Skip to main content
PMC home page
Neuroscience Bulletin logoLink to Neuroscience Bulletin
. 2011 Aug 5;27(4):275. doi: 10.1007/s12264-011-1008-6

Cannabinoid as a neuroprotective strategy in perinatal hypoxic-ischemic injury

大麻素在围产期缺血缺氧性脑损伤的保护作用

Daniel Alonso-Alconada 1, Antonia Alvarez 1, Enrique Hilario 1,✉
PMCID: PMC5560303  PMID: 21788999

Abstract

Perinatal hypoxia-ischemia remains the single most important cause of brain injury in the newborn, leading to death or lifelong sequelae. Because of the fact that there is still no specific treatment for perinatal brain lesions due to the complexity of neonatal hypoxic-ischemic pathophysiology, the search of new neuroprotective therapies is of great interest. In this regard, therapeutic possibilities of the endocannabinoid system have grown lately. The endocannabinoid system modulates a wide range of physiological processes in mammals and has demonstrated neuroprotective effects in different paradigms of acute brain injury, acting as a natural neuroprotectant. Concerning perinatal asphyxia, the neuroprotective role of this endogenous system is emerging these years. The present review mainly focused on the current knowledge of the cannabinoids as a new neuroprotective strategy against perinatal hypoxic-ischemic brain injury.

Keywords: perinatal hypoxia-ischemia, brain injury, neuroprotective strategies, endocannabinoid system

References

  • [1].Berger R., Garnier Y. Perinatal brain injury. J Perinat Med. 2000;28:261–285. doi: 10.1515/JPM.2000.034. [DOI] [PubMed] [Google Scholar]
  • [2].Volpe J. Perinatal brain injury: from pathogenesis to neuroprotection. Mental Retard Dev Disabil Res. 2001;7:56–64. doi: 10.1002/1098-2779(200102)7:1<56::AID-MRDD1008>3.0.CO;2-A. [DOI] [PubMed] [Google Scholar]
  • [3].Low J.A. Determining the contribution of asphyxia to brain damage in the neonate. J Obstet Gynaecol Res. 2004;30:276–286. doi: 10.1111/j.1447-0756.2004.00194.x. [DOI] [PubMed] [Google Scholar]
  • [4].Vannuci S., Hagberg H. Hypoxia-ischemia in the immature brain. J Exp Biol. 2004;207:3149–3154. doi: 10.1242/jeb.01064. [DOI] [PubMed] [Google Scholar]
  • [5].de Hann M., Wyatt J.S., Roth S., Vargha-Khadem F., Gadian D., Mishki M. Brain and cognitive-behavioural development after asphyxia at term birth. Dev Sci. 2006;9:350–358. doi: 10.1111/j.1467-7687.2006.00499.x. [DOI] [PubMed] [Google Scholar]
  • [6].Torfs C.P., van den Berg B., Oechsli F.W., Cummins S. Prenatal and perinatal factors in the etiology of cerebral palsy. J Pediatr. 1990;116:615–619. doi: 10.1016/S0022-3476(05)81615-4. [DOI] [PubMed] [Google Scholar]
  • [7].Mañeru C., Junque C., Botet F., Tallada M., Guardia J. Neuropsychological long-term sequelae of perinatal asphyxia. Brain Int. 2001;15:1029–1039. doi: 10.1080/02699050110074178. [DOI] [PubMed] [Google Scholar]
  • [8].Yager J.Y., Armstrong E.A., Black A.M. Treatment of the term newborn with brain injury: simplicity as the mother of invention. Pediatr Neurol. 2009;40:237–243. doi: 10.1016/j.pediatrneurol.2008.12.002. [DOI] [PubMed] [Google Scholar]
  • [9].Rivkin M.J. Hypoxic-ischemic brain injury in the term newborn: neuropathology, clinical aspects, and neuroimaging. Clin Perinatol. 1997;24:607–626. [PubMed] [Google Scholar]
  • [10].Volpe J.J. Hypoxic-ischemic encephalopathy. Clinical aspects. In: Volpe J.J., editor. Neurology of the Newborn. Philadelphia: WB Saunders Co; 1995. pp. 314–369. [Google Scholar]
  • [11].Nakaruma Y., Okureda T., Hashimoto T. Vascular architecture in white matter of neonates: its relationship to periventricular leukomalacia. J Neuropathol Exp Neurol. 1994;53:582–589. doi: 10.1097/00005072-199411000-00005. [DOI] [PubMed] [Google Scholar]
  • [12].Volpe J.J. Brain injury in the premature infant: overview of clinical aspects, neuropathology, and pathogenesis. Semin Pediatr Neurol. 1998;5:135–151. doi: 10.1016/S1071-9091(98)80030-2. [DOI] [PubMed] [Google Scholar]
  • [13].Pourcyrous M. Cerebral hemodynamic measurements in acute versus chronic asphyxia. Clin Perinatol. 1999;26:811–828. [PubMed] [Google Scholar]
  • [14].Back S.A., Luo N.L., Borenstein N.S., Levine J.M., Volpe J.J., Kinney H.C. Late oligodendrocyte progenitors coincide with the development window of vulnerability for human perinatal white matter injury. J Neurosci. 2001;21:1302–1312. doi: 10.1523/JNEUROSCI.21-04-01302.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [15].Hilario E., Rey-Santano M.C., Goñi-de-Cerio F., Alvarez F.J., Gastiasoro E., Mielgo V.E., et al. Cerebral blood flow and morphological changes after hypoxic-ischaemic injury in preterm lambs. Acta Paediatr. 2005;94:903–911. doi: 10.1080/08035250510031151. [DOI] [PubMed] [Google Scholar]
  • [16].Shalak L.F., Laptook A.R., Velaphi S.C., Perlman J.M. Amplitude-integrated electroencephalography coupled with an early neurologic examination enhances prediction of term infants at risk for persistent encephalopathy. Pediatrics. 2003;111:351–357. doi: 10.1542/peds.111.2.351. [DOI] [PubMed] [Google Scholar]
  • [17].Sanders R.D., Manning H.J., Robertson N.J., Ma D., Edwards A.D., Hagberg H., et al. Preconditioning and postinsult therapies for perinatal hypoxic-ischemic injury at term. Anesthesiology. 2010;113:233–249. doi: 10.1097/ALN.0b013e3181dc1b84. [DOI] [PubMed] [Google Scholar]
  • [18].Perlman J.M., Risser R. Can asphyxiated infants at risk for neonatal seizures be rapidly identified by current high-risk markers? Pediatrics. 1996;97:456–462. [PubMed] [Google Scholar]
  • [19].Walton M., Connor B., Lawlor P., Young D., Sirimanne E., Gluckman P., et al. Neuronal death and survival in two models of hypoxic-ischemic brain damage. Brain Res Rev. 1999;29:137–168. doi: 10.1016/S0165-0173(98)00053-8. [DOI] [PubMed] [Google Scholar]
  • [20].Ferriero D.M. Neonatal brain injury. N Engl J Med. 2004;351:1985–1995. doi: 10.1056/NEJMra041996. [DOI] [PubMed] [Google Scholar]
  • [21].Sugawara T., Fujimura M., Noshita N., Kim G.W., Saito A., Hayashi T., et al. Neuronal death/survival signaling pathways in cerebral ischemia. NeuroRx. 2004;1:17–25. doi: 10.1602/neurorx.1.1.17. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [22].Edwards A.D., Yue X., Cox P., Hope P.L., Azzopardi D.V., Squier M.V., et al. Apoptosis in the brains of infants suffering intrauterine cerebral injury. Pediatr Res. 1997;42:684–689. doi: 10.1203/00006450-199711000-00022. [DOI] [PubMed] [Google Scholar]
  • [23].Yue X., Mehmet H., Penrice J., Cooper C., Cady E.B., Wyatt J.S., et al. Apoptosis and necrosis in the newborn piglet brain following transient HI. Neuropathol Appl Neurobiol. 1997;23:16–25. doi: 10.1111/j.1365-2990.1997.tb01181.x. [DOI] [PubMed] [Google Scholar]
  • [24].Esteve J.M., Mompo J., García de la Asunción J., Satre J., Asensi M., Boix J., et al. Oxidative damage to mitochondrial DNA and glutathione oxidation in apoptosis studies in vivo and in vitro. FASEB J. 1999;13:1055–1064. doi: 10.1096/fasebj.13.9.1055. [DOI] [PubMed] [Google Scholar]
  • [25].Taylor D.L., Edwards A.D., Mehmet H. Oxidative metabolism, apoptosis and perinatal brain injury. Brain Pathol. 1999;9:93–117. doi: 10.1111/j.1750-3639.1999.tb00213.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [26].Ohyu J., Endo A., Itoh M., Takashima S. Hypocapnia under hypotension induces apoptotic neuronal cell death in the hippocampus of newborn rabbits. Pediatric Res. 2000;48:24–29. doi: 10.1203/00006450-200007000-00007. [DOI] [PubMed] [Google Scholar]
  • [27].Hilario E., Alvarez A., Alvarez F.J., Gastiasoro E., Valls-i-Soler A. Cellular mechanisms in perinatal hypoxic-ischemic brain injury. Current Pediatr Rev. 2006;2:131–141. doi: 10.2174/157339606776894667. [DOI] [Google Scholar]
  • [28].Hilario E., Cañavate M.L., Lacalle J., Alonso-Alconada D., Lara-Celador I., Alvarez-Granda L., et al. Cell death. A comprehensive approximation. Delayed cell death. In: Méndez-Vilas A., Díaz J., et al., editors. Microscopy: Science, Technology, Applications and Education. Badajoz: Formatex Research Centre; 2010. pp. 1025–1032. [Google Scholar]
  • [29].Gunn A.J., Gunn T., de Haan H., Williams C., Gluckman P. Dramatic neuronal rescue with prolonged selective head cooling after ischemia in fetal sheep. J Clin Invest. 1997;99:248–256. doi: 10.1172/JCI119153. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [30].Gonzalez F.F., Ferriero D.M. Therapeutics for neonatal brain injury. Pharmacol Ther. 2008;120:43–53. doi: 10.1016/j.pharmthera.2008.07.003. [DOI] [PubMed] [Google Scholar]
  • [31].Kelen D., Robertson N.J. Experimental treatments for hypoxic ischaemic encephalopathy. Early Hum Dev. 2010;86:369–377. doi: 10.1016/j.earlhumdev.2010.05.011. [DOI] [PubMed] [Google Scholar]
  • [32].Cilio M.R., Ferriero D.M. Synergistic neuroprotective therapies with hypothermia. Semin Fetal Neonatal Med. 2010;15:293–298. doi: 10.1016/j.siny.2010.02.002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [33].Nedelcu J., Klein M.A., Aguzzi A., Martin E. Resuscitative hypothermia protects the neonatal rat brain from hypoxic-ischemic injury. Brain Pathol. 2000;10:61–71. doi: 10.1111/j.1750-3639.2000.tb00243.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [34].Pabello N.G., Tracy S.J., Keller R.W., Jr. Protective effects of brief intra- and delayed postischemic hypothermia in a transient focal ischemia model in the neonatal rat. Brain Res. 2004;995:29–38. doi: 10.1016/j.brainres.2003.09.065. [DOI] [PubMed] [Google Scholar]
  • [35].den Hertog H., van der Worp B., van Gemert M., Dippel D. Therapeutic hypothermia in acute ischemic stroke. Expert Rev Neurother. 2007;7:155–164. doi: 10.1586/14737175.7.2.155. [DOI] [PubMed] [Google Scholar]
  • [36].Adachi M., Sohma O., Tsuneishi S., Takada S., Nakamura H. Combination effect of systemic hypothermia and cascase inhibitor administration against hypoxic-ischemic brain damage in neonatal rats. Pediatric Res. 2001;50:590–595. doi: 10.1203/00006450-200111000-00010. [DOI] [PubMed] [Google Scholar]
  • [37].Hashimoto T., Yonetani M., Nakamura H. Selective brain hypothermia protects against hypoxic-ischemic injury in newborn rats by reducing hydroxyl radical production. Kobe J Med Sci. 2003;49:83–91. [PubMed] [Google Scholar]
  • [38].Zhu C., Wang X., Cheng X., Qui L., Xu F., Simbruner G., et al. Postischemic hypothermia-induced tissue protection and diminished apoptosis after neonatal cerebral hypoxia-ischemia. Brain Res. 2004;996:67–75. doi: 10.1016/j.brainres.2003.10.013. [DOI] [PubMed] [Google Scholar]
  • [39].Wyatt J.S., Gluckman P.D., Liu P.Y., Azzopardi D., Ballard R., Edwards A.D., et al. Determinants of outcomes after head cooling for neonatal encephalopathy. Pediatrics. 2007;119:912–921. doi: 10.1542/peds.2006-2839. [DOI] [PubMed] [Google Scholar]
  • [40].Palmer C., Towfighi J., Roberts R.L., Heitjan D.F. Allopurinol administered after inducing damage with HI reduces brain injury in 7 days old rats. Pediatr Res. 1993;33:405–411. doi: 10.1203/00006450-199304000-00018. [DOI] [PubMed] [Google Scholar]
  • [41].Van Bel F., Shadid M., Moison R.M., Dorrepaal C.A., Fontijn J., Monteiro L., et al. Effect of allopurinol on postasphyxial free radical formation, cerebral hemodynamics, and electrical brain activity. Pediatrics. 1998;101:185–193. doi: 10.1542/peds.101.2.185. [DOI] [PubMed] [Google Scholar]
  • [42].Ferrari G., Yan C.Y.I., Greene L.A. Acetylcysteine (D- and L- sterioisomers) prevent apoptotic death of neuronal cells. J Neurosci. 1995;15:2857–2866. doi: 10.1523/JNEUROSCI.15-04-02857.1995. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [43].Yan C.Y.I., Ferrari G., Greene L.A. N-Acetylcysteine promoted survival of PC12 cells is glutathione independent but transcription dependent. J Biol Chem. 1995;270:26827–26832. doi: 10.1074/jbc.270.45.26827. [DOI] [PubMed] [Google Scholar]
  • [44].Jatana M., Singh I., Singh A.K., Jenkins D. Combination of systemic hypothermia and N-acetylcysteine attenuates hypoxic-ischemic brain injury in neonatal rats. Pediatr Res. 2006;59:684–689. doi: 10.1203/01.pdr.0000215045.91122.44. [DOI] [PubMed] [Google Scholar]
  • [45].Lee T.F., Jantzie L.L., Todd K.G., Cheung P.Y. Postresuscitation Nacetylcysteine treatment reduces cerebral hydrogen peroxide in the hypoxic piglet brain. Inten Care Med. 2008;34:190–197. doi: 10.1007/s00134-007-0880-z. [DOI] [PubMed] [Google Scholar]
  • [46].Sola A., Wen T.C., Hamrick S.E., Ferriero D.M. Potential for protection and repair following injury to the developing brain: a role for erythropoietin. Pediatr Res. 2005;57:110–117. doi: 10.1203/01.PDR.0000159571.50758.39. [DOI] [PubMed] [Google Scholar]
  • [47].Chang Y.S., Mu D., Wendland M., Sheldon R.A., Vexler Z.S., McQuillen P.S., et al. Erythropoietin improves functional and histological outcome in neonatal stroke. Pediatr Res. 2005;58:106–111. doi: 10.1203/01.PDR.0000163616.89767.69. [DOI] [PubMed] [Google Scholar]
  • [48].Gonzalez F.F., McQuillen P., Mu D., Chang Y., Wendland M., Vexler Z., et al. Erythropoietin enhances long-term neuroprotection and neurogenesis in neonatal stroke. Dev Neurosci. 2007;29:321–330. doi: 10.1159/000105473. [DOI] [PubMed] [Google Scholar]
  • [49].Carloni S., Perrone S., Buonocore G., Longini M., Proietti F., Balduini W. Melatonin protects from the long-term consequences of a neonatal hypoxic-ischemic brain injury in rats. J Pineal Res. 2008;44:157–164. doi: 10.1111/j.1600-079X.2007.00503.x. [DOI] [PubMed] [Google Scholar]
  • [50].Signorini C., Ciccoli L., Leoncini S., Carloni S., Perrone S., Comporti M., et al. Free iron, total F-isoprostanes and total F-neuroprostanes in a model of neonatal hypoxic-ischemic encephalopathy: neuroprotective effect of melatonin. J Pineal Res. 2009;46:148–154. doi: 10.1111/j.1600-079X.2008.00639.x. [DOI] [PubMed] [Google Scholar]
  • [51].Arvin K.L., Han B.H., Du Y., Lin S.Z., Paul S.M., Holtzman D.M. Minocycline markedly protects the neonatal brain against hypoxicischemic injury. Ann Neurol. 2002;52:54–61. doi: 10.1002/ana.10242. [DOI] [PubMed] [Google Scholar]
  • [52].Jantzie L.L., Cheung P.Y., Todd K.G. Doxycycline reduces cleaved caspase-3 and microglial activation in an animal model of neonatal hypoxia-ischemia. J Cereb Blood Flow Metab. 2005;25:314–325. doi: 10.1038/sj.jcbfm.9600025. [DOI] [PubMed] [Google Scholar]
  • [53].Carloni S., Mazzoni E., Cimino M., De Simoni M.G., Perego C., Scopa C., et al. Simvastatin reduces caspase-3 activation and inflammatory markers induced by hypoxia-ischemia in the newborn rat. Neurobiol Dis. 2006;21:119–126. doi: 10.1016/j.nbd.2005.06.014. [DOI] [PubMed] [Google Scholar]
  • [54].Carloni S., Girelli S., Buonocore G., Longini M., Balduini W. Simvastatin acutely reduces ischemic brain damage in the immature rat via Akt and CREB activation. Exp Neurol. 2009;220:82–89. doi: 10.1016/j.expneurol.2009.07.026. [DOI] [PubMed] [Google Scholar]
  • [55].Piomelli D. The molecular logic of endocannabinoid signalling. Nat Rev Neurosci. 2003;4:873–884. doi: 10.1038/nrn1247. [DOI] [PubMed] [Google Scholar]
  • [56].Di Marzo V., Bisogno T., De Petrocellis L. Endocannabinoids and related compounds: walking back and forth between plant natural products and animal physiology. Chem Biol. 2007;14:741–756. doi: 10.1016/j.chembiol.2007.05.014. [DOI] [PubMed] [Google Scholar]
  • [57].Ahn K., McKinney M.K., Cravatt B.F. Enzymatic pathways that regulate endocannabinoid signaling in the nervous system. Chem Rev. 2008;108:1687–1707. doi: 10.1021/cr0782067. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [58].Howlett A.C., Breivogel C.S., Childers S.R., Deadwyler S.A., Hampson R.E., Porrino L.J. Cannabinoid physiology and pharmacology: 30 years of progress. Neuropharmacology. 2004;247:345–358. doi: 10.1016/j.neuropharm.2004.07.030. [DOI] [PubMed] [Google Scholar]
  • [59].Kozak K.R., Gupta R.A., Moody J.S., Ji C., Boeglin W.E., DuBois R.N., et al. Lipoxygenase metabolism of 2-arachidonylglycerol. Generation of a peroxisome proliferator-activated receptor alpha agonist. J Biol Chem. 2002;277:23278–23286. doi: 10.1074/jbc.M201084200. [DOI] [PubMed] [Google Scholar]
  • [60].Craib S.J., Ellington H.C., Pertwee R.G., Ross R.A. A possible role of lipoxygenase in the activation of vanilloid receptors by anandamide in the guinea-pig bronchus. Br J Pharmacol. 2001;134:30–37. doi: 10.1038/sj.bjp.0704223. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [61].Galiègue S., Mary S., Marchand J., Dussossoy D., Carrière D., Carayon P., et al. Expression of central and peripheral cannabinoid receptors in human immune tissues and leukocyte subpopulations. Eur J Biochem. 1995;232:54–61. doi: 10.1111/j.1432-1033.1995.tb20780.x. [DOI] [PubMed] [Google Scholar]
  • [62].Núñez E., Benito C., Pazos M.R., Barbachano A., Fajardo O., González S., et al. Cannabinoid CB2 receptors are expressed by perivascular microglial cells in the human brain: an immunohistochemical study. Synapse. 2004;53:208–213. doi: 10.1002/syn.20050. [DOI] [PubMed] [Google Scholar]
  • [63].Van Sickle M.D., Duncan M., Kingsley P.J., Mouihate A., Urbani P., Mackie K., et al. Identification and functional characterization of brainstem cannabinoid CB2 receptors. Science. 2005;310:329–332. doi: 10.1126/science.1115740. [DOI] [PubMed] [Google Scholar]
  • [64].Onaivi E.S., Ishiguro H., Gong J.P., Patel S., Perchuk A., Meozzi P.A., et al. Discovery of the presence and functional expression of cannabinoid CB2 receptors in brain. Ann N Y Acad Sci. 2006;1074:514–536. doi: 10.1196/annals.1369.052. [DOI] [PubMed] [Google Scholar]
  • [65].Gong J.P., Onaivi E.S., Ishiguro H., Liu Q.R., Tagliaferro P.A., Brusco A., et al. Cannabinoid CB2 receptors: immunohistochemical localization in rat brain. Brain Res. 2006;1071:10–23. doi: 10.1016/j.brainres.2005.11.035. [DOI] [PubMed] [Google Scholar]
  • [66].Dewey W.L. Cannabinoid Pharmacology. Pharmacol Rev. 1986;38:151–178. [PubMed] [Google Scholar]
  • [67].Howlett A.C., Barth F., Bonner T.I., Cabral G., Casellas P., Devane W.A., et al. International Union of Pharmacology. XXVII. Classification of cannabinoid receptors. Pharmacol Rev. 2002;54:161–202. doi: 10.1124/pr.54.2.161. [DOI] [PubMed] [Google Scholar]
  • [68].Devane W.A., Hanus L., Breuer A., Pertwee R.G., Stevenson L.A., Griffin G., et al. Isolation and structure of a brain constituent that binds to the cannabinoid receptor. Science. 1992;258:1946–1949. doi: 10.1126/science.1470919. [DOI] [PubMed] [Google Scholar]
  • [69].Mechoulam R., Ben-Shabat S., Hanus L., Ligumsky M., Kaminski N.E., Schatz A.R., et al. Identification of an endogenous 2-monoglyceride, present in canine gut, that binds to cannabinoid receptors. Biochem Pharmacol. 1995;50:83–90. doi: 10.1016/0006-2952(95)00109-D. [DOI] [PubMed] [Google Scholar]
  • [70].Sugiura T., Kondo S., Sukagawa A., Nakane S., Shinoda A., Itoh K., et al. 2-Arachidonoylglycerol: a possible endogenous cannabinoid receptor ligand in brain. Biochem Biophys Res Commun. 1995;215:89–97. doi: 10.1006/bbrc.1995.2437. [DOI] [PubMed] [Google Scholar]
  • [71].Mackie K. Mechanisms of CB1 receptor signalling: endocannabinoid modulation of synaptic strength. Int J Obesity. 2006;30:19–23. doi: 10.1038/sj.ijo.0803273. [DOI] [PubMed] [Google Scholar]
  • [72].Hanus L., Abu-Lafi S., Fride E., Breuer A., Vogel Z., Shalev D.E., et al. 2-Arachidonyl glyceryl ether, an endogenous agonist of the cannabinoid CB1 receptor. Proc Natl Acad Sci U S A. 2001;98:3662–3665. doi: 10.1073/pnas.061029898. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [73].Porter A.C., Sauer J.M., Knierman M.D., Becker G.W., Berna M.J., Bao J., et al. Characterization of a novel endocannabinoid, virodhamine, with antagonist activity at the CB1 receptor. J Pharmacol Exp Ther. 2002;301:1020–1024. doi: 10.1124/jpet.301.3.1020. [DOI] [PubMed] [Google Scholar]
  • [74].Bisogno T., Melck D., Bobrov M.Y., Gretskaya N.M., Bezuglov V.V., De Petrocellis L., et al. N-acyl-dopamines: novel synthetic CB(1) cannabinoid-receptor ligands and inhibitors of anandamide inactivation with cannabimimetic activity in vitro and in vivo. Biochem J. 2000;3:817–824. doi: 10.1042/0264-6021:3510817. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [75].Huang S.M., Bisogno T., Trevisani M., Al-Hayani A., De Petrocellis L., Fezza F., et al. An endogenous capsaicin-like substance with high potency at recombinant and native vanilloid VR1 receptors. Proc Natl Acad Sci U S A. 2002;99:8400–8405. doi: 10.1073/pnas.122196999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [76].Rinaldi-Carmona M., Barth F., Héaulme M., Shire D., Calandra B., Martinez S., et al. SR141716A, a potent and selective antagonist of the brain cannabinoid receptor. FEBS Lett. 1994;350:240–244. doi: 10.1016/0014-5793(94)00773-X. [DOI] [PubMed] [Google Scholar]
  • [77].Rinaldi-Carmona M., Barth F., Millan J., Derocq J.M., Casellas P., Congy C., et al. SR 144528, the first potent and selective antagonist of the CB2 cannabinoid receptor. J Pharmacol Exp Ther. 1998;284:644–650. [PubMed] [Google Scholar]
  • [78].Devane W.A., Dysarz F.A., Johnson M.R., Melvin L.S., Howlett A.C. Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 1988;34:605–613. [PubMed] [Google Scholar]
  • [79].Bell M.R., D’Ambra T.E., Kumar V., Eissenstat M.A., Herrman J.L. Antinociceptive (aminoalkyl)-indoles. J Med Chem. 1991;34:1099–1110. doi: 10.1021/jm00107a034. [DOI] [PubMed] [Google Scholar]
  • [80].Jansen E.M., Haycock D.A., Ward S.J., Seybold V.S. Distribution of cannabinoid receptors in rat brain determined with aminoalkylindoles. Brain Res. 1992;575:93–102. doi: 10.1016/0006-8993(92)90428-C. [DOI] [PubMed] [Google Scholar]
  • [81].Kuster J.E., Stevenson J.I., Ward S.J., D’Ambra T.E., Haycock D.A. Aminoalkylindole binding in rat cerebellum: selective displacement by natural and synthetic cannabinoids. J Pharmacol Exp Ther. 1993;264:1352–1363. [PubMed] [Google Scholar]
  • [82].Di Marzo V., Fontana A., Cadas H., Schinelli S., Cimino G., Schwartz J.C., et al. Formation and inactivation of endogenous cannabinoid anandamide in central neurons. Nature. 1994;372:686–691. doi: 10.1038/372686a0. [DOI] [PubMed] [Google Scholar]
  • [83].Cravatt B.F., Lichtman A.H. The endogenous cannabinoid system and its role in nociceptive behavior. J Neurobiol. 2004;61:149–160. doi: 10.1002/neu.20080. [DOI] [PubMed] [Google Scholar]
  • [84].Ueda N. Endocannabinoid hydrolases. Prostaglandins Other Lipid Mediat. 2002;68–69:521–534. doi: 10.1016/S0090-6980(02)00053-9. [DOI] [PubMed] [Google Scholar]
  • [85].Ueda N., Yamanaka K., Yamamoto S. Purification and characterization of an acid amidase selective for N-palmitoylethanolamine, a putative endogenous anti-inflammatory substance. J Biol Chem. 2001;276:35552–35557. doi: 10.1074/jbc.M106261200. [DOI] [PubMed] [Google Scholar]
  • [86].Lo Verme J., Gaetani S., Fu J., Oveisi F., Burton K., Piomelli D. Regulation of food intake by oleoylethanolamide. Cell Mol Life Sci. 2005;62:708–716. doi: 10.1007/s00018-004-4494-0. [DOI] [PubMed] [Google Scholar]
  • [87].Kozak K.R., Marnett L.J. Oxidative metabolism of endocannabinoids. Prostaglandins Leukot Essent Fatty Acids. 2002;66:211–220. doi: 10.1054/plef.2001.0359. [DOI] [PubMed] [Google Scholar]
  • [88].Saario S.M., Savinainen J.R., Laitinen J.T., Järvinen T., Niemi R. Monoglyceride lipase-like enzymatic activity is responsible for hydrolysis of 2-arachidonoylglycerol in rat cerebellar membranes. Biochem Pharmacol. 2004;67:1381–1387. doi: 10.1016/j.bcp.2003.12.003. [DOI] [PubMed] [Google Scholar]
  • [89].Dinh T.P., Kathuria S., Piomelli D. RNA interference suggests a primary role for monoacylglycerol lipase in the degradation of the endocannabinoid 2-arachidonoylglycerol. Mol Pharmacol. 2004;66:1260–1264. doi: 10.1124/mol.104.002071. [DOI] [PubMed] [Google Scholar]
  • [90].Paria B.C., Dey S.K. Ligand-receptor signaling with endocannabinoids in preimplantation embryo development and implantation. Chem Phys Lipids. 2000;108:211–220. doi: 10.1016/S0009-3084(00)00197-3. [DOI] [PubMed] [Google Scholar]
  • [91].Fernandez-Ruiz J., Berrendero F., Hernandez M.L., Ramos J.A. The endogenous cannabinoid system and brain development. Trends Neurosci. 2000;23:14–20. doi: 10.1016/S0166-2236(99)01491-5. [DOI] [PubMed] [Google Scholar]
  • [92].Berrendero F., Sepe N., Ramos J.A., Di Marzo V., Fernández-Ruiz J.J. Analysis of cannabinoid receptor binding and mRNA expression and endogenous cannabinoid contents in the developing rat brain during late gestation and early postnatal period. Synapse. 1999;33:181–191. doi: 10.1002/(SICI)1098-2396(19990901)33:3<181::AID-SYN3>3.0.CO;2-R. [DOI] [PubMed] [Google Scholar]
  • [93].Romero J., Garcia-Palomero E., Berrendero F., Garcia-Gil L., Hernández M.L., Ramos J.A., et al. Atypical localization of cannabinoid receptors in white matter areas during rat brain development. Synapse. 1997;26:317–323. doi: 10.1002/(SICI)1098-2396(199707)26:3<317::AID-SYN12>3.0.CO;2-S. [DOI] [PubMed] [Google Scholar]
  • [94].Biegon A., Kerman I.A. Autoradiographic study of pre- and postnatal distribution of cannabinoid receptors in human brain. Neuroimage. 2001;14:1463–1468. doi: 10.1006/nimg.2001.0939. [DOI] [PubMed] [Google Scholar]
  • [95].Mato S., Del Olmo E., Pazos A. Ontogenetic development of cannabinoid receptor expression and signal transduction functionality in the human brain. Eur J Neurosci. 2003;17:1747–1754. doi: 10.1046/j.1460-9568.2003.02599.x. [DOI] [PubMed] [Google Scholar]
  • [96].Wilson R.I., Nicoll R.A. Endocannabinoid signaling in the brain. Science. 2002;296:678–682. doi: 10.1126/science.1063545. [DOI] [PubMed] [Google Scholar]
  • [97].Ohno-Shosaku T., Maejima T., Kano M. Endogenous cannabinoids mediate retrograde signals from depolarized postsynaptic neurons to presynaptic terminals. Neuron. 2001;29:729–738. doi: 10.1016/S0896-6273(01)00247-1. [DOI] [PubMed] [Google Scholar]
  • [98].Kyrou I., Valsamakis G., Tsigos C. The endocannabinoid system as a target for the treatment of visceral obesity and metabolic syndrome. Ann N Y Acad Sci. 2006;1083:270–305. doi: 10.1196/annals.1367.024. [DOI] [PubMed] [Google Scholar]
  • [99].Di Marzo V., Melck D., Bisogno T., De Petrocellis L. Endocannabinoids: endogenous cannabinoid receptor ligands with neuromodulatory action. Trends Neurosci. 1998;21:521–528. doi: 10.1016/S0166-2236(98)01283-1. [DOI] [PubMed] [Google Scholar]
  • [100].Maejima T., Hashimoto K., Yoshida T., Aiba A., Kano M. Presynaptic inhibition caused by retrograde signal from metabotropic glutamate to cannabinoid receptors. Neuron. 2001;31:463–475. doi: 10.1016/S0896-6273(01)00375-0. [DOI] [PubMed] [Google Scholar]
  • [101].Galve-Roperh I., Aguado T., Palazuelos J., Guzmán M. Mechanisms of control of neuron survival by the endocannabinoid system. Curr Pharm Des. 2008;14:2279–2288. doi: 10.2174/138161208785740117. [DOI] [PubMed] [Google Scholar]
  • [102].Gerdeman G., Lovinger D.M. CB1 cannabinoid receptor inhibits synaptic release of glutamate in rat dorsolateral striatum. J Neurophysiol. 2001;85:468–471. doi: 10.1152/jn.2001.85.1.468. [DOI] [PubMed] [Google Scholar]
  • [103].Galante M., Diana M.A. Group I metabotropic glutamate receptors inhibit GABA release atinterneuron-Purkinje cell synapses through endocannabinoid production. J Neurosci. 2004;24:4865–4874. doi: 10.1523/JNEUROSCI.0403-04.2004. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [104].Domenici M.R., Azad S.C., Marsicano G., Schierloh A., Wotjak C.T., Dodt H.U., et al. Cannabinoid receptor type 1 located on presynaptic terminals of principal neurons in the forebrain controls glutamatergic synaptic transmission. J Neurosci. 2006;26:5794–5799. doi: 10.1523/JNEUROSCI.0372-06.2006. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [105].Nemeth B., Ledent C., Freund T.F., Hajos N. CB1 receptor-dependent and -independent inhibition of excitatory postsynaptic currents in the hippocampus by WIN 55,212-2. Neuropharmacology. 2008;54:51–57. doi: 10.1016/j.neuropharm.2007.07.003. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [106].Bonfoco E., Krainc D., Ankarcrona M., Nicotera P., Lipton S.A. Apoptosis and necrosis: two distinct events induced, respectively, by mild and intense insults with N-methyl-d-aspartate or nitric oxide? superoxide in cortical cell cultures. Proc Natl Acad Sci U S A. 1995;92:7162–7166. doi: 10.1073/pnas.92.16.7162. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [107].Katona I., Sperlagh B., Sik A., Kafalvi A., Vizi E.S., Mackie K., et al. Presynaptically located CB1 cannabinoid receptors regulate GABA release from axon terminals of specific hippocampal interneurons. J Neurosci. 1999;19:4544–4558. doi: 10.1523/JNEUROSCI.19-11-04544.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [108].Hajos N., Katona I., Naiem S.S., Mackie K., Ledent C., Mody I., et al. Cannabinoids inhibit hippocampal GABAergic transmission and network oscillations. Eur J Neurosci. 2000;12:3239–3249. doi: 10.1046/j.1460-9568.2000.00217.x. [DOI] [PubMed] [Google Scholar]
  • [109].Pellegrini-Giampietro D.E., Mannaioni G., Bagetta G. Post-ischemic brain damage: the endocannabinoid system in the mechanisms of neuronal death. FEBS J. 2009;276:2–12. doi: 10.1111/j.1742-4658.2008.06765.x. [DOI] [PubMed] [Google Scholar]
  • [110].Ozaita A., Puighermanal E., Maldonado R. Regulation of PI3K/Akt/GSK-3 pathway by cannabinoids in the brain. J Neurochem. 2007;102:1105–1114. doi: 10.1111/j.1471-4159.2007.04642.x. [DOI] [PubMed] [Google Scholar]
  • [111].Freund T.F., Katona I., Piomelli D. Role of endogenous cannabinoids in synaptic signalling. Physiol Rev. 2003;83:1017–1066. doi: 10.1152/physrev.00004.2003. [DOI] [PubMed] [Google Scholar]
  • [112].Pacher P., Batkai S., Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58:389–462. doi: 10.1124/pr.58.3.2. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [113].Walter L., Stella N. Cannabinoids and neuroinflammation. Br J Pharmacol. 2004;141:775–785. doi: 10.1038/sj.bjp.0705667. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [114].Klein T.W. Cannabinoid-based drugs as anti-inflammatory therapeutics. Nat Rev Immunol. 2005;5:400–411. doi: 10.1038/nri1602. [DOI] [PubMed] [Google Scholar]
  • [115].Hampson A.J., Grimaldi M., Lolic M., Wink D., Rosenthal R., Axelrod J. Neuroprotective antioxidants from marijuana. Ann N Y Acad Sci. 2000;899:274–282. doi: 10.1111/j.1749-6632.2000.tb06193.x. [DOI] [PubMed] [Google Scholar]
  • [116].Nagayama T., Sinor A.D., Simon R.P., Chen J., Graham S.H., Jin K., et al. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999;19:2987–2995. doi: 10.1523/JNEUROSCI.19-08-02987.1999. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [117].Louw D.F., Yang F.W., Sutherland G.R. The effect of delta-9-tetrahydrocannabinol on forebrain ischemia in rat. Brain Res. 2000;857:183–187. doi: 10.1016/S0006-8993(99)02422-1. [DOI] [PubMed] [Google Scholar]
  • [118].Braida D., Pozzi M., Sala M. CP 55,940 protects against ischemiainduced electroencephalographic flattening and hyperlocomotion in Mongolian gerbils. Neurosci Lett. 2000;296:69–72. doi: 10.1016/S0304-3940(00)01634-7. [DOI] [PubMed] [Google Scholar]
  • [119].Mauler F., Hinz V., Augstein K.H., Fassbender M., Horvath E. Neuroprotective and brain edema reducing efficacy of the novel cannabinoid receptor agonist BAY 38-7271. Brain Res. 2003;989:99–111. doi: 10.1016/S0006-8993(03)03376-6. [DOI] [PubMed] [Google Scholar]
  • [120].Leker R.R., Gai N., Mechoulam R., Ovadia H. Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210. Stroke. 2003;34:2000–2006. doi: 10.1161/01.STR.0000079817.68944.1E. [DOI] [PubMed] [Google Scholar]
  • [121].Hayakawa K., Mishima K., Abe K., Hasebe N., Takamatsu F., Yasuda H., et al. Cannabidiol prevents infarction via the non-CB1 cannabinoid receptor mechanism. Neuroreport. 2004;15:2381–2385. doi: 10.1097/00001756-200410250-00016. [DOI] [PubMed] [Google Scholar]
  • [122].Parmentier-Batteur S., Jin K., Mao X.O., Xie L., Greenberg D.A. Increased severity of stroke in CB1 cannabinoid receptor knock-out mice. J Neurosci. 2002;22:9771–9775. doi: 10.1523/JNEUROSCI.22-22-09771.2002. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [123].van der Stelt M., Veldhuis W.B., van Haaften G.W., Fezza F., Bisogno T., Bar P.R., et al. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci. 2001;21:8765–8771. doi: 10.1523/JNEUROSCI.21-22-08765.2001. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [124].Panikashvili D., Shein N.A., Mechoulam R., Trembovler V., Kohen R., Alexandrovich A., et al. The endocannabinoid 2-AG protects the blood-brain barrier after closed head injury and inhibits mRNA expression of proinflammatory cytokines. Neurobiol Dis. 2006;22:257–264. doi: 10.1016/j.nbd.2005.11.004. [DOI] [PubMed] [Google Scholar]
  • [125].Schomacher M., Müller H.D., Sommer C., Schwab S., Schäbitz W.R. Endocannabinoids mediate neuroprotection after transient focal cerebral ischemia. Brain Res. 2008;1240:213–220. doi: 10.1016/j.brainres.2008.09.019. [DOI] [PubMed] [Google Scholar]
  • [126].Melis M., Pillolla G., Bisogno T., Minassi A., Petrosino S., Perra S., et al. Protective activation of the endocannabinoid system during ischemia in dopamine neurons. Neurobiol Dis. 2006;24:15–27. doi: 10.1016/j.nbd.2006.04.010. [DOI] [PubMed] [Google Scholar]
  • [127].Zani A., Braida D., Capurro V., Sala M. Delta9-tetrahydrocannabinol (THC) and AM 404 protect against cerebral ischaemia in gerbils through a mechanism involving cannabinoid and opioid receptors. Br J Pharmacol. 2007;152:1301–1311. doi: 10.1038/sj.bjp.0707514. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [128].Degn M., Lambertsen K.L., Petersen G., Meldgaard M., Artmann A., Clausen B.H., et al. Changes in brain levels of N-acylethanolamines and 2-arachidonoylglycerol in focal cerebral ischemia in mice. J Neurochem. 2007;103:1907–1916. doi: 10.1111/j.1471-4159.2007.04892.x. [DOI] [PubMed] [Google Scholar]
  • [129].Waksman Y., Olson J.M., Carlisle S.J., Cabral G.A. The central cannabinoid receptor (CB1) mediates inhibition of nitric oxide production by rat microglial cells. J Pharmacol Exp Ther. 1999;288:1357–1366. [PubMed] [Google Scholar]
  • [130].Klein T.W., Lane B., Newton C.A., Friedman H. The cannabinoid system and cytokine network. Proc Soc Exp Biol Med. 2000;225:1–8. doi: 10.1046/j.1525-1373.2000.22501.x. [DOI] [PubMed] [Google Scholar]
  • [131].Grundy R.I., Rabuffetti M., Beltramo M. Cannabinoids and neuroprotection. Mol Neurobiol. 2001;24:29–51. doi: 10.1385/MN:24:1-3:029. [DOI] [PubMed] [Google Scholar]
  • [132].Mechoulam R., Panikashvili D., Shohami E. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med. 2002;8:58–61. doi: 10.1016/S1471-4914(02)02276-1. [DOI] [PubMed] [Google Scholar]
  • [133].Fernandez-Lopez D., Martinez-Orgado J., Nuñez E., Romero J., Lorenzo P., Moro M.A., et al. Characterization of the neuroprotective effect of the cannabinoid agonist WIN-55212 in an in vitro model of hypoxic-ischemic brain damage in newborn rats. Pediatr Res. 2006;60:169–173. doi: 10.1203/01.pdr.0000228839.00122.6c. [DOI] [PubMed] [Google Scholar]
  • [134].Martinez-Orgado J., Fernandez-Lopez D., Lizasoain I., Romero J. The seek of neuroprotection: introducing cannabinoids. Recent Pat CNS Drug Discov. 2007;2:131–139. doi: 10.2174/157488907780832724. [DOI] [PubMed] [Google Scholar]
  • [135].Alonso-Alconada D., Alvarez F.J., Alvarez A., Mielgo V.E., Goñi-de-Cerio F., Rey-Santano M.C., et al. The cannabinoid receptor agonist WIN 55,212-2 reduces the initial cerebral damage after hypoxicischemic injury in fetal lambs. Brain Res. 2010;1362:150–159. doi: 10.1016/j.brainres.2010.09.050. [DOI] [PubMed] [Google Scholar]
  • [136].Gazzolo D., Vinesi P., Bartocci M., Geloso M.C., Bonacci W., Serra G., et al. Elevated S100 blood levels as an early indicator of intraventricular haemorrhage in preterm infants. Correlation with cerebral Doppler velocimetry. J Neurol Sci. 1999;170:32–35. doi: 10.1016/S0022-510X(99)00194-X. [DOI] [PubMed] [Google Scholar]
  • [137].Blennow M., Savman K., Ilves P., Thoresen M., Rosengren L. Brainspecific proteins in the cerebrospinal fluid of severely asphyxiated newborn infants. Acta Paediatr. 2001;90:1171–1175. doi: 10.1111/j.1651-2227.2001.tb03249.x. [DOI] [PubMed] [Google Scholar]
  • [138].Böttiger B.W., Möbes S., Glätzer R., Bauer H., Gries A., Bärtsch P., et al. Astroglial protein S-100 is an early and sensitive marker of hypoxic brain damage and outcome after cardiac arrest in humans. Circulation. 2001;103:2694–2698. doi: 10.1161/01.cir.103.22.2694. [DOI] [PubMed] [Google Scholar]
  • [139].Thorngren-Jerneck K., Alling C., Herbst A., Amer-Wahlin I., Marsal K. S100 protein in serum as a prognostic marker for cerebral injury in term newborn infants with hypoxic ischemic encephalopathy. Pediatr Res. 2004;55:406–412. doi: 10.1203/01.PDR.0000106806.75086.D3. [DOI] [PubMed] [Google Scholar]
  • [140].Goñi-de-Cerio F., Alvarez A., Alvarez F.J., Rey-Santano M.C., Alonso-Alconada D., Mielgo V.E., et al. MgSO4 treatment preserves the ischemia-induced reduction in S-100 protein without modification of the expression of endothelial tight junction molecules. Histol Histopathol. 2009;24:1129–1138. doi: 10.14670/HH-24.1129. [DOI] [PubMed] [Google Scholar]
  • [141].Fernández-López D., Pazos M.R., Tolón R.M., Moro M.A., Romero J., Lizasoain I., et al. The cannabinoid agonist WIN55212 reduces brain damage in an in vivo model of hypoxic-ischemic encephalopathy in newborn rats. Pediatr Res. 2007;62:255–260. doi: 10.1203/PDR.0b013e318123fbb8. [DOI] [PubMed] [Google Scholar]
  • [142].Fernández-López D., Pradillo J.M., García-Yébenes I., Martínez-Orgado J.A., Moro M.A., Lizasoain I. The cannabinoid WIN55212-2 promotes neural repair after neonatal hypoxia-ischemia. Stroke. 2010;41:2956–2964. doi: 10.1161/STROKEAHA.110.599357. [DOI] [PubMed] [Google Scholar]
  • [143].Fernández-Ruiz J., Romero J., Velasco G., Tolon R.M., Ramos J.A., Guzman M. Cannabinoid CB2 receptor: a new target for controlling neural cell survival? Trends Pharmacol Sci. 2007;28:39–45. doi: 10.1016/j.tips.2006.11.001. [DOI] [PubMed] [Google Scholar]
  • [144].Ashton J.C., Rahman R.M.A., Nair S.M., Sutherland B.A., Glass M., Appleton I. Cerebral hypoxia-ischemia and middle cerebral artery occlusion induce expression of the cannabinoide CB2 receptor in the brain. Neurosci Lett. 2007;412:114–117. doi: 10.1016/j.neulet.2006.10.053. [DOI] [PubMed] [Google Scholar]
  • [145].Mauler F., Horvath E., De Vry J., Jager R., Schwarz T., Sandmann S., et al. BAY 38-7271: a novel highly selective and highly potent cannabinoid receptor agonist for the treatment of traumatic brain injury. CNS Drug Rev. 2003;9:343–358. doi: 10.1111/j.1527-3458.2003.tb00259.x. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [146].Ni X., Geller E.B., Eppihimer M.J., Eisenstein T.K., Adler M.W., Tuma R.F. WIN 55212-2, a cannabinoid receptor agonist, attenuates leukocyte/endothelial interactions in an experimental autoimmune encephalomyelitis model. Mult Scler. 2004;10:158–164. doi: 10.1191/1352458504ms1009oa. [DOI] [PubMed] [Google Scholar]
  • [147].Ramirez B.G., Blazquez C., Gomez del Pulgar T., Guzman M., de Ceballos M.L. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25:1904–1913. doi: 10.1523/JNEUROSCI.4540-04.2005. [DOI] [PMC free article] [PubMed] [Google Scholar]
  • [148].Maresz K., Carrier E.J., Ponomarev E.D., Hillard C.J., Dittel B.N. Modulation of the cannabinoid CB2 receptor in microglial cells in response to inflammatory stimuli. J Neurochem. 2005;95:437–445. doi: 10.1111/j.1471-4159.2005.03380.x. [DOI] [PubMed] [Google Scholar]
  • [149].Fernández-Ruiz J., Pazos M.R., Garcia-Arencibia M., Sagredo O., Ramos J.A. Role of CB2 receptors in neuroprotective effects of cannabinoids. Mol Cell Endocrinol. 2008;286:91–96. doi: 10.1016/j.mce.2008.01.001. [DOI] [PubMed] [Google Scholar]
  • [150].Castillo A., Tolón M.R., Fernández-Ruiz J., Romero J., Martinez-Orgado J. The neuroprotective effect of cannabidiol in an in vitro model of newborn hypoxic-ischemic brain damage in mice is mediated by CB(2) and adenosine receptors. Neurobiol Dis. 2010;37:434–440. doi: 10.1016/j.nbd.2009.10.023. [DOI] [PubMed] [Google Scholar]

Articles from Neuroscience Bulletin are provided here courtesy of Springer

RESOURCES