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β-Caryophyllene Pretreatment Alleviates Focal Cerebral Ischemia-Reperfusion Injury by Activating PI3K/Akt Signaling Pathway

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Abstract

β-Caryophyllene (BCP) has been reported to be protective against focal cerebral ischemia–reperfusion (I/R) injury by its anti-oxidative and anti-inflammatory features. Recent study demonstrates that the BCP exhibits potential neuroprotection against I/R injury induced apoptosis, however, the mechanism remains unknown. Therefore, we investigate the underlying anti-apoptotic mechanism of BCP pretreatment in I/R injury. Sprague–Dawley rats (pretreated with BCP suspensions or solvent orally for 7 days) were subjected to transient Middle Cerebral Artery Occlusion (MCAO) for 90 min, followed by 24 h reperfusion. Results showed that BCP pretreatment improved the neurologic deficit score, lowered the infarct volume and decreased number of apoptotic cells in the hippocampus. Moreover, in western blot and RT-qPCR detections, BCP pretreatment down-regulated the expressions of Bax and p53, up-regulated the expression of Bcl-2, and enhanced the phosphorylation of Akt on Ser473. Blockage of PI3K activity by wortmannin not only abolished the BCP-induced decreases in infarct volume and neurologic deficit score, but also dramatically abrogated the enhancement of AKt phosphorylation. Our results suggested that BCP pre-treatment protects against I/R injury partly by suppressing apoptosis via PI3K/AKt signaling pathway activation.

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References

  1. Madathil RJ, Hira RS, Stoeckl M, Sterz F, Elrod JB, Nichol G (2016) Ischemia reperfusion injury as a modifiable therapeutic target for cardioprotection or neuroprotection in patients undergoing cardiopulmonary resuscitation. Resuscitation 105:85–91

    Article  Google Scholar 

  2. Xing B, Chen H, Zhang M, Zhao D, Jiang R, Liu X, Zhang S (2008) Ischemic postconditioning inhibits apoptosis after focal cerebral ischemia/reperfusion injury in the rat. Stroke 39:2362–2369

    Article  CAS  PubMed  Google Scholar 

  3. Ahmed MA, El Morsy EM, Ahmed AA (2014) Pomegranate extract protects against cerebral ischemia/reperfusion injury and preserves brain DNA integrity in rats. Life Sci 110:61–69

    Article  CAS  PubMed  Google Scholar 

  4. Feigin VL, Lawes CMM, Bennett DA, Anderson CS (2003) Stroke epidemiology: a review of population-based studies of incidence, prevalence, and case-fatality in the late 20th century. Lancet Neurol 2:43–53

    Article  PubMed  Google Scholar 

  5. Fresno Vara JA, Casado E, de Castro J, Cejas P, Belda-Iniesta C, Gonzalez-Baron M (2004) PI3K/Akt signalling pathway and cancer. Cancer Treat Rev 30:193–204

    Article  PubMed  Google Scholar 

  6. Li X, Wu C, Chen N, Gu H, Yen A, Cao L, Wang E, Wang L (2016) PI3K/Akt/mTOR signaling pathway and targeted therapy for glioblastoma. Oncotarget 7:33440–33450

    Google Scholar 

  7. Terragni J, Graham JR, Adams KW, Schaffer ME, Tullai JW, Cooper GM (2008) Phosphatidylinositol 3-kinase signaling in proliferating cells maintains an anti-apoptotic transcriptional program mediated by inhibition of FOXO and non-canonical activation of NFkappaB transcription factors. BMC Cell Biol 9:6

    Article  PubMed  PubMed Central  Google Scholar 

  8. Abe E, Fujiki M, Nagai Y, Shiqi K, Kubo T, Ishii K, Abe T, Kobayashi H (2010) The phosphatidylinositol-3 kinase/Akt pathway mediates geranylgeranylacetone-induced neuroprotection against cerebral infarction in rats. Brain Res 1330:151–157

    Article  CAS  PubMed  Google Scholar 

  9. Wang HY, Wang GL, Yu YH, Wang Y (2009) The role of phosphoinositide-3-kinase/Akt pathway in propofol-induced postconditioning against focal cerebral ischemia-reperfusion injury in rats. Brain Res 1297:177–184

    Article  CAS  PubMed  Google Scholar 

  10. Xu X, Chua CC, Gao J, Chua KW, Wang H, Hamdy RC, Chua BH (2008) Neuroprotective effect of humanin on cerebral ischemia/reperfusion injury is mediated by a PI3K/Akt pathway. Brain Res 1227:12–18

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  11. Zhang L, Ravipati AS, Koyyalamudi SR, Jeong SC, Reddy N, Bartlett J, Smith PT, de la Cruz M, Monteiro MC, Melguizo Á, Jiménez E, Vicente F (2013) Anti-fungal and anti-bacterial activities of ethanol extracts of selected traditional Chinese medicinal herbs. Asian Pacific. J Trop Med 6:673–681

    Google Scholar 

  12. Tung YT, Chua MT, Wang SY, Chang ST (2008) Anti-inflammation activities of essential oil and its constituents from indigenous cinnamon (Cinnamomum osmophloeum) twigs. Bioresour Technol 99:3908–3913

    Article  CAS  PubMed  Google Scholar 

  13. Legault J, Pichette A (2007) Potentiating effect of beta-caryophyllene on anticancer activity of alpha-humulene, isocaryophyllene and paclitaxel. J Pharm Pharmacol 59:1643–1647

    Article  CAS  PubMed  Google Scholar 

  14. Klimova EI, Vazquez Lopez EA, Klimova T (2014) Antigenotoxic capacity of beta-caryophyllene in mouse, and evaluation of its antioxidant and GST induction activities. J Toxicol Sci 39:849–859

    Article  Google Scholar 

  15. Cheng Y, Dong Z, Liu S (2014) Beta-caryophyllene ameliorates the Alzheimer-like phenotype in APP/PS1 mice through CB2 receptor activation and the PPARgamma pathway. Pharmacology 94:1–12

    Article  CAS  PubMed  Google Scholar 

  16. Bahi A, Al Mansouri S, Al Memari E, Al Ameri M, Nurulain SM, Ojha S (2014) Beta-caryophyllene, a CB2 receptor agonist produces multiple behavioral changes relevant to anxiety and depression in mice. Physiol Behav 135:119–124

    Article  CAS  PubMed  Google Scholar 

  17. Lou J, Cao G, Li R, Liu J, Dong Z, Xu L (2016) Beta-caryophyllene attenuates focal cerebral ischemia-reperfusion injury by Nrf2/HO-1 pathway in rats. Neurochem Res 41:1291–1304

    Article  CAS  PubMed  Google Scholar 

  18. Bederson JB, Pitts LH, Tsuji M, Nishimura MC, Davis RL, Bartkowski H (1986) Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke 17:472–476

    Article  CAS  PubMed  Google Scholar 

  19. Ljubisavljevic MR, Javid A, Oommen J, Parekh K, Nagelkerke N, Shehab S, Adrian TE (2015) The effects of different repetitive transcranial magnetic stimulation (rTMS) protocols on cortical gene expression in a rat model of cerebral ischemic-reperfusion Injury. PLoS One 10:e0139892

  20. Walker TL, Kempermann G (2014) One mouse, two cultures: isolation and culture of adult neural stem cells from the two neurogenic zones of individual mice. J Vis Exp 84:e51225

    Google Scholar 

  21. Liang L, Wang XY, Zhang XH, Ji B, Yan HC, Deng HZ, Wu XR (2012) Sophoridine exerts an anti-colorectal carcinoma effect through apoptosis induction in vitro and in vivo. Life Sci 91:1295–1303

    Article  CAS  PubMed  Google Scholar 

  22. Dirnagl U, Iadecola C, Moskowitz MA (1999) Pathobiology of ischaemic stroke: an integrated view. Trends Neurosci 22:391–397

    Article  CAS  PubMed  Google Scholar 

  23. Chang HJ, Kim JM, Lee JC, Kim WK, Chun HS (2013) Protective effect of beta-caryophyllene, a natural bicyclic sesquiterpene, against cerebral ischemic injury. J Med Food 16:471–480

    Article  CAS  PubMed  Google Scholar 

  24. Choi IY, Ju C, Jalin AMAA, Da IL, Prather PL, Kim WK (2013) activation of cannabinoid CB2 receptor–mediated AMPK/CREB pathway reduces cerebral ischemic injury. Am J Pathol 182:928–939

    Article  CAS  PubMed  Google Scholar 

  25. Al-Alami ZM, Shraideh ZA, Taha MO (2015) β-Caryophyllene as putative male contraceptive: enhances spermatogenesis but not spermiogenesis in albino rats. Med Chem Res 24:3876–3884

    Article  CAS  Google Scholar 

  26. Cheng Y, Dong Z, Liu S (2014) β-Caryophyllene ameliorates the Alzheimer-Like phenotype in APP/PS1 Mice through CB2 receptor activation and the PPARγ pathway. Pharmacology 94:1–12

    Article  CAS  PubMed  Google Scholar 

  27. Hosmer DW, Lemeshow S (2005) Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science 310:329–332

    Article  Google Scholar 

  28. Viscomi M, Oddi S, L, Pasquariello N, Florenzano F, Bernardi G, Molinari M, Maccarrone M (2009) Selective CB2 receptor agonism protects central neurons from remote axotomy-induced apoptosis through the PI3K/Akt pathway. J Neurosci Off J Soc Neurosci 29:4564–4570

    Article  CAS  Google Scholar 

  29. Ashton JC, Friberg D, Darlington CL, Smith PF (2006) Expression of the cannabinoid CB2 receptor in the rat cerebellum: An immunohistochemical study. Neurosci Lett 396:113–116

    Article  CAS  PubMed  Google Scholar 

  30. Gong JP, Onaivi ES, Ishiguro H, Liu QR, Tagliaferro PA, Brusco A, Uhl GR (2006) Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res 1071:10–23

    Article  CAS  PubMed  Google Scholar 

  31. Bisogno T, Oddi S, Piccoli A, Fazio D, Maccarrone M (2016) Type-2 cannabinoid receptors in neurodegeneration. Pharmacol Res 111:721–730

    Article  CAS  PubMed  Google Scholar 

  32. Javed H, Azimullah S, Haque ME, Ojha SK (2016) Cannabinoid type 2 (CB2) receptors activation protects against oxidative stress and neuroinflammation associated dopaminergic neurodegeneration in rotenone model of parkinson’s Disease. Front Neurosci 10:321

    Article  PubMed  PubMed Central  Google Scholar 

  33. Zhang M, Adler MW, Abood ME, Ganea D, Jallo J, Tuma RF (2009) CB2 receptor activation attenuates microcirculatory dysfunction during cerebral ischemic/reperfusion injury. Microvasc Res 78:86–94

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  34. Li Q, Wang F, Zhang YM, Zhou JJ, Zhang Y (2013) Activation of cannabinoid type 2 receptor by JWH133 protects heart against ischemia/reperfusion-induced apoptosis. Cell physiol biochem 31:693–702

    Article  CAS  PubMed  Google Scholar 

  35. Putcha GV, Deshmukh M, Jr JE (1999) BAX translocation is a critical event in neuronal apoptosis: regulation by neuroprotectants, BCL-2, and caspases. J Neurosci 19:7476–7485

    CAS  PubMed  Google Scholar 

  36. Gross A, Jockel J, Wei MC, Korsmeyer SJ (1998) Enforced dimerization of BAX results in its translocation, mitochondrial dysfunction and apoptosis. Embo J 17:3878–3885

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  37. Cheng EHYA, Wei MC, Weiler S, Flavell RA, Mak TW, Lindsten T, Korsmeyer SJ (2001) BCL-2, BCL-XL sequester BH3 domain-only molecules preventing BAX- and BAK-mediated mitochondrial apoptosis. Mol Cell 8:705–711

    Article  CAS  PubMed  Google Scholar 

  38. Zhang R, Xue YY, Lu SD, Wang Y, Zhang LM, Huang YL, Signore AP, Chen J, Sun FY (2006) Bcl-2 enhances neurogenesis and inhibits apoptosis of newborn neurons in adult rat brain following a transient middle cerebral artery occlusion. Neurobiol Dis 24:345–356

    Article  CAS  PubMed  Google Scholar 

  39. He H, Distelhorst CW (1997) Maintenance of calcium homeostasis in the endoplasmic reticulum by Bcl-2. J Cell Biol 138(:):1219–1228

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  40. Lam M, Dubyak G, Chen L, Nuñez G, Miesfeld RL, Distelhorst CW (1994) Evidence that BCL-2 represses apoptosis by regulating endoplasmic reticulum-associated Ca2 + fluxes. Proc Natl Acad Sci USA 91:6569–6573

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  41. Clarke AR, Purdie CA, Harrison DJ, Morris RG, Bird CC, Hooper ML, Wyllie AH (1993) Thymocyte apoptosis induced by p53-dependent and independent pathways. Nature 362:849–852

    Article  CAS  PubMed  Google Scholar 

  42. Lowe SW, Schmitt EM, Smith SW, Osborne BA, Jacks T (1993) P53 is required for radiation-induced apoptosis in mouse thymocytes. Nature 362:847–849

    Article  CAS  PubMed  Google Scholar 

  43. Miyashita T, Reed JC (1995) Tumor suppressor p53 is a direct transcriptional activator of the human bax gene. Cell 80:293–299

    Article  CAS  PubMed  Google Scholar 

  44. Xu D (2002) Ets1 is required for p53 transcriptional activity in UV-induced apoptosis in embryonic stem cells.EMBO J 21:4081–4093

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  45. Wang JK, Yu LN, Zhang FJ, Yang MJ, Yu J, Yan M, Chen G (2010) Postconditioning with sevoflurane protects against focal cerebral ischemia and reperfusion injury via PI3K/Akt pathway. Brain Res 1357:142–151

    Article  CAS  PubMed  Google Scholar 

  46. Crumrine RC, Thomas AL, Morgan PF (1994) Attenuation of p53 expression protects against focal ischemic damage in transgenic mice. J Cereb Blood Flow Metab 14:887–891

    Article  CAS  PubMed  Google Scholar 

  47. Leker RR, Aharonowiz M, Greig NH, Ovadia H (2004) The role of p53-induced apoptosis in cerebral ischemia: effects of the p53 inhibitor pifithrin alpha. Exp Neurol 187:478–486

    Article  CAS  PubMed  Google Scholar 

  48. Cantley LC (2002) The phosphoinositide 3-kinase pathway. Science 296:1655–1657

    Article  CAS  PubMed  Google Scholar 

  49. Song G, Ouyang G, Bao S (2005) The activation of Akt/PKB signaling pathway and cell survival. J Cell Mol Med 9:59

    Article  CAS  PubMed  Google Scholar 

  50. Stemke-Hale K, Gonzalez-Angulo AM, Lluch A, Neve RM, Kuo WL, Davies M, Carey M, Hu Z, Guan Y, Sahin A, Symmans WF, Pusztai L, Nolden LK, Horlings H, Berns K, Hung MC, van de Vijver MJ, Valero V, Gray JW, Bernards R, Mills GB, Hennessy BT (2008) An integrative genomic and proteomic analysis of PIK3CA, PTEN, and AKT mutations in breast cancer. Cancer Res 68:6084–6091

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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Funding

Funding was provided by Chongqing Research Program of Basic Research and Frontier Technology (No. cstc2016jcyjA0373).

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Correspondence to Lu Xu or Zhi Dong.

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Zhang, Q., An, R., Tian, X. et al. β-Caryophyllene Pretreatment Alleviates Focal Cerebral Ischemia-Reperfusion Injury by Activating PI3K/Akt Signaling Pathway. Neurochem Res 42, 1459–1469 (2017). https://doi.org/10.1007/s11064-017-2202-3

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  • DOI: https://doi.org/10.1007/s11064-017-2202-3

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