1,196
Views
17
CrossRef citations to date
0
Altmetric
Reviews

Beneficial and deleterious effects of cannabinoids in the brain: the case of ultra-low dose THC

Pages 551-562 | Received 17 Sep 2018, Accepted 29 Jan 2019, Published online: 13 Mar 2019

References

  • Solowij N, Pesa N. Cannabis and cognition: short-and long-term effects. In: Castle D, Murray RM, D’Souza DC, editors. Marijuana and madness. Cambridge: Cambridge University Press; 2011. p. 91–102.
  • Zuurman L, Ippel AE, Moin E, Jma: VG. Biomarkers for the effects of cannabis and THC in healthy volunteers. Br J Clin Pharmacol. 2009;67(1):5–21. doi:10.1111/j.1365-2125.2008.03329.x.
  • Sagar KA, Gruber SA. Marijuana matters: reviewing the impact of marijuana on cognition, brain structure and function, & exploring policy implications and barriers to research. Int Rev Psychiatry. 2018;30(3):251–67. doi:10.1080/09540261.2018.1460334.
  • Di Marzo V, Bifulco M, De Petrocellis L. The endocannabinoid system and its therapeutic exploitation. Nature Rev Drug Discov. 2004;3(9):771–84. doi:10.1038/nrd1495.
  • Schrot RJ, Hubbard JR. Cannabinoids: medical implications. Ann Med. 2016;48(3):128–41. doi:10.3109/07853890.2016.1145794.
  • Giacoppo S, Mandolino G, Galuppo M, Bramanti P, Mazzon E. Cannabinoids: new promising agents in the treatment of neurological diseases. Molecules. 2014;19(11):18781–816. doi:10.3390/molecules191118781.
  • Pacher P, Batkai S, Kunos G. The endocannabinoid system as an emerging target of pharmacotherapy. Pharmacol Rev. 2006;58(3):389–462. doi:10.1124/pr.58.3.2.
  • Kano M, Ohno-Shosaku T, Hashimotodani Y, Uchigashima M, Watanabe M. Endocannabinoid-mediated control of synaptic transmission. Physiol Rev. 2009;89(1):309–80. doi:10.1152/physrev.00019.2008.
  • Hall W, Solowij N. Adverse effects of cannabis. Lancet. 1998;352(9140):1611–16. doi:10.1016/S0140-6736(98)05021-1.
  • Iversen L. Cannabis and the brain. Brain. 2003;126:1252–70.
  • Solowij N, Pesa N. Cognitive abnormalities and cannabis use. Rev Bras Psiquiatr. 2010;32:S31–S40.
  • Egerton A, Allison C, Brett RR, Pratt JA. Cannabinoids and prefrontal cortical function: insights from preclinical studies. Neurosci Biobehav Rev. 2006;30(5):680–95. doi:10.1016/j.neubiorev.2005.12.002.
  • Pattij T, Wiskerke J, Schoffelmeer ANM. Cannabinoid modulation of executive functions. Eur J Pharmacol. 2008;585(2–3):458–63. doi:10.1016/j.ejphar.2008.02.099.
  • Solowij N, Michie PT. Cannabis and cognitive dysfunction: parallels with endophenotypes of schizophrenia? J Psychiatry Neurosci. 2007;32(1):30–52.
  • Solowij N, Grenyer BFS. Are the adverse consequences of cannabis use age-dependent? Addiction. 2002;97(9):1083–86.
  • Jager G, Kahn RS, Van Den Brink W, Van Ree JM, Ramsey NF. Long-term effects of frequent cannabis use on working memory and attention: an fMRI study. Psychopharmacology (Berl). 2006;185(3):358–68. doi:10.1007/s00213-005-0298-7.
  • Kanayama G, Rogowska J, Pope HG, Gruber SA, Yurgelun-Todd DA. Spatial working memory in heavy cannabis users: a functional magnetic resonance imaging study. Psychopharmacology (Berl). 2004;176(3–4):239–47. doi:10.1007/s00213-004-1885-8.
  • Cohen M, Rasser PE, Peck G, Carr VJ, Ward PB, Thompson PM, Johnston P, Baker A, Schall U. Cerebellar grey-matter deficits, cannabis use and first-episode schizophrenia in adolescents and young adults. Int J Neuropsychopharmacol. 2011;15(3):1–11.
  • Solowij N, Yucel M, Respondek C, Whittle S, Lindsay E, Pantelis C, Lubman DI. Cerebellar white-matter changes in cannabis users with and without schizophrenia. Psychol Med. 2011;41(11):2349–59. doi:10.1017/S003329171100050X.
  • Fehr KA, Kalant H, LeBlanc AE. Residual learning deficit after heavy exposure to cannabis or alcohol in rats. Science. 1976;192(4245):1249–51.
  • Stiglick A, Kalant H. Behavioral effects of prolonged administration of delta 9-tetrahydrocannabinol in the rat. Psychopharmacology (Berl). 1983;80(4):325–30.
  • Rubino T, Realini N, Braida D, Guidi S, Capurro V, Vigano D, Guidali C, Pinter M, Sala M, Bartesaghi R, et al. Changes in hippocampal morphology and neuroplasticity induced by adolescent THC treatment are associated with cognitive impairment in adulthood. Hippocampus. 2009;19(8):763–72. doi:10.1002/hipo.20554.
  • Lawston J, Borella A, Robinson JK, Whitaker-Azmitia PM. Changes in hippocampal morphology following chronic treatment with the synthetic cannabinoid WIN 55,212-2. Brain Res. 2000;877(2):407–10.
  • Scallet AC. Neurotoxicology of cannabis and THC: a review of chronic exposure studies in animals. Pharmacol Biochem Behav. 1991;40(3):671–76.
  • Scallet AC, Uemura E, Andrews A, Ali SF, McMillan DE, Paule MG, Brown RM, Slikker W Jr. Morphometric studies of the rat hippocampus following chronic delta-9-tetrahydrocannabinol (THC). Brain Res. 1987;436(1):193–98.
  • Sanchez C, Galve-Roperh I, Rueda D, Guzman M. Involvement of sphingomyelin hydrolysis and the mitogen-activated protein kinase cascade in the Delta9-tetrahydrocannabinol-induced stimulation of glucose metabolism in primary astrocytes. Mol Pharmacol. 1998;54(5):834–43.
  • Chan GCK, Hinds TR, Impey S, Storm DR. Hippocampal neurotoxicity of Delta(9)-tetrahydrocannabinol. J Neurosci. 1998;18(14):5322–32.
  • Del Pulgar TG, Velasco G, Sanchez C, Haro A, Guzman M. De novo-synthesized ceramide is involved in cannabinoid-induced apoptosis. Biochem J. 2002;363:183–188.
  • Downer EJ, Fogarty MP, Campbell VA. Tetrahydrocannabinol-induced neurotoxicity depends on CB1 receptor-mediated c-Jun N-terminal kinase activation in cultured cortical neurons. Br J Pharmacol. 2003;140(3):547–57. doi:10.1038/sj.bjp.0705464.
  • Nagayama T, Sinor AD, Simon RP, Chen J, Graham SH, Jin K, Greenberg DA. Cannabinoids and neuroprotection in global and focal cerebral ischemia and in neuronal cultures. J Neurosci. 1999;19(8):2987–95.
  • van der Stelt M, Veldhuis WB, Bar PR, Veldink GA, Vliegenthart JF, Nicolay K. Neuroprotection by Delta9-tetrahydrocannabinol, the main active compound in marijuana, against ouabain-induced in vivo excitotoxicity. J Neurosci. 2001a;21(17):6475–79. doi:10.1523/JNEUROSCI.21-17-06475.2001.
  • van der Stelt M, Veldhuis WB, van Haaften GW, Fezza F, Bisogno T, Bar PR, Veldink GA, Vliegenthart JF, Di Marzo V, Nicolay K. Exogenous anandamide protects rat brain against acute neuronal injury in vivo. J Neurosci. 2001b;21(22):8765–71. doi:10.1523/JNEUROSCI.21-22-08765.2001.
  • Panikashvili D, Simeonidou C, Ben-Shabat S, Hanus L, Breuer A, Mechoulam R, Shohami E. An endogenous cannabinoid (2-AG) is neuroprotective after brain injury. Nature. 2001;413(6855):527–31. doi:10.1038/35097089.
  • Tourino C, Zimmer A, Valverde O. THC prevents MDMA neurotoxicity in mice. PLoS One. 2010;5(2):e9143. doi:10.1371/journal.pone.0009143.
  • Shouman B, Fontaine RH, Baud O, Schwendimann L, Keller M, Spedding M, Lelievre V, Gressens P. Endocannabinoids potently protect the newborn brain against AMPA-kainate receptor-mediated excitotoxic damage. Br J Pharmacol. 2006;148(4):442–51. doi:10.1038/sj.bjp.0706755.
  • Mackie K, Hille B. Cannabinoids inhibit N-type calcium channels in neuroblastoma-glioma cells. Proc Natl Acad Sci U S A. 1992;89(9):3825–29.
  • Caulfield MP, Brown DA. Cannabinoid receptor agonists inhibit Ca current in Ng108-15 neuroblastoma-cells via a pertussis toxin-sensitive mechanism. Br J Pharmacol. 1992;106(2):231–32.
  • Shen M, Piser TM, Seybold VS, Thayer SA. Cannabinoid receptor agonists inhibit glutamatergic synaptic transmission in rat hippocampal cultures. J Neurosci. 1996;16(14):4322–34.
  • Hillard CJ, Muthian S, Kearn CS. Effects of CB(1) cannabinoid receptor activation on cerebellar granule cell nitric oxide synthase activity. FEBS Lett. 1999;459(2):277–81.
  • Facchinetti F, Del Giudice E, Furegato S, Passarotto M, Leon A. Cannabinoids ablate release of TNFalpha in rat microglial cells stimulated with lypopolysaccharide. Glia. 2003;41(2):161–68. doi:10.1002/glia.10177.
  • Leker RR, Gai N, Mechoulam R, Ovadia H. Drug-induced hypothermia reduces ischemic damage: effects of the cannabinoid HU-210. Stroke. 2003;34(8):2000–06. doi:10.1161/01.STR.0000079817.68944.1E.
  • Wagner JA, Jarai Z, Batkai S, Kunos G. Hemodynamic effects of cannabinoids: coronary and cerebral vasodilation mediated by cannabinoid CB(1) receptors. Eur J Pharmacol. 2001;423(2–3):203–10.
  • Hampson AJ, Grimaldi M, Axelrod J, Wink D. Cannabidiol and (-)Delta(9)-tetrahydrocannabinol are neuroprotective antioxidants. Proc Natl Acad Sci U S A. 1998;95(14):8268–73.
  • Hansen HH, Schmid PC, Bittigau P, Lastres-Becker I, Berrendero F, Manzanares J, Ikonomidou C, Schmid HHO, Fernandez-Ruiz JJ, Hansen HS. Anandamide, but not 2-arachidonoylglycerol, accumulates during in vivo neurodegeneration. J Neurochem. 2001;78(6):1415–27.
  • Bilkei-Gorzo A. The endocannabinoid system in normal and pathological brain ageing. Philos Trans R Soc Lond B Biol Sci. 2012;367(1607):3326–41. doi:10.1098/rstb.2011.0388.
  • Di Marzo V, Stella N, Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nature Rev Neurosci. 2015;16(1):30–42. doi:10.1038/nrn3876.
  • Mechoulam R, Panikashvili D, Shohami E. Cannabinoids and brain injury: therapeutic implications. Trends Mol Med. 2002;8(2):58–61.
  • Fernandez-Ruiz J, Gomez-Ruiz M, Garcia C, Hernandez M, Ramos JA. Modeling neurodegenerative disorders for developing cannabinoid-based neuroprotective therapies. Methods Enzymol. 2017;593:175–198. doi:10.1016/bs.mie.2017/06/021.
  • Milton NGN. Anandamide and noladin ether prevent neurotoxicity of the human amyloid-beta peptide. Neurosci Lett. 2002;332(2):127–30.
  • Lastres-Becker I, Molina-Holgado F, Ramos JA, Mechoulam R, Fernandez-Ruiz J. Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson’s disease. Neurobiol Dis. 2005;19(1–2):96–107. doi:10.1016/j.nbd.2004.11.009.
  • Lastres-Becker I, Bizat N, Boyer F, Hantraye P, Fernandez-Ruiz J, Brouillet E. Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivo. Neuroreport. 2004;15(15):2375–79.
  • Ramirez BG, Blazquez C, Del Pulgar TG, Guzman N, Mal: DC. Prevention of Alzheimer’s disease pathology by cannabinoids: neuroprotection mediated by blockade of microglial activation. J Neurosci. 2005;25(8):1904–13. doi:10.1523/JNEUROSCI.4540-04.2005.
  • Martin-Moreno AM, Brera B, Spuch C, Carro E, Garcia-Garcia L, Delgado M, Pozo MA, Innamorato NG, Cuadrado A, de Ceballos ML. Prolonged oral cannabinoid administration prevents neuroinflammation, lowers beta-amyloid levels and improves cognitive performance in Tg APP 2576 mice. J Neuroinflammation. 2012;9:8. doi:10.1186/1742-2094-9-8.
  • Bachmeier C, Beaulieu-Abdelahad D, Mullan M, Paris D. Role of the cannabinoid system in the transit of beta-amyloid across the blood-brain barrier. Mol Cell Neurosci. 2013;56:255–262. doi:10.1016/j.mcn.2013.06.004.
  • Aso E, Sanchez-Plac A, Vegas-Lozano E, Maldonado R, Ferrer I. Cannabis-based medicine reduces multiple pathological processes in A beta PP/PS1 mice. J Alzheimers Dis. 2015;43(3):977–91. doi:10.3233/JAD-141014.
  • Marchalant Y, Cerbai F, Brothers HM, Wenk GL. Cannabinoid receptor stimulation is anti-inflammatory and improves memory in old rats. Neurobiol Aging. 2008;29(12):1894–901. doi:10.1016/j.neurobiolaging.2007.04.028.
  • Bilkei-Gorzo A, Albayram O, Draffehn A, Michel K, Piyanova A, Oppenheimer H, Dvir-Ginzberg M, Racz I, Ulas T, Imbeault S, et al. A chronic low dose of [Delta]9-tetrahydrocannabinol (THC) restores cognitive function in old mice. Nat Med. 2017;23(6):782–87. doi:10.1038/nm.4311.
  • Marchalant Y, Brothers HM, Wenk GL. Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged rat brain. Mol Psychiatry. 2009;14(12):1068–69. doi:10.1038/mp.2009.62.
  • Li Y, Kim J. Distinct roles of neuronal and microglial CB2 cannabinoid receptors in the mouse hippocampus. Neuroscience. 2017;363:11–25. doi:10.1016/j.neuroscience.2017.08.053.
  • Onaivi ES, Ishiguro H, Gu SZ, Liu QR. CNS effects of CB2 cannabinoid receptors: beyond neuro-immuno-cannabinoid activity. J Psychopharmacol. 2012;26(1):92–103. doi:10.1177/0269881111400652.
  • Sierra S, Luquin N, Rico AJ, Gomez-Bautista V, Roda E, Dopeso-Reyes IG, Vazquez A, Martinez-Pinilla E, Labandeira-Garcia JL, Franco R, et al. Detection of cannabinoid receptors CB1 and CB2 within basal ganglia output neurons in macaques: changes following experimental parkinsonism. Brain Struct Funct. 2015;220(5):2721–38. doi:10.1007/s00429-014-0823-8.
  • Zhang HY, Gao M, Shen H, Bi GH, Yang HJ, Liu QR, Wu J, Gardner EL, Bonci A, Xi ZX. Expression of functional cannabinoid CB2 receptor in VTA dopamine neurons in rats. Addict Biol. 2017;22(3):752–65. doi:10.1111/adb.12367.
  • Cascio MG, Gauson LA, Stevenson LA, Ross RA, Pertwee RG. Evidence that the plant cannabinoid cannabigerol is a highly potent alpha(2)-adrenoceptor agonist and moderately potent 5HT(1A) receptor antagonist. Br J Pharmacol. 2010;159(1):129–41. doi:10.1111/j.1476-5381.2009.00515.x.
  • Console-Bram L, Brailoiu E, Brailoiu GC, Sharir H, Abood ME. Activation of GPR18 by cannabinoid compounds: a tale of biased agonism. Br J Pharmacol. 2014;171(16):3908–17. doi:10.1111/bph.12746.
  • De Petrocellis L, Di Marzo V. Non-CB1, non-CB2 Receptors for endocannabinoids, plant cannabinoids, and synthetic cannabimimetics: focus on G-protein-coupled receptors and transient receptor potential channels. J Neuroimmune Pharm. 2010;5(1):103–21. doi:10.1007/s11481-009-9177-z.
  • Sterin-Borda L, Del Zar CF, Borda E. Differential CB1 and CB2 cannabinoid receptor-inotropic response of rat isolated atria: endogenous signal transduction pathways. Biochem Pharmacol. 2005;69(12):1705–13. doi:10.1016/j.bcp.2005.03.027.
  • Mukhopadhyay S, Howlett AC. Chemically distinct ligands promote differential CB1 cannabinoid receptor-Gi protein interactions. Mol Pharmacol. 2005;67(6):2016–24. doi:10.1124/mol.104.003558.
  • Roloff AM, Thayer SA. Modulation of excitatory synaptic transmission by Delta(9)-Tetrahydrocannabinol switches from agonist to antagonist depending on firing rate. Mol Pharmacol. 2009;75(4):892–900. doi:10.1124/mol.108.051482.
  • Bologov A, Gafni M, Keren O, Sarne Y. Dual neuroprotective and neurotoxic effects of cannabinoid drugs in vitro. Cell Mol Neurobiol. 2011;31(2):195–202. doi:10.1007/s10571-010-9604-y.
  • Downer EJ, Gowran A, Campbell VA. A comparison of the apoptotic effect of Delta(9)-tetrahydrocannabinol in the neonatal and adult rat cerebral cortex. Brain Res. 2007;1175:39–47. doi:10.1016/j.brainres.2007.07.076.
  • Solowij N, Jones KA, Rozman ME, Davis SM, Ciarrochi J, Heaven PCL, Lubman DI, Yucel M. Verbal learning and memory in adolescent cannabis users, alcohol users and non-users. Psychopharmacology. 2011;216(1):131–44. doi:10.1007/s00213-011-2203-x.
  • Meier MH, Caspi A, Ambler A, Harrington H, Houts R, Keefe RSE, McDonald K, Ward A, Poulton R, Moffitt TE. Persistent cannabis users show neuropsychological decline from childhood to midlife. Proc Natl Acad Sci U S A. 2012;109(40):E2657–E2664. doi:10.1073/pnas.1206820109.
  • Tzavara ET, Wade M, Nomikos GG. Biphasic effects of cannabinoids on acetylcholine release in the hippocampus: site and mechanism of action. J Neurosci. 2003;23(28):9374–84.
  • Norris C, Szkudlarek HJ, Pereira B, Laviolette SR. Delta9-tetrahydrocannabinol (THC) produces bi-phasic rewarding and avversive effects in the anterior vs. posterior nucleus accumbens shell through dissociable mu vs. kappa opiate receptor mechanisms and differential modulation of medium spiny neuron activity states. 28th Annual Symposium on the Cannabinoids. Leiden, Holland: International Cannabinoid Research Society, Research Triangle Park, NC, USA; 2018. p. 42.
  • Bellocchio L, Lafenetre P, Cannich A, Cota D, Puente N, Grandes P, Chaouloff F, Piazza PV, Marsicano G. Bimodal control of stimulated food intake by the endocannabinoid system. Nat Neurosci. 2010;13(3):281–83. doi:10.1038/nn.2494.
  • Funada M, Takebayashi-Ohsawa M. Synthetic cannabinoid AM2201 induces seizures: involvement of cannabinoid CB1 receptors and glutamatergic transmission. Toxicol Appl Pharmacol. 2018;338:1–8. doi:10.1016/j.taap.2017.10.007.
  • Keren O, Sarne Y. Multiple mechanisms of CB1 cannabinoid receptors regulation. Brain Res. 2003;980(2):197–205.
  • Calabrese EJ. Hormetic mechanisms. Crit Rev Toxicol. 2013;43(7):580–606. doi:10.3109/10408444.2013.808172.
  • Sulcova E, Mechoulam R, Fride E. Biphasic effects of anandamide. Pharmacol Biochem Behav. 1998;59(2):347–52.
  • Murray JE, Bevins RA. Cannabinoid conditioned reward and aversion: behavioral and neural processes. ACS Chem Neurosci. 2010;1(4):265–78. doi:10.1021/cn100005p.
  • Sugiura T, Kodaka T, Kondo S, Nakane S, Kondo H, Waku K, Ishima Y, Watanabe K, Yamamoto I. Is the cannabinoid CB1 receptor a 2-arachidonoylglycerol receptor? Structural requirements for triggering a Ca2+ transient in NG108-15 cells. J Biochem. 1997;122(4):890–95.
  • Rubovitch V, Gafni M, Sarne Y. The cannabinoid agonist DALN positively modulates L-type voltage-dependent calcium-channels in N18TG2 neuroblastoma cells. Brain Res Mol Brain Res. 2002;101(1–2):93–102.
  • Bash R, Rubovitch V, Gafni M, Sarne Y. The stimulatory effect of cannabinoids on calcium uptake is mediated by Gs GTP-binding proteins and cAMP formation. Neurosignals. 2003;12(1):39–44. doi:10.1159/000068915.
  • Sarne Y, Keren O. Are cannabinoid drugs neurotoxic or neuroprotective? Med Hypotheses. 2004;63(2):187–92. doi:10.1016/j.mehy.2004.02.043.
  • Amal H, Fridman-Rozevich L, Senn R, Strelnikov A, Gafni M, Keren O, Sarne Y. Long-term consequences of a single treatment of mice with an ultra-low dose of Delta9-tetrahydrocannabinol (THC). Behav Brain Res. 2010;206(2):245–53. doi:10.1016/j.bbr.2009.09.021.
  • Senn R, Keren O, Hefetz A, Sarne Y. Long-term cognitive deficits induced by a single, extremely low dose of tetrahydrocannabinol (THC): behavioral, pharmacological and biochemical studies in mice. Pharmacol Biochem Behav. 2008;88(3):230–37. doi:10.1016/j.pbb.2007.08.005.
  • Tselnicker I, Keren O, Hefetz A, Pick CG, Sarne Y. A single low dose of tetrahydrocannabinol induces long-term cognitive deficits. Neurosci Lett. 2007;411(2):108–11. doi:10.1016/j.neulet.2006.10.033.
  • Tselnicker I. A single ultra-low dose of delta-9-tetrahydrocannabinol causes long-term cognitive dificits in mice [MSc. Thesis]. Tel-Aviv: Tel-Aviv university; 2005.
  • Dirnagl U, Simon RP, Hallenbeck JM. Ischemic tolerance and endogenous neuroprotection. Trends Neurosci. 2003;26(5):248–54. doi:10.1016/S0166-2236(03)00071-7.
  • Kitagawa K, Matsumoto M, Kuwabara K, Tagaya M, Ohtsuki T, Hata R, Ueda H, Handa N, Kimura K, Kamada T. ‘Ischemic tolerance’ phenomenon detected in various brain regions. Brain Res. 1991;561(2):203–11.
  • Pignataro G, Scorziello A, Di Renzo G, Annunziato L. Post-ischemic brain damage: effect of ischemic preconditioning and postconditioning and identification of potential candidates for stroke therapy. FEBS J. 2009;276(1):46–57. doi:10.1111/j.1742-4658.2008.06769.x.
  • Zhao H. Ischemic postconditioning as a novel avenue to protect against brain injury after stroke. J Cereb Blood Flow Metab. 2009;29(5):873–85. doi:10.1038/jcbfm.2009.13.
  • Assaf F, Fishbein M, Gafni M, Keren O, Sarne Y. Pre- and post-conditioning treatment with an ultra-low dose of Delta9-tetrahydrocannabinol (THC) protects against pentylenetetrazole (PTZ)-induced cognitive damage. Behav Brain Res. 2011;220(1):194–201. doi:10.1016/j.bbr.2011.02.005.
  • Fishbein M, Gov S, Assaf F, Gafni M, Keren O, Sarne Y. Long-term behavioral and biochemical effects of an ultra-low dose of Delta9-tetrahydrocannabinol (THC): neuroprotection and ERK signaling. Exp Brain Res. 2012;221(4):437–48. doi:10.1007/s00221-012-3186-5.
  • Fishbein-Kaminietsky M, Gafni M, Sarne Y. Ultralow doses of cannabinoid drugs protect the mouse brain from inflammation-induced cognitive damage. J Neurosci Res. 2014;92(12):1669–77. doi:10.1002/jnr.23452.
  • Murry CE, Jennings RB, Reimer KA. Preconditioning with ischemia: a delay of lethal cell injury in ischemic myocardium. Circulation. 1986;74(5):1124–36.
  • Waldman M, Hochhauser E, Fishbein M, Aravot D, Shainberg A, Sarne Y. An ultra-low dose of tetrahydrocannabinol provides cardioprotection. Biochem Pharmacol. 2013;85(11):1626–33. doi:10.1016/j.bcp.2013.03.014.
  • Hochhauser E, Lahat E, Sultan M, Pappo O, Waldman M, Sarne Y, Shainberg A, Gutman M, Safran M, Ben Ari Z. Ultra low dose Delta 9-Tetrahydrocannabinol protects mouse liver from ischemia reperfusion injury. Cell Physiol Biochem. 2015;36(5):1971–81. doi:10.1159/000430165.
  • Sarne Y, Toledano R, Rachmany L, Sasson E, Doron R. Reversal of age-related cognitive impairments in mice by an extremely low dose of tetrahydrocannabinol. Neurobiol Aging. 2018;61:177–86. doi:10.1016/j.neurobiolaging.2017.09.025.
  • Albayram O, Bilkei-Gorzo A, Zimmer A. Loss of CB1 receptors leads to differential age-related changes in reward-driven learning and memory. Front Aging Neurosci. 2012;4:8.
  • Fasano S, Brambilla R. Ras-ERK signaling in behavior: old questions and new perspectives. Front Behav Neurosci. 2011;5:79.
  • Hausenloy DJ, Yellon DM. Preconditioning and postconditioning: underlying mechanisms and clinical application. Atherosclerosis. 2009;204(2):334–41. doi:10.1016/j.atherosclerosis.2008.10.029.
  • Jin RL, Li WB, Li QJ, Zhang M, Man XH, Sun XC, Zhao HG, Qi J. The role of extracellular signal-regulated kinases in the neuroprotection of limb ischernic preconditioning. Neurosci Res. 2006;55(1):65–73. doi:10.1016/j.neures.2006.01.006.
  • Cunha C, Brambilla R, Thomas KL. A simple role for BDNF in learning and memory? Front Mol Neurosci. 2010;3:1.
  • Lipsky RH, Marini AM. Brain-derived neurotrophic factor in neuronal survival and behavior-related plasticity. Ann N Y Acad Sci. 2007;1122:130–43. doi:10.1196/annals.1403.009.
  • Yin JC, Tully T. CREB and the formation of long-term memory. Curr Opin Neurobiol. 1996;6(2):264–68.
  • Lee HT, Chang YC, Wang LY, Wang ST, Huang CC, Ho CJ. cAMP response element-binding protein activation in ligation preconditioning in neonatal brain. Ann Neurol. 2004;56(5):611–23. doi:10.1002/ana.20259.
  • Lee TH, Yang JT, Ko YS, Kato H, Itoyama Y, Kogure K. Influence of ischemic preconditioning on levels of nerve growth factor, brain-derived neurotrophic factor and their high-affinity receptors in hippocampus following forebrain ischemia. Brain Res. 2008;1187:1–11. doi:10.1016/j.brainres.2007.09.078.
  • Lin WY, Chang YC, Lee HT, Huang CC. CREB activation in the rapid, intermediate, and delayed ischemic preconditioning against hypoxic-ischemia in neonatal rat. J Neurochem. 2009;108(4):847–59. doi:10.1111/j.0022-3042.2008.05828.x.
  • Truettner J, Busto R, Zhao WZ, Ginsberg MD, Perez-Pinzon MA. Effect of ischemic preconditioning on the expression of putative neuroprotective genes in the rat brain. Mol Brain Res. 2002;103(1–2):106–15.
  • Villeda SA, Plambeck KE, Middeldorp J, Castellano JM, Mosher KI, Luo J, Smith LK, Bieri G, Lin K, Berdnik D, et al. Young blood reverses age-related impairments in cognitive function and synaptic plasticity in mice. Nat Med. 2014;20(6):659–63. doi:10.1159/000430165.
  • Gao J, Wang WY, Mao YW, Graff J, Guan JS, Pan L, Mak G, Kim D, Su SC, Tsai LH. A novel pathway regulates memory and plasticity via SIRT1 and miR-134. Nature. 2010;466(7310):1105–U1120. doi:10.1038/nature09271.
  • Gueguen C, Palmier B, Plotkine M, Marchand-Leroux C, Bessson VC. Neurological and histological consequences induced by in vivo cerebral oxidative stress: evidence for beneficial effects of SRT1720, a Sirtuin 1 activator, and Sirtuin 1-mediated neuroprotective effects of poly(ADP-ribose) polymerase inhibition. PLoS One. 2014;9(2). doi:10.1371/journal.pone.0087367.
  • Herskovits AZ, Guarente L. SIRT1 in neurodevelopment and brain senescence. Neuron. 2014;81(3):471–83. doi:10.1016/j.neuron.2014.01.028.
  • Michan S, Li Y, Chou MMH, Parrella E, Ge HY, Long JM, Allard JS, Lewis K, Miller M, Xu W, et al. SIRT1 is essential for normal cognitive function and synaptic plasticity. J Neurosci. 2010;30(29):9695–707. doi:10.1523/JNEUROSCI.0027-10.2010.
  • Zhang XS, Wu Q, Wu LY, Ye ZN, Jiang TW, Li W, Zhuang Z, Zhou ML, Zhang X, Hang CH. Sirtuin 1 activation protects against early brain injury after experimental subarachnoid hemorrhage in rats. Cell Death Dis. 2016;7:1–12. doi:10.1038/cddis.2016.292.
  • Baur JA, Sinclair DA. Therapeutic potential of resveratrol: the in vivo evidence. Nature Rev Drug Discov. 2006;5(6):493–506. doi:10.1038/nrd2060.
  • Cristofol R, Porquet D, Corpas R, Coto-Montes A, Serret J, Camins A, Pallas M, Sanfeliu C. Neurons from senescence-accelerated SAMP8 mice are protected against frailty by the sirtuin 1 promoting agents melatonin and resveratrol. J Pineal Res. 2012;52(3):271–81. doi:10.1111/j.1600-079X.2011.00939.x.
  • Ramis MR, Esteban S, Miralles A, Tan DX, Reiter RJ. Caloric restriction, resveratrol and melatonin: role of SIRT1 and implications for aging and related-diseases. Mech Ageing Dev. 2015;146:28–41. doi:10.1016/j.mad.2015.03.008.
  • Koronowski KB, Dave KR, Saul I, Camarena V, Thompson JW, Neumann JT, Young JI, Perez-Pinzon MA. Resveratrol preconditioning induces a novel extended window of ischemic tolerance in the mouse brain. Stroke. 2015;46(8):2293–98. doi:10.1161/STROKEAHA.115.009876.
  • Morris BJ. Seven sirtuins for seven deadly diseases of aging. Free Radic Biol Med. 2013;56:133–171. doi:10.1016/j.freeradbiomed.2012.10.525.
  • DiNieri JA, Wang XY, Szutorisz H, Spano SM, Kaur J, Casaccia P, Dow-Edwards D, Hurd YL. Maternal cannabis use alters ventral striatal dopamine D2 gene regulation in the offspring. Biol Psychiatry. 2011;70(8):763–69. doi:10.1016/j.biopsych.2011.06.027.
  • Campolongo P, Trezza V, Cassano T, Gaetani S, Morgese MG, Ubaldi M, Soverchia L, Antonelli T, Ferraro L, Massi M, et al. Perinatal exposure to delta-9-tetrahydrocannabinol causes enduring cognitive deficits associated with alteration of cortical gene expression and neurotransmission in rats. Addict Biol. 2007;12(3–4):485–95. doi:10.1111/j.1369-1600.2007.00074.x.
  • Fernandez-Ruiz J, Gomez M, Hernandez M, De Miguel R, Ramos JA. Cannabinoids and gene expression during brain development. Neurotox Res. 2004;6(5):389–401.
  • Aguado T, Carracedo A, Julien B, Velasco G, Milman G, Mechoulam R, Alvarez L, Guzman M, Galve-Roperh I. Cannabinoids induce glioma stem-like cell differentiation and inhibit gliomagenesis. J Biolog Chem. 2007;282(9):6854–62. doi:10.1074/jbc.M608900200.
  • Eljaschewitsch E, Witting A, Mawrin C, Lee T, Pm S, Wolf S, Hoertnagl H, Cs R, Schneider-Stock R, Nitsch R, et al. The endocannabinoid anandamide protects neurons during CNS inflammation by induction of MKP-1 in microglial cells. Neuron. 2006;49(1):67–79. doi:10.1016/j.neuron.2005.11.027.
  • Paradisi A, Pasquariello N, Barcaroli D, Maccarrone M. Anandamide regulates keratinocyte differentiation by inducing DNA methylation in a CB1 receptor-dependent manner. J Biolog Chem. 2008;283(10):6005–12. doi:10.1074/jbc.M707964200.
  • Hwang JY, Aromolaran KA, Zukin RS. The emerging field of epigenetics in neurodegeneration and neuroprotection. Nature Rev Neurosci. 2017;18(6):347–61. doi:10.1038/nrn.2017.46.
  • Simon RP. Epigenetic modulation of gene expression governs the brain’s response to injury. Neurosci Lett. 2016;625:16–19. doi:10.1016/j.neulet.2015.12.024.
  • Zhao CM, Deng W, Gage FH. Mechanisms and functional implications of adult neurogenesis. Cell. 2008;132(4):645–60. doi:10.1016/j.cell.2008.01.033.
  • Goncalves MB, Suetterlin P, Yip P, Molina-Holgado F, Walker DJ, Oudin MJ, Zentar MP, Pollard S, Yanez-Munoz RJ, Williams G, et al. A diacylglycerol lipase-CB2 cannabinoid pathway regulates adult subventricular zone neurogenesis in an age-dependent manner. Mol Cell Neurosci. 2008;38(4):526–36. doi:10.1016/j.mcn.2008.05.001.
  • Galve-Roperh I, Aguado T, Rueda D, Velasco G, Guzman M. Endocannabinoids: a new family of lipid mediators involved in the regulation of neural cell development. Curr Pharm Des. 2006;12(18):2319–25.
  • Jiang W, Zhang Y, Xiao L, Van Cleemput J, Ji SP, Bai G, Zhang X. Cannabinoids promote embryonic and adult hippocampus neurogenesis and produce anxiolytic- and antidepressant-like effects. J Clin Invest. 2005;115(11):3104–16. doi:10.1172/JCI25509.
  • Suliman NA, Taib CNM, Moklas MAM, Basir R. Delta-9-Tetrahydrocannabinol (a dagger(9)-THC) Induce neurogenesis and improve cognitive performances of male Sprague Dawley rats. Neurotox Res. 2018;33(2):402–11. doi:10.1007/s12640-017-9806-x.
  • Brown JP, Couillard-Despres S, Cooper-Kuhn CM, Winkler J, Aigner L, Kuhn HG. Transient expression of doublecortin during adult neurogenesis. J Comp Neurol. 2003;467(1):1–10. doi:10.1002/cne.10874.
  • Couillard-Despres S, Winner B, Schaubeck S, Aigner R, Vroemen M, Weidner N, Bogdahn U, Winkler J, Kuhn HG, Aigner L. Doublecortin expression levels in adult brain reflect neurogenesis. Eur J Neurosci. 2005;21(1):1–14. doi:10.1111/j.1460-9568.2004.03813.x.
  • Wang T, Collet JP, Shapiro S, Ware MA. Adverse effects of medical cannabinoids: a systematic review. Can Med Assoc J. 2008;178(13):1669–78. doi:10.1503/cmaj.071178.
  • Reagan-Shaw S, Nihal M, Ahmad N. Dose translation from animal to human studies revisited. FASEB J. 2008;22(3):659–61. doi:10.1096/fj.07-9574LSF.

Reprints and Corporate Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

To request a reprint or corporate permissions for this article, please click on the relevant link below:

Academic Permissions

Please note: Selecting permissions does not provide access to the full text of the article, please see our help page How do I view content?

Obtain permissions instantly via Rightslink by clicking on the button below:

If you are unable to obtain permissions via Rightslink, please complete and submit this Permissions form. For more information, please visit our Permissions help page.