Protective Effect of β-Caryophyllene, a Natural Bicyclic Sesquiterpene, Against Cerebral Ischemic Injury

다국어 초록 (Multilingual Abstract)

β-Caryophyllene (trans-4,11,11-trimethyl-8-methylenebicyclo[7,2,0]undec-4-ene), found in various plants, is a natural bicyclic sesquiterpene with a low toxicity. Here, we show that a single intraperitoneal injection of β-caryophyllene (10 mg/kg) significantly reduced the cortical infarct volume by 67% when given immediately before middle cerebral artery occlusion (MCAO). Neurological deficits caused by MCAO were also significantly decreased by β-caryophyllene. β-Caryophyllene treatment of cortical cells exposed to oxygen–glucose deprivation revealed a significant protection in a dosedependent manner. However, β-caryophyllene neither suppressed N-methyl-d-aspartate excitotoxicity in cultured cortical cells nor markedly decreased the oxidative stress measured in the cellular or acellular systems. By contrast, treatments with bcaryophyllene dose-dependently inhibited mRNA expression of inducible nitric oxide synthetase, interleukin (IL)-1b, IL-6, and cyclooxygenase 2 in C6 microglial cells, and decreased the level of nitric oxide and prostaglandin E2 at a 100 lM concentration. All of these findings suggest that β-caryophyllene has a potent neuroprotective activity, and its neuroprotection may be partly related to the modulation of inflammatory mediators.

참고문헌 (Reference)

1 LaVoie EJ, "Toxicity studies on clove cigarette smoke and constituents of clove: determination of the LD50 of eugenol by intratracheal instillation in rats and hamsters" 59 : 78-81, 1986

2 Baricevic D, "Topical anti-inflammatory activity of Salvia officinalis L. leaves: the relevance of ursolic acid" 75 : 125-132, 2001

3 DeGraba TJ, "The role of inflammation after acute stroke: utility of pursuing anti-adhesion molecule therapy" 51 : 62-68, 1998

4 Marcocci L, "The nitric oxide-scavenging properties of Ginkgo biloba extract EGB 761" 201 : 748-755, 1994

5 Ikeda Y, "The molecular basis of brain injury and brain edema: the role of oxygen free radicals" 27 : 1-11, 1990

6 Wang Q, "The inflammatory response in stroke" 184 : 53-68, 2007

7 Yavuz O, "The effect of 2-chloro adenosine on lipid peroxide level during experimental cerebral ischemia-reperfusion in gerbils" 22 : 337-341, 1997

8 Halliwell B, "The deoxyribose method: a simple ‘‘test tube’’ assay for determination of rate constants for reactions of hydroxyl radicals" 26 : 215-219, 1987

9 Aruoma OI, "The antioxidant action of N-acetyl cysteine: its reaction with hydrogen peroxide, hydroxyl radical, superoxide and hypochlorous acid" 6 : 593-597, 1989

10 Abe K, "Strong attenuation of ischemic and postischemic brain edema in rats by a novel free radical scavenger" 19 : 480-485, 1988

11 Cornwell PA, "Sesquiterpene components of volatile oils as skin penetration enhancers for the hydrophilic permeant 5- fluorouracil" 46 : 261-269, 1994

12 Kim JM, "S-Allyl-Lcysteine attenuates cerebral ischemic injury by scavenging peroxynitrite and inhibiting the activity of extracellular signalregulated kinase" 40 : 827-835, 2006

13 Ischiropoulos H, "Reactive species in ischemic rat lung injury: Contribution of peroxynitrite" 269 : L158-L164, 1995

14 Chang HJ, "Quantitative structure-activity relationship (QSAR) for neuroprotective activity of terpenoids" 80 : 835-841, 2007

15 Carney JM, "Protection against oxidative damage to CNS by a-phenyl-tert-butyl nitrone (PBN) and other spintrapping agents: A novel series of nonlipid free radical scavengers" 3 : 47-57, 1991

16 Agarwal RB, "Phytochemical investigation and evaluation of anti-inflammatory and anti-arthritic activities of essential oil of Strobilanthus ixiocephala Benth" 41 : 890-894, 2003

17 Fukuyama N, "Peroxynitrite formation in focal cerebral ischemiareperfusion in rats occurs predominantly in the peri-infarct region" 18 : 123-129, 1998

18 Wolf PA, "Pathophysiology, diagnosis and management, In Stroke" Churchill Livingstone 3-27, 1997

19 int’ Veld BA, "Nonsteroidal antiinflammatory drugs and the risk of Alzheimer’s disease" 345 : 1515-1521, 2001

20 Thiyagarajan M, "Neuroprotective effect of curcumin in middle cerebral artery occlusion induced focal cerebral ischemia in rats" 74 : 969-985, 2004

21 Opdyke DL, "Monographs on fragrance raw materials" 11 : 1011-1081, 1973

22 Mehta LS, "Molecular targets in cerebral ischemia for developing novel therapeutics" 54 : 34-66, 2007

23 Sattler R, "Molecular mechanisms of glutamate receptor-mediated excitotoxic neuronal cell death" 24 : 107-129, 2001

24 Belayev L, "Middle cerebral artery occlusion in the rat by intraluminal suture. Neurological and pathological evaluation of an improved model" 27 : 1616-1622, 1996

25 Ne`ve J, "Inhibition of the myeloperoxidase chlorinating activity by non-steroidal anti-inflammatory drugs investigated with a human recombinant enzyme" 417 : 37-43, 2001

26 Lourens AC, "In vitro biological activity and essential oil composition of four indigenous South African Helichrysum species" 95 : 253-258, 2004

27 Robak J, "Flavonoids are scavenger of superoxide anions" 37 : 837-841, 1988

28 FEMA, "FEMA Database: Beta-Caryophyllene (FEMA No. 2252)" Flavor and Extract Manufacturers Association 12-, 1979

29 Dugan LL, "Excitotoxicity, free radicals, and cell membrane changes" 35 : 17-21, 1994

30 Huang Z, "Effects of cerebral ischemia in mice deficient in neuronal nitric oxide synthase" 265 : 1883-1885, 1994

31 Kubo I, "Cytotoxic and antioxidative sesquiterpenoids from Heterotheca inuloides" 62 : 427-430, 1996

32 Sairanen T, "Cyclooxygenase-2 is induced globally in infarcted human brain" 43 : 738-747, 1998

33 Bednar MM, "Antiplatelet therapy in acute cerebral ischemia" 30 : 887-893, 1999

34 Dyken ML, "Antiplatelet agents and stroke prevention" 18 : 441-450, 1998

35 Singh G, "Antioxidant and biocidal activities of Carum nigrum (seed) essential oil, oleoresin, and their selected components" 54 : 174-181, 2006

36 Re R, "Antioxidant activity applying and improved ABTS radical cation decolorization assay" 26 : 1231-1237, 1999

37 Heck JD, "An evaluation of food flavoring ingredients in a genetic toxicity screening battery" 9 : 257-, 1989

38 Cho JY, "Amelioration of dextran sulfate sodium-induced colitis in mice by oral administration of b-caryophyllene, a sesquiterpene" 80 : 932-939, 2007