neuron impairments induced by kainic acid in rats. Neurotoxicology 2016; 55: 48-57
    CrossrefPubMedSearch in Google Scholar
  • 33 Chang Y, Lu CW, Chen YJ, Lin TY, Huang SK, Wang SJ. Astaxanthin protects against kainic acid-induced seizures and pathological consequences. Neurochem Int 2018; 116: 85-94
    CrossrefPubMedSearch in Google Scholar
  • 34 Barrie AP, Nicholls DG, Sanchez-Prieto J, Sihra TS. An ion channel locus for the protein kinase C potentiation of transmitter glutamate release from guinea pig cerebrocortical synaptosomes. J Neurochem 1991; 57: 1398-1404
    CrossrefPubMedSearch in Google Scholar
  • 35 Nicholls DG. Presynaptic modulation of glutamate release. Prog Brain Res 1998; 116: 15-22
    PubMedSearch in Google Scholar
  • 36 Andrade-Talavera Y, Duque-Feria P, Negrete-Díaz JV, Sihra TS, Flores G, Rodríguez-Moreno A. Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+-calmodulin at mossy fiber-CA3 synapses. J Neurochem 2012; 122: 891-899
    CrossrefPubMedSearch in Google Scholar
  • 37 Rodríguez-Moreno A, Sihra TS. Presynaptic kainate receptor-mediated facilitation of glutamate release involves Ca2+-calmodulin and PKA in cerebrocortical synaptosomes. FEBS Lett 2013; 587: 788-792
    CrossrefPubMedSearch in Google Scholar
  • 38 Friedman LK, Pellegrini-Giampietro DE, Sperber EF, Bennett M, Moshe SL, Zukin RS. Kainate-induced status epilepticus alters glutamate and GABAA receptor gene expression in adult rat hippocampus: an in situ hybridization study. J Neurosci 1994; 14: 2697-2707
    CrossrefPubMedSearch in Google Scholar
  • 39 Bahn S, Volk B, Widsen W. Kainate receptor gene expression in the developing rat brain. J Neurosci 1994; 14: 5525-5547
    CrossrefPubMedSearch in Google Scholar
  • 40 Śmiałowska M, Gołembiowska K, Kajta M, Zięba B, Dziubina A, Domin H. Selective mGluR1 antagonist EMQMCM inhibits the kainate-induced excitotoxicity in primary neuronal cultures and in the rat hippocampus. Neurotox Res 2012; 21: 379-392
    CrossrefPubMedSearch in Google Scholar
  • 41 Domin H, Zieba B, Golembiowska K, Kowalska M, Dziubina A, Smialowska M. Neuroprotective potential of mGluR5 antagonist MTEP: effects on kainate-induced excitotoxicity in the rat hippocampus. Pharmacol Rep 2010; 62: 1051-1061
    CrossrefPubMedSearch in Google Scholar
  • 42 Lin KC, Wang CC, Wang SJ. Bupropion attenuates kainic acid-induced seizures and neuronal cell death in rat hippocampus. Prog Neuropsychopharmacol Biol Psychiatry 2013; 45: 207-214
    CrossrefPubMedSearch in Google Scholar
  • 43 Chiu KM, Lu CW, Lee MY, Wang MJ, Lin TY, Wang SJ. Neuroprotective and anti-inflammatory effects of lidocaine in kainic acid-injected rats. Neuroreport 2016; 27: 501-507
    CrossrefPubMedSearch in Google Scholar
  • 44 Lu CW, Lin TY, Chang CY, Huang SK, Wang SJ. Ciproxifan, a histamine H3 receptor antagonist and inverse agonist, presynaptically inhibits glutamate release in rat hippocampus. Toxicol Appl Pharmacol 2017; 319: 12-27
    CrossrefPubMedSearch in Google Scholar
  • 45 Nicholls DG, Sihra TS. Synaptosomes possess an exocytotic pool of glutamate. Nature 1986; 321: 772-773
    CrossrefPubMedSearch in Google Scholar
  • 46 Grynkiewicz G, Poenie M, Tsien RY. A new generation of Ca2+ indicators with greatly improved fluorescence properties. J Biol Chem 1985; 260: 3440-3450
    CrossrefPubMedSearch in Google Scholar