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Protective Effects of Cannabidiol Against Hippocampal Cell Death and Cognitive Impairment Induced by Bilateral Common Carotid Artery Occlusion in Mice

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Abstract

The present study investigated whether cannabidiol (CBD), a major non-psychoactive constituent of marijuana, protects against hippocampal neurodegeneration and cognitive deficits induced by brain ischemia in adult mice. Male Swiss mice were subjected to a 17 min of bilateral common carotid artery occlusion (BCCAO) and tested in the Morris water maze 7 days later. CBD (3, 10, and 30 mg/kg) was administered 30 min before and 3, 24, and 48 h after BCCAO. After behavioral testing, the brains were removed and processed to evaluate hippocampal cell survival and degeneration using Nissl staining and FluoroJade C histochemistry, respectively. Astroglial response was examined using immunohistochemistry for glial fibrillary acidic protein (GFAP). CBD (3–30 mg/kg) improved spatial learning performance in BCCAO mice. The Nissl and FJC staining results showed a decrease in hippocampal neurodegeneration after CBD (10 and 30 mg/kg) treatment. GFAP immunoreactivity was also decreased in ischemic mice treated with CBD (30 mg/kg). These findings suggest a protective effect of CBD on neuronal death induced by ischemia and indicate that CBD might exert beneficial therapeutic effects in brain ischemia. The mechanisms that underlie the neuroprotective effects of CBD in BCCAO mice might involve the inhibition of reactive astrogliosis.

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References

  • Anderson CA, Arciniegas DB (2010) Cognitive sequelae of hypoxic-ischemic brain injury: a review. Neurorehabilitation 26(1):47–63

    PubMed  Google Scholar 

  • Auriel E, Bornstein NM (2010) Neuroprotection in acute ischemic stroke-current status. J Cell Mol Med 4(9):2200–2202

    Article  Google Scholar 

  • Bachevalier J, Meunier M (1996) Cerebral ischemia: are the memory deficits associated with hippocampal cell loss? Hippocampus 6(5):553–560

    Article  PubMed  CAS  Google Scholar 

  • Blum S, Luchsinger JA, Manly JJ, Schupf N, Stern Y, Brown TR, DeCarli C, Small SA, Mayeux R, Brickman AM (2012) Memory after silent stroke: hippocampus and infarcts both matter. Neurology 78(1):38–46

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Bora KS, Arora S, Shri R (2011) Role of Ocimum basilicum L. in prevention of ischemia and reperfusion-induced cerebral damage, and motor dysfunctions in mice brain. J Ethnopharmacol 137(3):1360–1365

    Article  PubMed  Google Scholar 

  • Braida D, Pegorini S, Arcidiacono MV, Consalez GG, Croci L, Sala M (2003) Post-ischemic treatment with cannabidiol prevents electroencephalographic flattening, hyperlocomotion and neuronal injury in gerbils. Neurosci Lett 346(1–2):61–64

    Article  PubMed  CAS  Google Scholar 

  • Campos AC, Moreira FA, Gomes FV, Del Bel EA, Guimarães FS (2012) Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders. Philos Trans R Soc Lond B 367(1607):3364–3378

    Article  CAS  Google Scholar 

  • Campos AC, Ortega Z, Palazuelos J, Fogaça MV, Aguiar DC, Díaz-Alonso J, Ortega-Gutiérrez S, Vázquez-Villa H, Moreira FA, Guzmán M, Galve-Roperh I, Guimarães FS (2013) The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 16(6):1407–1419. doi:10.1017/S1461145712001502

    Article  PubMed  CAS  Google Scholar 

  • Carty ML, Wixey JA, Kesby J, Reinebrant HE, Colditz PB, Gobe G (2010) Long-term losses of amygdala corticotropin-releasing factor neurons are associated with behavioural outcomes following neonatal hypoxia–ischemia. Behav Brain Res 208:609–618

    Article  PubMed  CAS  Google Scholar 

  • Caruana DA, Nesbitt C, Mumby DG, Chapman CA (2008) Seizure activity in the rat hippocampus, perirhinal and prefrontal cortex associated with transient global cerebral ischemia. J Neural Transm 115(3):401–411

    Article  PubMed  CAS  Google Scholar 

  • Castillo A, Tolón MR, Fernández-Ruiz J, Romero J, Martinez-Orgado J (2010) 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 37(2):434–440

    Article  PubMed  CAS  Google Scholar 

  • Cheung WM, Wang CK, Kuo JS, Lin TN (1999) Changes in the level of glial fibrillary acidic protein (GFAP) after mild and severe focal cerebral ischemia. Chin J Physiol 42(4):227–235

    PubMed  CAS  Google Scholar 

  • Colangelo AM, Cirillo G, Lavitrano ML, Alberghina L, Papa M (2012) Targeting reactive astrogliosis by novel biotechnological strategies. Biotechnol Adv 30(1):261–271

    Article  PubMed  CAS  Google Scholar 

  • Corbett D, Crooks P (1997) Ischemic preconditioning: a long term survival study using behavioural and histological endpoints. Brain Res. 760(1–2):129–136

    Article  PubMed  CAS  Google Scholar 

  • Corbett D, Nurse S (1998) The problem of assessing effective neuroprotection in experimental cerebral ischemia. Prog Neurobiol. 54(5):531–548

    Article  PubMed  CAS  Google Scholar 

  • de la Tremblaye PB, Plamondon H (2011) Impaired conditioned emotional response and object recognition are concomitant to neuronal damage in the amygdala and perirhinal cortex in middle-aged ischemic rats. Behav Brain Res 219(2):227–233

    Article  PubMed  Google Scholar 

  • Duan YL, Wang SY, Zeng QW, Su DS, Li W, Wang XR, Zhao Z (2011) Astroglial reaction to delta opioid peptide [D-Ala2, D-Leu5] enkephalin confers neuroprotection against global ischemia in the adult rat hippocampus. Neuroscience 192:81–90

    Article  PubMed  CAS  Google Scholar 

  • Esposito G, Scuderi C, Valenza M, Togna GI, Latina V, De Filippis D, Cipriano M, Carratù MR, Iuvone T, Steardo L (2011) Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement. PLoS One 6(12):e28668

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Fernández-Ruiz J, Sagredo O, Pazos MR, García C, Pertwee R, Mechoulam R, Martínez-Orgado J (2013) Cannabidiol for neurodegenerative disorders: important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol 75(2):323–333

    Article  PubMed  PubMed Central  Google Scholar 

  • Franklin KBJ, Paxinos G (1997) The mouse brain in stereotaxic coordinates, 2nd edn. Editora Academic Press, San Diego

    Google Scholar 

  • Garcia C, Palomo-Garo C, Garcia-Arencibia M, Ramos J, Pertwee R, Fernández-Ruiz J (2011) Symptom-relieving and neuroprotective effects of the phytocannabinoid D9-THCV in animal modeks of Parkinson’s disease. Br J Pharmacol 164(7):1495–1506

    Article  Google Scholar 

  • Harvey BS, Ohlsson KS, Mååg JL, Musgrave IF, Smid SD (2012) Contrasting protective effects of cannabinoids against oxidative stress and amyloid-β evoked neurotoxicity in vitro. Neurotoxicology 33(1):138–146

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa K, Mishima K, Irie K, Hazekawa M, Mishima S, Fujioka M, Orito K, Egashira N, Katsurabayashi S, Takasaki K, Iwasaki K, Fujiwara M (2008) Cannabidiol prevents a post-ischemic injury progressively induced by cerebral ischemia via a high-mobility group box1-inhibiting mechanism. Neuropharmacology 55(8):1280–1286

    Article  PubMed  CAS  Google Scholar 

  • Hayakawa K, Irie K, Sano K, Watanabe T, Higuchi S, Enoki M, Nakano T, Harada K, Ishikane S, Ikeda T, Fujioka M, Orito K, Iwasaki K, Mishima K, Fujiwara M (2009) Therapeutic time window of cannabidiol treatment on delayed ischemic damage via high-mobility group box1-inhibiting mechanism. Biol Pharm Bull 32(9):1538–1544

    Article  PubMed  CAS  Google Scholar 

  • Iuvone T, Esposito G, Esposito R, Santamaria R, Di Rosa M, Izzo AA (2004) Neuroprotective effect of cannabidiol, a non-psychoactive component from Cannabis sativa, on beta-amyloid-induced toxicity in PC12 cells. J Neurochem 89(1):134–141

    Article  PubMed  CAS  Google Scholar 

  • Kartsounis LD, Rudge P, Stevens JM (1995) Bilateral lesions of CA1 and CA2 fields of the hippocampus are sufficient to cause a severe amnesic syndrome in humans. J Neurol Neurosurg Psychiatry 59(1):95–98

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Kindy MS, Bhat AN, Bhat NR (1992) Transient ischemia stimulates glial fibrillary acid protein and vimentin gene expression in the gerbil neocortex, striatum and hippocampus. Brain Res Mol Brain Res 13(3):199–206

    Article  PubMed  CAS  Google Scholar 

  • Kumaran D, Udayabanu M, Kumar M, Aneja R, Katyal A (2008) Involvement of angiotensin converting enzyme in cerebral hypoperfusion induced anterograde memory impairment and cholinergic dysfunction in rats. Neuroscience 155(3):626–639

    Article  PubMed  CAS  Google Scholar 

  • Lafuente H, Alvarez FJ, Pazos MR, Alvarez A, Rey-Santano MC, Mielgo V, Murgia-Esteve X, Hilario E, Martinez-Orgado J (2011) Cannabidiol reduces brain damage and improves functional recovery after acute hypoxia–ischemia in newborn pigs. Pediatr Res 70(3):272–277

    Article  PubMed  CAS  Google Scholar 

  • Lee TH, Kato H, Kogure K, Itoyama Y (1996) Temporal profile of nerve growth factor like immunoreactivity after transient focal cerebral ischemia in rats (1996). Brain Res 713:199–210

    Article  PubMed  CAS  Google Scholar 

  • Mao X, Yin W, Liu M, Ye M, Liu P, Liu J, Xu S, Pi R (2011) Osthole, a natural coumarin, improves neurobehavioral functions and reduces infarct volume and matrix metalloproteinase-9 activity after transient focal cerebral ischemia in rats. Brain Res 1385:275–280

    Article  PubMed  CAS  Google Scholar 

  • Mateen FJ, Josephs KA, Trenerry MR, Felmlee-Devine MD, Weaver AL, Carone M, White RD (2011) Long-term cognitive outcomes following out-of-hospital cardiac arrest: a population-based study. Neurology 77(15):1438–1445

    Article  PubMed  CAS  Google Scholar 

  • Mechoulam R, Shohami E (2007) Endocannabinoids and traumatic brain injury. Mol Neurobiol 36(1):68–74

    Article  PubMed  CAS  Google Scholar 

  • Moulaert VR, Wachelder EM, Verbunt JA, Wade DT, van Heugten CM (2010) Determinants of quality of life in survivors of cardiac arrest. J Rehabil Med 42(6):553–558

    Article  PubMed  Google Scholar 

  • Neumann JT, Cohan CH, Dave KR, Wright CB, Perez-Pinzon MA (2013) Global cerebral ischemia: synaptic and cognitive dysfunction. Curr Drug Targets 14(1):20–35

    Article  PubMed  CAS  Google Scholar 

  • Nikonenko AG, Radenovic L, Andjus PR, Skibo GG (2009) Structural features of ischemic damage in the hippocampus. Anat Rec (Hoboken) 292(12):1914–1921

    Article  CAS  Google Scholar 

  • Norenberg MD (1996) Astrocytic-ammonia interactions in hepatic encephalopathy. Semin Liver Dis 16(3):245–253

    Article  PubMed  CAS  Google Scholar 

  • Pazos MR, Cinquina V, Gómez A, Layunta R, Santos M, Fernández-Ruiz J, Martínez-Orgado J (2012) Cannabidiol administration after hypoxia–ischemia to newborn rats reduces long-term brain injury and restores neurobehavioral function. Neuropharmacology 63(5):776–783

    Article  PubMed  CAS  Google Scholar 

  • Pazos MR, Mohammed N, Lafuente H, Santos M, Martínez-Pinilla E, Moreno E, Valdizan E, Romero J, Pazos A, Franco R, Hillard CJ, Alvarez FJ, Martínez-Orgado J (2013) Mechanisms of cannabidiol neuroprotection in hypoxic newborn pigs: role of 5HT1A and CB2 receptors. Neuropharmacology 71:282–291

    Article  PubMed  CAS  Google Scholar 

  • Pekny M, Pekna M (2004) Astrocyte intermediate filaments in CNS pathologies and regeneration. J Pathol. 204(4):428–437

    Article  PubMed  CAS  Google Scholar 

  • Pekny M, Nilsson M (2005) Astrocyte activation and reactive gliosis. Glia 50(4):427–434

    Article  PubMed  Google Scholar 

  • Peskine A, Picq C, Pradat-diehl P (2010) Neurological sequelae after cerebral anoxia. Brain Inj 24(5):755–761

    Article  PubMed  CAS  Google Scholar 

  • Petito CK, Halaby IA (1993) Relationship between ischemia and ischemic neuronal necrosis to astrocyte expression of glial fibrillary acidic protein. Int J Dev Neurosci 11(2):239–247

    Article  PubMed  CAS  Google Scholar 

  • Prediger RD, Fernandes MS, Rial D, Wopereis S, Pereira VS, Bosse TS, Da Silva CB, Carradore RS, Machado MS, Cechinel-Filho V, Costa-Campos L (2008) Effects of acute administration of the hydroalcoholic extract of mate tea leaves (Ilex paraguariensis) in animal models of learning and memory. J Ethnopharmacol 120(3):465–473

    Article  PubMed  Google Scholar 

  • Ridet JL, Malhotra SK, Privat A, Gage FH (1997) Reactive astrocytes: cellular and molecular cues to biological function. Trends Neurosci 20(12):570–577

    Article  PubMed  CAS  Google Scholar 

  • Robel S, Berninger B, Götz M (2011) The stem cell potential of glia: lessons from reactive gliosis. Nat Rev Neurosci 12(2):88–104

    Article  PubMed  CAS  Google Scholar 

  • Sachdev PS, Chen X, Joscelyne A, Wen W, Brodaty H (2007) Amygdala in stroke/transient ischemic attack patients and its relationship to cognitive impairment and psychopathology: the Sydney stroke study. Am J Geriatr Psychiatry 15:487–496

    Article  PubMed  Google Scholar 

  • Sagredo O, Pazos MR, Satta V, Ramos JA, Pertwee RG, Fernández-Ruiz J (2011) Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington’s disease. J Neurosci Res 89(9):1509–1518

    Article  PubMed  CAS  Google Scholar 

  • Schmued LC, Stowers CC, Scallet AC, Xu L (2005) Fluoro-Jade C results in ultra high resolution and contrast labeling of degenerating neurons. Brain Res 1035(1):24–31

    Article  PubMed  CAS  Google Scholar 

  • Seif el Nasr M, Nuglisch J, Krieglstein J (1992) Prevention of ischemia-induced cerebral hypothermia by controlling the environmental temperature. J Pharmacol Toxicol Methods 27(1):23–26

    Article  PubMed  CAS  Google Scholar 

  • Shinjyo N, Di Marzo V (2013) The effect cannabichromene on adult neural stem/progenitor cells. Neurochem 63(5):432–437

    Article  CAS  Google Scholar 

  • Soares LM, Schiavon AP, Milani H, de Oliveira RM (2013) Cognitive impairment and persistent anxiety-related responses following bilateral common carotid artery occlusion in mice. Behav Brain Res 249:28–37

    Article  PubMed  Google Scholar 

  • Stoll G, Jander S, Schroeter M (1998) Inflammation and glial responses in ischemic brain lesions. Prog Neurobiol 56(2):149–171

    Article  PubMed  CAS  Google Scholar 

  • Szydlowska K, Gozdz A, Dabrowski M, Zawadzka M, Kaminska B (2010) Prolonged activation of ERK triggers glutamate-induced apoptosis of astrocytes: neuroprotective effect of FK506. J Neurochem 113(4):904–918

    Article  PubMed  CAS  Google Scholar 

  • Takuma K, Baba A, Matsuda T (2004) Astrocyte apoptosis: implications for neuroprotection. Prog Neurobiol 72(2):111–127

    Article  PubMed  CAS  Google Scholar 

  • Valdeolivas S, Satta V, Pertwee RG, Fernández-Ruiz J, Sagredo O (2012) Sativex-like combination of phytocannabinoids is neuroprotective in malonate-lesioned rats, an inflammatory model of Huntington’s disease: role of CB1 and CB2 receptors. ACS Chem Neurosci 3(5):400–406

    Article  PubMed  CAS  PubMed Central  Google Scholar 

  • Zhang L, Fu F, Zhang X, Zhu M, Wang T, Fan H (2010) Escin attenuates cognitive deficits and hippocampal injury after transient global cerebral ischemia in mice via regulating certain inflammatory genes. Neurochem Int 57(2):119–127

    Article  PubMed  CAS  Google Scholar 

  • Zola-Morgan S, Squire LR, Amaral DG (1986) Human amnesia and the medial temporal region: enduring memory impairment following a bilateral lesion limited to field CA1 of the Hippocampus. J Neurosci 6(10):2950–2967

    PubMed  CAS  Google Scholar 

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Acknowledgments

The authors thank Marco Alberto Trombelli for his technical support. This study was supported by Conselho Nacional de Desenvolvimento Científico e Tecnológico (CNPq), FAPESP, State University of Maringá and Fundação Araucária.

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The authors have no conflict of interest.

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Authors and Affiliations

  1. Department of Pharmacology and Therapeutics, State University of Maringá, Av. Colombo, 5790, Maringa, PR, 87020-900, Brazil

    Angélica Pupin Schiavon, Lígia Mendes Soares, Jéssica Mendes Bonato, Humberto Milani & Rúbia Maria Weffort de Oliveira

  2. Department of Pharmacology, School of Medicine, USP, Av. Bandeirantes, Ribeirão Prêto, SP, 14015-000, Brazil

    Francisco Silveira Guimarães

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  1. Angélica Pupin Schiavon
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  2. Lígia Mendes Soares
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  3. Jéssica Mendes Bonato
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  6. Rúbia Maria Weffort de Oliveira
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Correspondence to Rúbia Maria Weffort de Oliveira.

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Schiavon, A.P., Soares, L.M., Bonato, J.M. et al. Protective Effects of Cannabidiol Against Hippocampal Cell Death and Cognitive Impairment Induced by Bilateral Common Carotid Artery Occlusion in Mice. Neurotox Res 26, 307–316 (2014). https://doi.org/10.1007/s12640-014-9457-0

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  • DOI: https://doi.org/10.1007/s12640-014-9457-0

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