VCE-003.2, a novel cannabigerol derivative, enhances neuronal progenitor cell survival and alleviates symptomatology in murine models of Huntington's disease

Scientific Reports

Volumn 6, Issue , 2016, Pages

  Díaz Alonso, Javier ^a,b,c   Paraíso Luna, Juan ^a,b,c   Navarrete, Carmen ^d   Del Río, Carmen ^e   Cantarero, Irene ^b   Palomares, Belén ^a,b,c   Aguareles, José ^a,b,c   Fernández Ruiz, Javier ^d   Bellido, María Luz ^f   Pollastro, Federica ^f   Appendino, Giovanni ^f   Calzado, Marco A ^e   Galve Roperh, Ismael ^a,b,c   Muñoz, Eduardo ^e  

^a INSTITUTO RAMÓN Y CAJAL DE INVESTIGACIÓN SANITARIA IRYCIS   (Spain)

^b UNIVERSIDAD COMPLUTENSE DE MADRID   (Spain)

^c CENTRO DE INVESTIGACIÓN BIOMÉDICA EN RED SOBRE ENFERMEDADES NEURODEGENERATIVAS CIBERNED   (Spain)

^d VivaCell Biotechnology España ^*  (Spain)

^e HOSPITAL UNIVERSITARIO REINA SOFÍA   (Spain)

^f UNIVERSITY OF EASTERN PIEDMONT   (Italy)

Author keywords

[No Author keywords available]

Indexed keywords

CANNABIGEROL; CANNABINOID; NEUROPROTECTIVE AGENT; QUINONE DERIVATIVE; VCE-003;

ANIMAL; C57BL MOUSE; CELL CULTURE; CELL DIFFERENTIATION; CELL LINE; CELL SURVIVAL; DISEASE MODEL; DRUG EFFECT; GENE EXPRESSION; GENETICS; HEK293 CELL LINE; HUMAN; HUNTINGTON CHOREA; MALE; MESENCHYMAL STROMA CELL; METABOLISM; NEURAL STEM CELL; PATHOLOGY; PHYSIOLOGY; RAT; TUMOR CELL LINE;

ANIMALS; CANNABINOIDS; CELL DIFFERENTIATION; CELL LINE; CELL LINE, TUMOR; CELL SURVIVAL; CELLS, CULTURED; DISEASE MODELS, ANIMAL; GENE EXPRESSION; HEK293 CELLS; HUMANS; HUNTINGTON DISEASE; MALE; MESENCHYMAL STROMAL CELLS; MICE, INBRED C57BL; NEURAL STEM CELLS; NEUROPROTECTIVE AGENTS; QUINONES; RATS;

EID: 84979294063     PISSN: None     EISSN: 20452322     Source Type: Journal    
DOI: 10.1038/srep29789     Document Type: Article

References (48)

1. Di Marzo, V., Stella, N. & Zimmer A. Endocannabinoid signalling and the deteriorating brain. Nat. Rev. Neurosci. 16, 30-42 (2015).
2. McCaw, E. A. et al. Structure, expression and regulation of the cannabinoid receptor gene (CB1) in Huntington's disease transgenic mice. Eur. J. Biochem. 271, 4909-4920 (2004).
3. Dowie, M. J. et al. Altered CB1 receptor and endocannabinoid levels precede motor symptom onset in a transgenic mouse model of Huntington's disease. Neuroscience 163, 456-465 (2009).
4. Blázquez, C. et al. Loss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington's disease. Brain 134, 119-136 (2011).
5. Galve-Roperh, I. et al. Cannabinoid receptor signaling in progenitor/stem cell proliferation and differentiation. Prog. Lipid Res. 52, 633-650 (2013).
6. Izzo, A. A., Borrelli, F., Capasso, R., Di Marzo, V. & Mechoulam, R. Non-psychotropic plant cannabinoids: new therapeutic opportunities from an ancient herb. Trends Pharmacol. Sci. 30, 515-527 (2009).
7. Valdeolivas, S. et al. Neuroprotective Properties of Cannabigerol in Huntington's Disease: Studies in R6/2 Mice and 3-Nitropropionate-lesioned Mice. Neurotherapeutics 12, 185-199 (2015).
8. Sagredo, O. et al. Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease. J Neurosci Res 89, 1509-1518 (2011).
9. García-Caldentey, J. et al. A double-blind, randomized, cross-over, placebo-controlled, pilot trial with Sativex in Huntington's disease. J. Neurol. in press, doi: 10. 1007/s00415-016-8145-9.
10. Gervois, P., Fruchart, J.-C. & Staels, B. Drug Insight: mechanisms of action and therapeutic applications for agonists of peroxisome proliferator-activated receptors. Nat. Clin. Pract. Endocrinol. Metab. 3, 145-156 (2007).
11. Chiang, M.-C., Chern, Y. & Huang, R.-N. PPARgamma rescue of the mitochondrial dysfunction in Huntington's disease. Neurobiol. Dis. 45, 322-328 (2012).
12. Chiang, M.-C. et al. Rosiglitazone activation of PPAR-dependent signaling is neuroprotective in mutant huntingtin expressing cells. Exp. Cell Res. 338, 183-193 (2015).
13. Jin, J. et al. Neuroprotective effects of PPAR-agonist rosiglitazone in N171-82Q mouse model of Huntington's disease. J. Neurochem. 125, 410-419 (2013).
14. Stergiopoulos, A. & Politis, P. K. The role of nuclear receptors in controlling the fine balance between proliferation and differentiation of neural stem cells. Arch. Biochem. Biophys. 534, 27-37 (2013).
15. Rosen, C. J. Revisiting the rosiglitazone story-lessons learned. N. Engl. J. Med. 363, 803-806 (2010).
16. Granja, A. G. et al. A cannabigerol quinone alleviates neuroinflammation in a chronic model of multiple sclerosis. J. Neuroimmune Pharmacol. 7, 1002-1016 (2012).
17. Kogan, N. M. et al. HU-331, a novel cannabinoid-based anticancer topoisomerase II inhibitor. Mol. Cancer Ther. 6, 173-183 (2007).
18. Carrillo-Salinas, F. J. et al. A cannabigerol derivative suppresses immune responses and protects mice from experimental autoimmune encephalomyelitis. PLoS One 9, 1-12 (2014).
19. Avonto, C. et al. An NMR spectroscopic method to identify and classify thiol-trapping agents: revival of Michael acceptors for drug discovery? Angew. Chem. Int. Ed. Engl. 50, 467-471 (2011).
20. Benvenuti, S. et al. Rosiglitazone stimulates adipogenesis and decreases osteoblastogenesis in human mesenchymal stem cells. J. Endocrinol. Invest. 30, RC26-30 (2007).
21. Higgins, L. S. & Mantzoros, C. S. The Development of INT131 as a Selective PPARgamma Modulator: Approach to a Safer Insulin Sensitizer. PPAR Res. 2008, 936906 (2008).
22. Santiago-Mora, R., Casado-Díaz, A., De Castro, M. D. & Quesada-Gómez, J. M. Oleuropein enhances osteoblastogenesis and inhibits adipogenesis: The effect on differentiation in stem cells derived from bone marrow. Osteoporos. Int. 22, 675-684 (2011).
23. Akune, T. et al. PPARgamma insufficiency enhances osteogenesis through osteoblast formation from bone marrow progenitors. J. Clin. Invest. 113, 846-855 (2004).
24. Lecka-Czernik, B. Bone loss in diabetes: use of antidiabetic thiazolidinediones and secondary osteoporosis. Curr. Osteoporos. Rep. 8, 178-184 (2010).
25. Martin, H. L., Mounsey, R. B., Mustafa, S., Sathe, K. & Teismann, P. Pharmacological manipulation of peroxisome proliferatoractivated receptor(PPAR?) reveals a role for anti-oxidant protection in a model of Parkinson's disease. Exp. Neurol. 235, 528-538 (2012).
26. Thal, S. C. et al. Pioglitazone reduces secondary brain damage after experimental brain trauma by PPAR-independent mechanisms. J. Neurotrauma 28, 983-993 (2011).
27. Esposito, G. et al. Cannabidiol reduces a-induced neuroinflammation and promotes hippocampal neurogenesis through PPAR? involvement. PLoS One 6, e28668 (2011).
28. Campos, A. C. et al. The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system. Int J Neuropsychopharmacol 16, 1407-1419 (2013).
29. Schönhofen, P. et al. Cannabidiol Exposure During Neuronal Differentiation Sensitizes Cells Against Redox-Active Neurotoxins. Mol. Neurobiol. 52, 26-37 (2015).
30. Lazarov, O., Mattson, M. P., Peterson, D. A., Pimplikar, S. W. & van Praag, H. When neurogenesis encounters aging and disease. Trends Neurosci. 33, 569-579 (2010).
31. Bolzán, A. D. & Bianchi, M. S. Genotoxicity of streptonigrin: A review. Mutat. Res. 488, 25-37 (2001).
32. Li, V.-S., Choi, D., Tang, M.-S. & Kohn, H. Concerning in Vitro Mitomycin-DNA Alkylation. J Am Chem Soc 118, 3765-3766 (1996).
33. Pelicano, H., Carney, D. & Huang, P. ROS stress in cancer cells and therapeutic implications. Drug Resist. Updat. 7, 97-110 (2004).
34. Lu, H.-R. et al. Reactive oxygen species elicit apoptosis by concurrently disrupting topoisomerase II and DNA-dependent protein kinase. Mol. Pharmacol. 68, 983-994 (2005).
35. Joshi, G. et al. Glutathione elevation by gamma-glutamyl cysteine ethyl ester as a potential therapeutic strategy for preventing oxidative stress in brain mediated by in vivo administration of adriamycin: Implication for chemobrain. J. Neurosci. Res. 85, 497-503 (2007).
36. Satoh, T., McKercher, S. R. & Lipton, S. A. Nrf2/ARE-mediated antioxidant actions of pro-electrophilic drugs. Free Radic. Biol. Med. 66, 45-57 (2014).
37. Hayes, J. D., McMahon, M., Chowdhry, S. & Dinkova-Kostova, A. T. Cancer chemoprevention mechanisms mediated through the Keap1-Nrf2 pathway. Antioxid. Redox Signal. 13, 1713-1748 (2010).
38. Morimoto, R. I. Proteotoxic stress and inducible chaperone networks in neurodegenerative disease and aging. Genes Dev. 22, 1427-1438 (2008).
39. Satoh, T., Saitoh, S., Hosaka, M. & Kosaka, K. Simple ortho-and para-hydroquinones as compounds neuroprotective against oxidative stress in a manner associated with specific transcriptional activation. Biochem. Biophys. Res. Commun. 379, 537-541 (2009).
40. Bornheim, L. M. & Grillo, M. P. Characterization of cytochrome P450 3A inactivation by cannabidiol: possible involvement of cannabidiol-hydroxyquinone as a P450 inactivator. Chem. Res. Toxicol. 11, 1209-1216 (1998).
41. Chiarlone, A. et al. A restricted population of CB1 cannabinoid receptors with neuroprotective activity. Proc. Natl. Acad. Sci. 111, 8257-8262 (2014).
42. Dowie, M. J. et al. Behavioural and molecular consequences of chronic cannabinoid treatment in Huntington's disease transgenic mice. Neuroscience 170, 324-336 (2010).
43. Palazuelos, J. et al. Microglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity. Brain 132, 3152-3164 (2009).
44. Bouchard, J. et al. Cannabinoid Receptor 2 Signaling in Peripheral Immune Cells Modulates Disease Onset and Severity in Mouse Models of Huntington's Disease. J. Neurosci. 32, 18259-18268 (2012).
45. Johri, A., Chandra, A. & Beal, M. F. PGC-1, mitochondrial dysfunction, and Huntington's disease. Free Radic. Biol. Med. 62, 37-46 (2013).
46. Palazuelos, J., Ortega, Z., Díaz-Alonso, J., Guzmán, M. & Galve-Roperh, I. CB2 cannabinoid receptors promote neural progenitor cell proliferation via mTORC1 signaling. J. Biol. Chem. 287, 1198-1209 (2012).
47. Blázquez, C. et al. The CB1 cannabinoid receptor signals striatal neuroprotection via a PI3K/Akt/mTORC1/BDNF pathway. Cell Death Differ. 22, 1618-1629 (2015).
48. Fernagut, P. O. et al. Subacute systemic 3-nitropropionic acid intoxication induces a distinct motor disorder in adult C57Bl/6 mice: behavioural and histopathological characterisation. Neuroscience 114, 1005-1017 (2002).