Cannabidivarin completely rescues cognitive deficits and delays neurological and motor defects in male Mecp2 mutant mice
Abstract
Background:
Recent evidence suggests that 2-week treatment with the non-psychotomimetic cannabinoid cannabidivarin (CBDV) could be beneficial towards neurological and social deficits in early symptomatic Mecp2 mutant mice, a model of Rett syndrome (RTT).
Aim:
The aim of this study was to provide further insights into the efficacy of CBDV in Mecp2-null mice using a lifelong treatment schedule (from 4 to 9 weeks of age) to evaluate its effect on recognition memory and neurological defects in both early and advanced stages of the phenotype progression.
Methods:
CBDV 0.2, 2, 20 and 200 mg/kg/day was administered to Mecp2-null mice from 4 to 9 weeks of age. Cognitive and neurological defects were monitored during the whole treatment schedule. Biochemical analyses were carried out in brain lysates from 9-week-old wild-type and knockout mice to evaluate brain-derived neurotrophic factor (BDNF) and insulin-like growth factor-1 (IGF-1) levels as well as components of the endocannabinoid system.
Results:
CBDV rescues recognition memory deficits in Mecp2 mutant mice and delays the appearance of neurological defects. At the biochemical level, it normalizes BDNF/IGF1 levels and the defective PI3K/AKT/mTOR pathway in Mecp2 mutant mice at an advanced stage of the disease. Mecp2 deletion upregulates CB1 and CB2 receptor levels in the brain and these changes are restored after CBDV treatment.
Conclusions:
CBDV administration exerts an enduring rescue of memory deficits in Mecp2 mutant mice, an effect that is associated with the normalization of BDNF, IGF-1 and rpS6 phosphorylation levels as well as CB1 and CB2 receptor expression. CBDV delays neurological defects but this effect is only transient.
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References
Amada N, Yamasaki Y, Williams CM, et al. (2013) Cannabidivarin (CBDV) suppresses pentylenetetrazole (PTZ)-induced increases in epilepsy-related gene expression. PeerJ 1: e214.
Amir RE, Van den Veyver IB, Wan M, et al. (1999) Rett syndrome is caused by mutations in X-linked MECP2, encoding methyl-CpG-binding protein 2. Nat Genet 23: 185–188.
Avraham Y, Grigoriadis N, Poutahidis T, et al. (2011) Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. Br J Pharmacol 162: 1650–1658.
Bisogno T, Howell F, Williams G, et al. (2003) Cloning of the first sn1-DAG lipases points to the spatial and temporal regulation of endocannabinoid signaling in the brain. J Cell Biol 163: 463–468.
Brodie MJ, Ben-Menachem E (2018) Cannabinoids for epilepsy: What do we know and where do we go? Epilepsia 59: 291–296.
Busquets-Garcia A, Gomis-González M, Guegan T, et al. (2013) Targeting the endocannabinoid system in the treatment of fragile X syndrome. Nat Med 19: 603–607.
Campolongo P, Trezza V (2012) The endocannabinoid system: A key modulator of emotions and cognition. Front Behav Neurosci 6: 73.
Campos AC, Fogaça MV, Scarante FF, et al. (2017) Plastic and neuroprotective mechanisms involved in the therapeutic effects of cannabidiol in psychiatric disorders. Front Pharmacol 8: 269.
Campos AC, Fogaca MV, Sonego AB, et al. (2016) Cannabidiol, neuroprotection and neuropsychiatric disorders. Pharmacol Res 112: 119–127.
Castro J, Garcia RI, Kwok S, et al. (2014) Functional recovery with recombinant human IGF1 treatment in a mouse model of Rett Syndrome. Proc Natl Acad Sci U S A 111: 9941–9946.
Chahrour M, Zoghbi HY (2007) The story of Rett syndrome: From clinic to neurobiology. Neuron 56: 422–437.
Chang Q, Khare G, Dani V, et al. (2006) The disease progression of Mecp2 mutant mice is affected by the level of BDNF expression. Neuron 49: 341–348.
Chen MJ, Russo-Neustadt AA (2007) Running exercise- and antidepressant-induced increases in growth and survival-associated signaling molecules are IGF-dependent. Growth Factors 25: 118–131.
Chen WG, Chang Q, Lin Y, et al. (2003) Derepression of BDNF transcription involves calcium-dependent phosphorylation of MeCP2. Science 302: 885–889.
Cobolli Gigli C, Scaramuzza L, Gandaglia A, et al. (2016) MeCP2 related studies benefit from the use of CD1 as genetic background. PLoS One 11: e0153473.
Crippa JA, Guimarães FS, Campos AC, et al. (2018) Translational investigation of the therapeutic potential of cannabidiol (CBD): Toward a new age. Front Immunol 9: 2009.
De Petrocellis L, Ligresti A, Moriello AS, et al. (2011) Effects of cannabinoids and cannabinoid-enriched Cannabis extracts on TRP channels and endocannabinoid metabolic enzymes. Br J Pharmacol 163: 1479–1494.
De Petrocellis L, Orlando P, Moriello AS, et al. (2012) Cannabinoid actions at TRPV channels: effects on TRPV3 and TRPV4 and their potential relevance to gastrointestinal inflammation. Acta Physiol (Oxf) 204: 255–266.
Deiana S, Watanabe A, Yamasaki Y, et al. (2012) Plasma and brain pharmacokinetic profile of cannabidiol (CBD), cannabidivarine (CBDV), Delta(9)-tetrahydrocannabivarin (THCV) and cannabigerol (CBG) in rats and mice following oral and intraperitoneal administration and CBD action on obsessive-compulsive behaviour. Psychopharmacology (Berl) 219: 859–873.
Della Sala G, Putignano E, Chelini G, et al. (2016) Dendritic spine instability in a mouse model of CDKL5 disorder is rescued by insulin-like growth factor 1. Biol Psychiatry 80: 302–311.
Deogracias R, Yazdani M, Dekkers MP, et al. (2012) Fingolimod, a sphingosine-1 phosphate receptor modulator, increases BDNF levels and improves symptoms of a mouse model of Rett syndrome. Proc Natl Acad Sci U S A 109: 14230–14235.
Dyer AH, Vahdatpour C, Sanfeliu A, et al. (2016) The role of Insulin-Like Growth Factor 1 (IGF-1) in brain development, maturation and neuroplasticity. Neuroscience 325: 89–99.
Fernández-Ruiz J, Gonzáles S (2005) Cannabinoid control of motor function at the basal ganglia. Handb Exp Pharmacol (168): 479–507.
Fernandez-Ruiz J, Sagredo O, Pazos MR, et al. (2013) Cannabidiol for neurodegenerative disorders: Important new clinical applications for this phytocannabinoid? Br J Clin Pharmacol 75: 323–333.
Gadalla KK, Bailey ME, Spike RC, et al. (2013) Improved survival and reduced phenotypic severity following AV9/MECP2 gene transfer to neonatal and juvenile male Mecp2 knockout mice. Mol Ther 21: 18–30.
Gallily R, Yekhtin Z, Hanuš LO (2015) Overcoming the bell-shaped dose-response of cannabidiol by using cannabis extract enriched in cannabidiol. Pharmacol Pharm 6: 75–85.
Giacometti E, Luikenhuis S, Beard C, et al. (2007) Partial rescue of MeCP2 deficiency by postnatal activation of MeCP2. Proc Natl Acad Sci USA 104: 1931–1936.
Gomis-González M, Busquets-Garcia A, Matute C, et al. (2016) Possible therapeutic doses of cannabinoid type 1 receptor antagonist reverses key alterations in fragile X syndrome mouse model. Genes (Basel). 7: pii: E56.
Guy J, Gan J, Selfridge J, et al. (2007) Reversal of neurological defects in a mouse model of Rett syndrome. Science 315: 1143–1147.
Hagberg B (2002) Clinical manifestations and stages of Rett syndrome. Ment Retard Dev Disabil Res Rev 8: 61–65.
Hill AJ, Mercier MS, Hill TD, et al. (2012a) Cannabidivarin is anticonvulsant in mouse and rat. Br J Pharmacol 167: 1629–1642.
Hill AJ, Williams CM, Whalley BJ, et al. (2012b) Phytocannabinoids as novel therapeutic agents in CNS disorders. Pharmacol Ther 133: 79–97.
Hill TD, Cascio MG, Romano B, et al. (2013) Cannabidivarin-rich cannabis extracts are anticonvulsant in mouse and rat via a CB1 receptor-independent mechanism. Br J Pharmacol 170: 679–692.
Hosie S, Malone DT, Liu S, et al. (2018) Altered amygdala excitation and CB1 receptor modulation of aggressive behavior in the neuroligin-3R451C mouse model of autism. Front Cell Neurosci 12: 234.
Howell CJ, Sceniak MP, Lang M, et al. (2018) Activation of the medial prefrontal cortex reverses cognitive and respiratory symptoms in a mouse model of Rett syndrome. eNeuro 4.
Huppke P, Köhler K, Brockmann K, et al. (2007) Treatment of epilepsy in Rett syndrome. Eur J Paediatr Neurol 11: 10–16.
Iannotti FA, Hill CL, Leo A, et al. (2014) Nonpsychotropic plant cannabinoids, cannabidivarin (CBDV) and cannabidiol (CBD), activate and desensitize transient receptor potential vanilloid 1 (TRPV1) channels in vitro: potential for the treatment of neuronal hyperexcitability. ACS Chem Neurosci 5: 1131–1141.
Iannotti FA, Pagano E, Moriello AS, et al. (2018) Effects of non-euphoric plant cannabinoids on muscle quality and performance of dystrophic mdx mice. Br J Pharmacol. Epub ahead of print 3 August 2018.
Johnson RA, Lam M, Punzo AM, et al. (2012) 7,8-dihydroxyflavone exhibits therapeutic efficacy in a mouse model of Rett syndrome. J Appl Physiol 112: 704–710.
Jung KM, Sepers M, Henstridge CM, et al. (2012) Uncoupling of the endocannabinoid signalling complex in a mouse model of fragile X syndrome. Nat Commun 3: 1080.
Karhson DS, Hardan AY, Parker KJ (2016) Endocannabinoid signaling in social functioning: An RDoC perspective. Transl Psychiatry 6: e905.
Karhson DS, Krasinska KM, Dallaire JA, et al. (2018) Plasma anandamide concentrations are lower in children with autism spectrum disorder. Mol Autism 9: 18.
Katona I (2015) Cannabis and endocannabinoid signaling in epilepsy. Handb Exp Pharmacol 231: 285–316.
Kerr DM, Gilmartin A, Roche M (2016) Pharmacological inhibition of fatty acid amide hydrolase attenuates social behavioural deficits in male rats prenatally exposed to valproic acid. Pharmacol Res 113: 228–235.
Khwaja OS, Ho E, Barnes KV, et al. (2014) Safety, pharmacokinetics, and preliminary assessment of efficacy of mecasermin (recombinant human IGF-1) for the treatment of Rett syndrome. Proc Natl Acad Sci U S A 111: 4596–4601.
Kline DD, Ogier M, Kunze DL, et al. (2010) Exogenous brain-derived neurotrophic factor rescues synaptic dysfunction in Mecp2-null mice. J Neurosci 30: 5303–5310.
Kron M, Lang M, Adams IT, et al. (2014) A BDNF loop-domain mimetic acutely reverses spontaneous apneas and respiratory abnormalities during behavioral arousal in a mouse model of Rett syndrome. Dis Model Mech 7: 1047–1055.
Li W, Pozzo-Miller L (2014) BDNF deregulation in Rett syndrome. Neuropharmacology 76: 737–746.
Ligresti A, De Petrocellis L, Di Marzo V (2016) From phytocannabinoids to cannabinoid receptors and endocannabinoids: Pleiotropic physiological and pathological roles through complex pharmacology. Physiol Rev 96: 1593–1659.
Magen I, Avraham Y, Ackerman Z, et al. (2010) Cannabidiol ameliorates cognitive and motor impairments in bile-duct ligated mice via 5-HT1A receptor activation. Br J Pharmacol 159: 950–957.
Martinowich K, Hattori D, Wu H, et al. (2003) DNA methylation-related chromatin remodeling in activity-dependent BDNF gene regulation. Science 302: 890–893.
Nagarkatti P, Pandey R, Rieder SA, et al. (2009) Cannabinoids as novel anti-inflammatory drugs. Future Med Chem 1: 1333–1349.
Neul JL, Lane JB, Lee HS, et al. (2014) Developmental delay in Rett syndrome: Data from the natural history study. J Neurodev Disord 6: 20.
Ogier M, Wang H, Hong E, et al. (2007) Brain-derived neurotrophic factor expression and respiratory function improve after ampakine treatment in a mouse model of Rett syndrome. J Neurosci 27: 10912–10917.
Pardridge WM, Kang YS, Buciak JL (1994) Transport of human recombinant brain-derived neurotrophic factor (BDNF) through the rat blood-brain barrier in vivo using vector-mediated peptide drug delivery. Pharm Res 11: 738–746.
Pini G, Congiu L, Benincasa A, et al. (2016) Illness severity, social and cognitive ability, and EEG analysis of ten patients with Rett syndrome treated with Mecasermin (Recombinant Human IGF-1). Autism Res Treat 2016: 5073078.
Pini G, Scusa MF, Benincasa A, et al. (2014) Repeated insulin-like growth factor 1 treatment in a patient with Rett syndrome: A single case study. Front Pediatr 2: 52.
Pini G, Scusa MF, Congiu L, et al. (2012) IGF1 as a potential treatment for Rett syndrome: Safety assessment in six Rett patients. Autism Res Treat 2012: 679801.
R Core Team (2013) R: A Language and Environment for Statistical Computing. Vienna, Austria: R foundation for Statistical Computing.
Ricceri L, De Filippis B, Laviola G (2008) Mouse models of Rett syndrome: From behavioural phenotyping to preclinical evaluation of new therapeutic approaches. Behav Pharmacol 19: 501–517.
Ricciardi S, Boggio EM, Grosso S, et al. (2011) Reduced AKT/mTOR signaling and protein synthesis dysregulation in a Rett syndrome animal model. Hum Mol Genet 20: 1182–1196.
Rosenthaler S, Pohn B, Kolmanz C, et al. (2014) Differences in receptor binding affinity of several phytocannabinoids do not explain their effects on neural cell cultures. Neurotoxicol Teratol 46: 49–56.
Roux JC, Zala D, Panayotis N, et al. (2012) Modification of Mecp2 dosage alters axonal transport through the Huntingtin/Hap1 pathway. Neurobiol Dis 45: 786–795.
Sceniak MP, Lang M, Enomoto AC, et al. (2016) Mechanisms of functional hypoconnectivity in the medial prefrontal cortex of Mecp2 null mice. Cereb Cortex 26: 1938–1956.
Schmid DA, Yang T, Ogier M, et al. (2012) A TrkB small molecule partial agonist rescues TrkB phosphorylation deficits and improves respiratory function in a mouse model of Rett syndrome. J Neurosci 32: 1803–1810.
Sciolino NR, Bortolato M, Eisenstein SA, et al. (2010) Social isolation and chronic handling alter endocannabinoid signaling and behavioral reactivity to context in adult rats. Neuroscience 168: 371–386.
Servadio M, Melancia F, Manduca A, et al. (2016) Targeting anandamide metabolism rescues core and associated autistic-like symptoms in rats prenatally exposed to valproic acid. Transl Psychiatry 6: e902.
Steffenburg U, Hagberg G, Hagberg B (2001) Epilepsy in a representative series of Rett syndrome. Acta Paediatr 90: 34–39.
Szczesna K, de la Caridad O, Petazzi P, et al. (2014) Improvement of the Rett syndrome phenotype in a MeCP2 mouse model upon treatment with levodopa and a dopa-decarboxylase inhibitor. Neuropsychopharmacology 39: 2846–2856.
Tropea D, Giacometti E, Wilson NR, et al. (2009) Partial reversal of Rett Syndrome-like symptoms in MeCP2 mutant mice. Proc Natl Acad Sci U S A 106: 2029–2034.
Tropea D, Kreiman G, Lyckman A, et al. (2006) Gene expression changes and molecular pathways mediating activity-dependent plasticity in visual cortex. Nat Neurosci 9: 660–668.
Vigli D, Cosentino L, Raggi C, et al. (2018) Chronic treatment with the phytocannabinoid Cannabidivarin (CBDV) rescues behavioural alterations and brain atrophy in a mouse model of Rett syndrome. Neuropharmacology 140: 121–129.
Volkow ND, Baler RD, Compton WM, et al. (2014) Adverse health effects of marijuana use. N Engl J Med 370: 2219–2227.
Wei D, Allsop S, Tye K, et al. (2017) Endocannabinoid signaling in the control of social behavior. Trends Neurosci 40: 385–396.
Wei D, Dinh D, Lee D, et al. (2016) Enhancement of anandamide-mediated endocannabinoid signaling corrects autism-related social impairment. Cannabis Cannabinoid Res 1: 81–89.
Yoshii A, Constantine-Paton M (2007) BDNF induces transport of PSD-95 to dendrites through PI3K-AKT signaling after NMDA receptor activation. Nat Neurosci 10: 702–711.
Zamberletti E, Gabaglio M, Parolaro D (2017) The endocannabinoid system and autism spectrum disorders: Insights from animal models. Int J Mol Sci 18: pii: E1916.
Zamberletti E, Gabaglio M, Prini P, et al. (2015) Cortical neuroinflammation contributes to long-term cognitive dysfunctions following adolescent delta-9-tetrahydrocannabinol treatment in female rats. Eur Neuropsychopharmacol 25: 2404–2415.
Zhang J, Hu M, Teng Z, et al. (2014) Synaptic and cognitive improvements by inhibition of 2-AG metabolism are through upregulation of microRNA-188-3p in a mouse model of Alzheimer’s disease. J Neurosci 34: 14919–14933.
Zheng WH, Quirion R (2004) Comparative signaling pathways of insulin-like growth factor-1 and brain-derived neurotrophic factor in hippocampal neurons and the role of the PI3 kinase pathway in cell survival. J Neurochem 89: 844–852.
Zuardi AW, Rodrigues NP, Silva AL, et al. (2017) Inverted U-shaped dose-response curve of the anxiolytic effect of cannabidiol during public speaking in real life. Front Pharmacol 8: 259.
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Article first published online: May 14, 2019
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