title: Cannabidiol normalizes caspase 3, synaptophysin, and mitochondrial fission protein DNM1L expression levels in rats with brain iron overload: implications for neuroprotection.
abstract: We have recently shown that chronic treatment with cannabidiol (CBD) was able to recover memory deficits induced by brain iron loading in a dose-dependent manner in rats. Brain iron accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson's and Alzheimer's, and has been related to cognitive deficits in animals and human subjects. Deficits in synaptic energy supply have been linked to neurodegenerative diseases, evidencing the key role played by mitochondria in maintaining viable neural cells and functional circuits. It has also been shown that brains of patients suffering from neurodegenerative diseases have increased expression of apoptosisrelated proteins and specific DNA fragmentation. Here, we have analyzed the expression level of brain proteins involved with mitochondrial fusion and fission mechanisms (DNM1L and OPA1), the main integral transmembrane protein of synaptic vesicles (synaptophysin), and caspase 3, an apoptosis-related protein, to gain a better understanding of the potential of CBD in restoring the damage caused by iron loading in rats. We found that CBD rescued iron-induced effects, bringing hippocampal DNM1L, caspase 3, and synaptophysin levels back to values comparable to the control group. Our results suggest that iron affects mitochondrial dynamics, possibly trigging synaptic loss and apoptotic cell death and indicate that CBD should be considered as a potential molecule with memory-rescuing and neuroprotective properties to be used in the treatment of cognitive deficits observed in neurodegenerative disorders.
authors.affiliation: Neurobiology and Developmental Biology Laboratory, Faculty of Biosciences, Pontifical Catholic University, 90619-900, Porto Alegre, RS, Brazil.
authors.forename: Vanessa Kappel
authors.initials: VK
authors.lastname: da Silva
authors.forename: Betânia Souza
authors.initials: BS
authors.lastname: de Freitas
authors.forename: Arethuza
authors.initials: A
authors.lastname: da Silva Dornelles
authors.forename: Laura Roesler
authors.initials: LR
authors.lastname: Nery
authors.forename: Lucio
authors.initials: L
authors.lastname: Falavigna
authors.forename: Rafael Dal Ponte
authors.initials: RD
authors.lastname: Ferreira
authors.forename: Maurício Reis
authors.initials: MR
authors.lastname: Bogo
authors.forename: Jaime Eduardo Cecílio
authors.initials: JE
authors.lastname: Hallak
authors.forename: Antônio Waldo
authors.initials: AW
authors.lastname: Zuardi
authors.forename: José Alexandre S
authors.initials: JA
authors.lastname: Crippa
authors.forename: Nadja
authors.initials: N
authors.lastname: Schröder
mesh_terms: D000818:Animals; D001921:Brain / Q000187:drug effects / Q000378:metabolism; D002185:Cannabidiol / Q000494:pharmacology* / Q000627:therapeutic use; D053148:Caspase 3 / Q000096:biosynthesis*; D034281:Dynamins / Q000096:biosynthesis*; D005260:Female; D005786:Gene Expression Regulation / Q000187:drug effects*; D019190:Iron Overload / Q000378:metabolism* / Q000517:prevention & control; D008297:Male; D008928:Mitochondria / Q000187:drug effects / Q000378:metabolism; D063154:Mitochondrial Dynamics / Q000187:drug effects / Q000502:physiology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D011247:Pregnancy; D011897:Random Allocation; D051381:Rats; D017208:Rats, Wistar; D016708:Synaptophysin / Q000096:biosynthesis*
chemical_list: D018696:Neuroprotective Agents; D016708:Synaptophysin; C569016:Syp protein, rat; D002185:Cannabidiol; C505410:Casp3 protein, rat; D053148:Caspase 3; C519851:Dnm1l protein, rat; D034281:Dynamins
references.citation: Expert Rev Neurother. 2013 Mar;13(3):247-50
references.pmid: 23448214
references.citation: J Neurochem. 1991 Feb;56(2):446-51
references.pmid: 1988548
references.citation: Neurotoxicology. 2011 Jan;32(1):75-82
references.pmid: 21130806
references.citation: Eur J Neurosci. 2005 May;21(9):2521-8
references.pmid: 15932609
references.citation: Pol J Pharmacol. 2004 Nov-Dec;56(6):689-700
references.pmid: 15662081
references.citation: J Neurosci Res. 2012 Jun;90(6):1183-9
references.pmid: 22345048
references.citation: Brain Res. 2007 Feb 23;1134(1):162-70
references.pmid: 17196181
references.citation: Drug Alcohol Depend. 2011 Apr 1;114(2-3):242-5
references.pmid: 21050680
references.citation: Top Magn Reson Imaging. 2006 Feb;17(1):41-50
references.pmid: 17179896
references.citation: Reprod Sci. 2012 Mar;19(3):298-305
references.pmid: 22383778
references.citation: Brain Imaging Behav. 2009 Jun 1;3(2):167-175
references.pmid: 20161183
references.citation: Cereb Cortex. 2013 Jul;23(7):1533-41
references.pmid: 22645251
references.citation: Biochem Biophys Res Commun. 2010 Sep 3;399(4):548-54
references.pmid: 20678484
references.citation: Synapse. 2008 Apr;62(4):302-9
references.pmid: 18241047
references.citation: Behav Brain Res. 2001 Sep 28;124(1):77-85
references.pmid: 11423168
references.citation: Curr Neurovasc Res. 2010 Feb;7(1):15-22
references.pmid: 20158466
references.citation: Brain. 1991 Aug;114 ( Pt 4):1953-75
references.pmid: 1832073
references.citation: Curr Opin Clin Nutr Metab Care. 2009 Jan;12(1):22-9
references.pmid: 19057183
references.citation: Neuron. 2012 Sep 6;75(5):762-77
references.pmid: 22958818
references.citation: Anal Biochem. 1976 May 7;72:248-54
references.pmid: 942051
references.citation: Mult Scler. 2006 Aug;12(4):437-44
references.pmid: 16900757
references.citation: J Neurochem. 2010 Jan;112(1):183-92
references.pmid: 19845829
references.citation: J Alzheimers Dis. 2005 Apr;7(2):103-17; discussion 173-80
references.pmid: 15851848
references.citation: Mol Genet Metab. 2012 Nov;107(3):375-82
references.pmid: 22999741
references.citation: Neuropharmacology. 2012 Oct;63(5):776-83
references.pmid: 22659086
references.citation: J Neurochem. 2009 May;109 Suppl 1:153-9
references.pmid: 19393022
references.citation: Neuropsychopharmacology. 2011 Jun;36(7):1375-84
references.pmid: 21389980
references.citation: J Alzheimers Dis. 2013;34(4):797-812
references.pmid: 23271321
references.citation: J Neuropathol Exp Neurol. 1997 Aug;56(8):933-44
references.pmid: 9258263
references.citation: Neuropharmacology. 2008 Oct;55(5):788-92
references.pmid: 18619476
references.citation: Hum Mol Genet. 2012 Jun 1;21(11):2538-47
references.pmid: 22367970
references.citation: Neurotox Res. 2011 May;19(4):527-35
references.pmid: 20369315
references.citation: Neurology. 2007 May 22;68(21):1820-5
references.pmid: 17515544
references.citation: J Alzheimers Dis. 2010;20 Suppl 2:S551-68
references.pmid: 20463401
references.citation: J Psychopharmacol. 2013 Jan;27(1):19-27
references.pmid: 23042808
references.citation: Cell. 2006 Jun 30;125(7):1241-52
references.pmid: 16814712
references.citation: Brain Res. 2009 Jan 23;1250:63-74
references.pmid: 19046944
references.citation: Nat Rev Neurosci. 2004 Nov;5(11):863-73
references.pmid: 15496864
references.citation: Proc Natl Acad Sci U S A. 1998 Jul 7;95(14):8268-73
references.pmid: 9653176
references.citation: Nucleic Acids Res. 2001 May 1;29(9):e45
references.pmid: 11328886
references.citation: Future Med Chem. 2010 Jan;2(1):51-64
references.pmid: 20161623
references.citation: Proc Natl Acad Sci U S A. 2008 Dec 9;105(49):19318-23
references.pmid: 19050078
references.citation: Synapse. 2003 Jun 15;48(4):198-204
references.pmid: 12687639
references.citation: Neurobiol Dis. 2010 Feb;37(2):434-40
references.pmid: 19900555
references.citation: Eur J Neurosci. 2007 Aug;26(4):843-51
references.pmid: 17672854
references.citation: Psychopharmacology (Berl). 2012 Feb;219(4):1133-40
references.pmid: 21870037
references.citation: Expert Opin Ther Targets. 2012 Apr;16(4):407-20
references.pmid: 22448595
references.citation: Brain Res Dev Brain Res. 2001 Sep 23;130(1):109-14
references.pmid: 11557099
references.citation: Radiology. 2009 Nov;253(2):497-504
references.pmid: 19709998
references.citation: J Neurosci. 2009 Feb 18;29(7):2053-63
references.pmid: 19228959
references.citation: AJNR Am J Neuroradiol. 2006 Feb;27(2):430-9
references.pmid: 16484425
references.citation: Ann Neurol. 1992 Mar;31(3):286-92
references.pmid: 1637136
references.citation: J Magn Reson Imaging. 2009 Apr;29(4):793-8
references.pmid: 19306401
references.citation: Neurobiol Aging. 2012 Mar;33(3):510-517.e2
references.pmid: 20542597
references.citation: Nat Rev Mol Cell Biol. 2005 Aug;6(8):657-63
references.pmid: 16025099
references.citation: Toxicol Appl Pharmacol. 1999 Aug 15;159(1):25-30
references.pmid: 10448122
references.citation: J Neurochem. 2004 Apr;89(1):134-41
references.pmid: 15030397
references.citation: Arch Neurol. 1992 Jul;49(7):711-7
references.pmid: 1497497
references.citation: Curr Opin Cell Biol. 2003 Dec;15(6):706-16
references.pmid: 14644195
references.citation: Neuroscience. 2012 Jan 3;200:42-9
references.pmid: 22067609
references.citation: Curr Alzheimer Res. 2007 Sep;4(4):403-11
references.pmid: 17908043