Neuroprotective effects of phytocannabinoid-based medicines in experimental models of Huntington's disease
Abstract
We studied whether combinations of botanical extracts enriched in either Δ(9)-tetrahydrocannabinol (Δ(9)-THC) or cannabidiol (CBD), which are the main constituents of the cannabis-based medicine Sativex, provide neuroprotection in rat models of Huntington's disease (HD). We used rats intoxicated with 3-nitropropionate (3NP) that were given combinations of Δ(9)-THC- and CBD-enriched botanical extracts. The issue was also studied in malonate-lesioned rats. The administration of Δ(9)-THC- and CBD-enriched botanical extracts combined in a ratio of 1:1 as in Sativex attenuated 3NP-induced GABA deficiency, loss of Nissl-stained neurons, down-regulation of CB(1) receptor and IGF-1 expression, and up-regulation of calpain expression, whereas it completely reversed the reduction in superoxide dismutase-1 expression. Similar responses were generally found with other combinations of Δ(9)-THC- and CBD-enriched botanical extracts, suggesting that these effects are probably related to the antioxidant and CB(1) and CB(2) receptor-independent properties of both phytocannabinoids. In fact, selective antagonists for both receptor types, i.e., SR141716 and AM630, respectively, were unable to prevent the positive effects on calpain expression caused in 3NP-intoxicated rats by the 1:1 combination of Δ(9)-THC and CBD. Finally, this combination also reversed the up-regulation of proinflammatory markers such as inducible nitric oxide synthase observed in malonate-lesioned rats. In conclusion, this study provides preclinical evidence in support of a beneficial effect of the cannabis-based medicine Sativex as a neuroprotective agent capable of delaying disease progression in HD, a disorder that is currently poorly managed in the clinic, prompting an urgent need for clinical trials with agents showing positive results in preclinical studies.
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CBD attenuates the depletion of tyrosine hydroxylase, GABA and dopamine levels by modulating the expression of inducible NO synthase and reducing the production of ROS-generating NADPH oxidases.
“and attenuates the depletion of tyrosine hydroxylase, GABA and dopamine levels by modulating the expression of the inducible isoform of NO synthase and reducing the production of ROS-generating NADPH oxidases (114–120).”
From Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age (2018) · cites this paper as [120]
Cites
Cannabidiol and (−)Δ <sup>9</sup> -tetrahydrocannabinol are neuroprotective antioxidants
Hampson, A. J., Grimaldi, M., Axelrod, J., & Wink, D. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.14.8268 · Cited by 850 · see citing works
Molecular Mechanisms and Potential Therapeutical Targets in Huntington's Disease
Zuccato, C., Valenza, M., & Cattaneo, E. (2010) · Physiological Reviews · doi:10.1152/physrev.00041.2009 · Cited by 848 · see citing works
Russo, E. B., & Guy, G. W. (2005) · Medical Hypotheses · doi:10.1016/j.mehy.2005.08.026 · Cited by 608 · see citing works
Maps and guide to microdissection of the rat brain
Palkovits, M., & Brownstein, M. (1988) · Medical Entomology and Zoology · Cited by 550 · see citing works
Emerging strategies for exploiting cannabinoid receptor agonists as medicines
Pertwee, R. G. (2009) · British Journal of Pharmacology · doi:10.1111/j.1476-5381.2008.00048.x · Cited by 436 · see citing works
Self-citationReplicating Huntington's disease phenotype in experimental animals
Brouillet, E. (1999) · Progress in Neurobiology · doi:10.1016/s0301-0082(99)00005-2 · Cited by 413 · see citing works
Lastres-Becker, I., Molina-Holgado, F., Ramos, J. A., Mechoulam, R., & Fernández-Ruiz, J. (2005) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.11.009 · Cited by 407 · see citing works
Self-citationMicroglial CB2 cannabinoid receptors are neuroprotective in Huntington's disease excitotoxicity
Palazuelos, J., Aguado, T., Pazos, M. R., Julien, B., Carrasco, C., Resel, E., Sagredo, O., Benito, C., Romero, J., Azcoitia, I., et al. (2009) · Brain · doi:10.1093/brain/awp239 · Cited by 382 · see citing works
Self-citationMaps and guide to microdissection of the rat brain
Bruyn, G. W. (1988) · Journal of the Neurological Sciences · doi:10.1016/0022-510x(88)90044-5 · Cited by 370 · see citing works
Cannabinoid CB2 receptor: a new target for controlling neural cell survival?
Fernández‐Ruíz, J., Romero, J., Velasco, G., Tolón, R. M., Ramos, J. A., & Guzmán, M. (2006) · Trends in Pharmacological Sciences · doi:10.1016/j.tips.2006.11.001 · Cited by 362 · see citing works
Self-citationBrouillet, E., Jacquard, C., Bizat, N., & Blum, D. L. (2005) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2005.03515.x · Cited by 361 · see citing works
Controlled clinical trial of cannabidiol in Huntington's disease
Consroe, P. F., Laguna, J., Allender, J. R., Snider, S. R., Stern, L. Z., Sandyk, R., Kennedy, K., & Schram, K. H. (1991) · Pharmacology Biochemistry and Behavior · doi:10.1016/0091-3057(91)90386-g · Cited by 324 · see citing works
Marsicano, G., Moosmann, B., Hermann, H., Lutz, B., & Behl, C. (2002) · Journal of Neurochemistry · doi:10.1046/j.0022-3042.2001.00716.x · Cited by 313 · see citing works
Mitochondria in Huntington's disease
Damiano, M. G., Galvan, L., Déglon, N., & Brouillet, E. (2009) · Biochimica et Biophysica Acta (BBA) - Molecular Basis of Disease · doi:10.1016/j.bbadis.2009.07.012 · Cited by 282 · see citing works
Calkins, M. J., Jakel, R. J., Johnson, D. A., Chan, K., Kan, Y. W., & Johnson, J. A. (2005) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0408487101 · Cited by 247 · see citing works
Mochel, F., Charles, P., Seguin, F., Barritault, J., Coussieu, C., Périn, L., Bouc, Y. L., Gervais, C., Carcelain, G., Vassault, A. J., et al. (2007) · PLoS ONE · doi:10.1371/journal.pone.0000647 · Cited by 239 · see citing works
Yang, L., Calingasan, N. Y., Wille, E. J., Cormier, K., Smith, K., Ferrante, R. J., & Beal, M. F. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06074.x · Cited by 232 · see citing works
Neuroprotective Antioxidants from Marijuana a
Hampson, A. J., GRIMALDI, M., Miljkovic-Lolic, M., Wink, D. A., Rosenthal, R., & Axelrod, J. (2000) · Annals of the New York Academy of Sciences · doi:10.1111/j.1749-6632.2000.tb06193.x · Cited by 203 · see citing works
Sagredo, O., González, S., Aroyo, I., Pazos, M. R., Benito, C., Lastres‐Becker, I., Romero, J. P., Tolón, R. M., Mechoulam, R., Brouillet, E., et al. (2009) · Glia · doi:10.1002/glia.20838 · Cited by 201 · see citing works
Self-citationLoss of striatal type 1 cannabinoid receptors is a key pathogenic factor in Huntington’s disease
Blázquez, C., Chiarlone, A., Sagredo, O., Aguado, T., Pazos, M. R., Resel, E., Palazuelos, J., Julien, B., Salazar‐Roa, M., Börner, C., et al. (2010) · Brain · doi:10.1093/brain/awq278 · Cited by 201 · see citing works
Self-citationBoll, M.-C., Alcaraz-Zubeldia, M., Montes, S., & Rios, C. (2008) · Neurochemical Research · doi:10.1007/s11064-008-9610-3 · Cited by 173 · see citing works
Bizat, N., Hermel, J., Boyer, F., Jacquard, C., Créminon, C., Ouary, S., Escartin, C., Hantraye, P., Krajewski, S., & Brouillet, E. (2003) · Journal of Neuroscience · doi:10.1523/jneurosci.23-12-05020.2003 · Cited by 163 · see citing works
A pilot study using nabilone for symptomatic treatment in Huntington's disease
Curtis, A., Mitchell, I., Patel, S., Ives, N. J., & Rickards, H. E. (2009) · Movement Disorders · doi:10.1002/mds.22809 · Cited by 158 · see citing works
Alvarez, F. J., Lafuente, H., Rey-Santano, M. C., Mielgo, V., Gastiasoro, E., Rueda, M. A., Pertwee, R. G., Castillo, A. I., Romero, J., & Martínez-Orgado, J. A. (2008) · Pediatric Research · doi:10.1203/pdr.0b013e318186e5dd · Cited by 151 · see citing works
Self-citationSagredo, O., Ramos, J. A., Decio, A., Mechoulam, R., & Fernández‐Ruiz, J. (2007) · European Journal of Neuroscience · doi:10.1111/j.1460-9568.2007.05717.x · Cited by 147 · see citing works
Self-citationAcute Neuronal Injury, Excitotoxicity, and the Endocannabinoid System
van der Stelt, M., Veldhuis, W. B., Maccarrone, M., Bär, P. R., Nicolay, K., Veldink, G. A., Marzo, V. D., & Vliegenthart, J. F. G. (2002) · Molecular Neurobiology · doi:10.1385/mn:26:2-3:317 · Cited by 144 · see citing works
Lastres‐Becker, I., de Miguel, R., PETROCELLIS, L. D., Makriyannis, A., Marzo, V. D., & Fernández‐Ruíz, J. (2003) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2003.01595.x · Cited by 143 · see citing works
In Vivo Calpain/Caspase Cross-talk during 3-Nitropropionic Acid-induced Striatal Degeneration
Bizat, N., Hermel, J., Humbert, S., Jacquard, C., Créminon, C., Escartin, C., Saudou, F., Krajewski, S., Hantraye, P., & Brouillet, E. (2003) · Journal of Biological Chemistry · doi:10.1074/jbc.m305057200 · Cited by 125 · see citing works
Fontaine, M. A. L., Geddes, J. W., Banks, A., & Butterfield, D. A. (2000) · Journal of Neurochemistry · doi:10.1046/j.1471-4159.2000.0751709.x · Cited by 118 · see citing works
Lastres‐Becker, I., Hansen, H. H., Berrendero, F., de Miguel, R., Pérez‐Rosado, A., Manzanares, J., Ramos, J. A., & Fernández‐Ruíz, J. (2002) · Synapse · doi:10.1002/syn.10054 · Cited by 116 · see citing works
Self-citationPouladi, M. A., Xie, Y., Skotte, N. H., Ehrnhoefer, D. E., Graham, R. K., Kim, J. E., Bissada, N., Yang, X. W., Paganetti, P., Friedlander, R. M., et al. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq026 · Cited by 104 · see citing works
Neurochemical substrates of rigidity and chorea in Huntington's disease
Storey, E., & Beal, M. F. (1993) · Brain · doi:10.1093/brain/116.5.1201 · Cited by 99 · see citing works
Isoniazid‐induced elevation of CSF GABA levels and effects on chorea in huntington's disease
Manyam, B. V., Katz, L., Hare, T. A., Kaniefski, K., & Tremblay, R. D. (1981) · Annals of Neurology · doi:10.1002/ana.410100107 · Cited by 94 · see citing works
Kaempferol protects against rat striatal degeneration induced by 3‐nitropropionic acid
Lagoa, R., López‐Sánchez, C., Samhan-Arias, A. K., Gañán, C., García‐Martínez, V., & Gutiérrez‐Merino, C. (2009) · Journal of Neurochemistry · doi:10.1111/j.1471-4159.2009.06331.x · Cited by 91 · see citing works
The endocannabinoid system as a target for the treatment of neuronal damage
Fernández‐Ruíz, J., García, C., Sagredo, O., Gómez‐Ruíz, M., & de Lago, E. (2010) · Expert Opinion on Therapeutic Targets · doi:10.1517/14728221003709792 · Cited by 89 · see citing works
Self-citationTadros, M. G., Khalifa, A. E., Abdel‐Naim, A. B., & Arafa, H. M. M. (2005) · Pharmacology Biochemistry and Behavior · doi:10.1016/j.pbb.2005.10.018 · Cited by 79 · see citing works
Pintor, A., Tebano, M. T., Martire, A., et al. (2006) · Neuropharmacology · doi:10.1016/j.neuropharm.2006.06.013 · Cited by 73 · see citing works
Herrera‐Mundo, M. N., Silva‐Adaya, D., Maldonado, P. D., Galván‐Arzate, S., Andrés-Martínez, L., de la Cruz, V. P., Pedraza‐Chaverrí, J., & Santamarı́a, A. (2006) · Neuroscience Research · doi:10.1016/j.neures.2006.04.018 · Cited by 70 · see citing works
The Endocannabinoid System in Huntingtons Disease
Pazos, M. R., Sagredo, O., & Fernández‐Ruíz, J. (2008) · Current Pharmaceutical Design · doi:10.2174/138161208785740108 · Cited by 69 · see citing works
Self-citationMelatonin protects against neuronal damage induced by 3-nitropropionic acid in rat striatum
Nam, E.-J., Lee, S. M., Koh, S., Joo, W. S., Maeng, S., Im, H. I., & Kim, Y. S. (2005) · Brain Research · doi:10.1016/j.brainres.2005.03.053 · Cited by 60 · see citing works
Potential involvement of cannabinoid receptors in 3-nitropropionic acid toxicity in vivo
Lastres‐Becker, I., Bizat, N., Boyer, F., Hantraye, P., Fernández‐Ruíz, J., & Brouillet, E. (2004) · Neuroreport · doi:10.1097/00001756-200410250-00015 · Cited by 59 · see citing works
Huntington's disease: progress toward effective disease-modifying treatments and a cure
Johnson, C. D., & Davidson, B. L. (2010) · Human Molecular Genetics · doi:10.1093/hmg/ddq148 · Cited by 59 · see citing works
Nabilone Could Treat Chorea and Irritability in Huntington’s Disease
Curtis, A., & Rickards, H. E. (2006) · Journal of Neuropsychiatry · doi:10.1176/jnp.2006.18.4.553 · Cited by 57 · see citing works
Minocycline in phenotypic models of Huntington's disease
Bantubungi, K., Jacquard, C., Greco, A., Pintor, A., Chtarto, A., Taï, K., Galas, M., Tenenbaum, L., Déglon, N., Popoli, P., et al. (2004) · Neurobiology of Disease · doi:10.1016/j.nbd.2004.09.017 · Cited by 53 · see citing works
Roze, E. F., Bonnet, C., Bétuing, S., & Caboche, J. (2010) · Advances in experimental medicine and biology · doi:10.1007/978-1-4419-6448-9_5 · Cited by 53 · see citing works
Alexi, T., Hughes, P. E., van Roon‐Mom, W., et al. (1999) · Experimental Neurology · doi:10.1006/exnr.1999.7168 · Cited by 49 · see citing works
Cannabinoids in neurodegeneration and neuroprotection
Fernández‐Ruíz, J., González, S. R., Romero, J., & Ramos, J. A. (2005) · Birkhäuser-Verlag eBooks · doi:10.1007/3-7643-7358-x_5 · Cited by 46 · see citing works
Self-citationCalkins, M. J., Townsend, J. A., Johnson, D. A., & Johnson, J. A. (2010) · Experimental Neurology · doi:10.1016/j.expneurol.2010.04.008 · Cited by 40 · see citing works
Túnez, I., Muñoz, M. C., & Montilla, P. (2005) · Pharmacology · doi:10.1159/000084169 · Cited by 26 · see citing works
Kalonia, H., Kumar, P., & Kumar, A. (2010) · European Journal of Pharmacology · doi:10.1016/j.ejphar.2010.02.031 · Cited by 22 · see citing works
Cannabinoid-Based Medicines for Neurological Disorders—Clinical Evidence
Wright, S. (2007) · Molecular Neurobiology · doi:10.1007/s12035-007-0003-4 · Cited by 19 · see citing works
Increased activity of surviving locus ceruleus neurons in Alzheimer's disease
Moser (1999) · Pure Amsterdam UMC · doi:10.1002/1531-8249(199901)45:1
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Campos, A. C., Moreira, F. A., Gomes, F. V., Del Bel, E. A., & Guimarães, F. S. (2012) · Philosophical Transactions of the Royal Society B: Biological Sciences · doi:10.1098/rstb.2011.0389 · Cited by 475 · see citing works
Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age
Crippa, J. A., Guimarães, F. S., Campos, A. C., & Zuardi, A. W. (2018) · Frontiers in Immunology · doi:10.3389/fimmu.2018.02009 · Cited by 308 · see citing works
Campos, A. C., Fogaça, M. V., Scarante, F. F., Joca, S. R. L., Sales, A. J., Gomes, F. V., Sonego, A. B., Rodrigues, N. S., Galve-Roperh, I., & Guimarães, F. S. (2017) · Frontiers in Pharmacology · doi:10.3389/fphar.2017.00269 · Cited by 175 · see citing works
- Authors
- Sagredo, O., Pazos, M. R., Satta, V., Ramos, J. A., Pertwee, R. G., & Fernández‐Ruiz, J.
- Affiliations
- Universidad Complutense de Madrid (ES)
- University of Aberdeen (GB)
- Venue
- Journal of Neuroscience Research
- Publisher
- Wiley
- Published
- 2011-06-14
- Volume
- 89
- Issue
- 9
- Pages
- 1509-1518
- ISSN
- 0360-4012 (ISSN-L)
- 1097-4547
- OpenAlex
- W2087045001
- Cited by
- 105
- References
- 52
- Citations by year
- 2026: 2 · 2025: 6 · 2024: 6 · 2023: 7 · 2022: 6 · 2021: 3 · 2020: 7 · 2019: 6 · 2018: 6 · 2017: 11 · 2016: 9 · 2015: 10 · 2014: 8 · 2013: 8 · 2012: 7
- FWCI
- 6.07
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Journal of Neuroscience Research (publishedVersion)
- PubMed (publishedVersion)
- UNICA IRIS Institutional Research Information System (University of Cagliari) (submittedVersion)
- Funders
- GW Pharmaceuticals
- National Institutes of Health
- Topics
- Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
- Life Sciences › Neuroscience › Cellular and Molecular Neuroscience › Genetic Neurodegenerative Diseases
- Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
- Keywords
- Huntington's disease, neuroprotection, phytocannabinoids, Sativex, delta-9-tetrahydrocannabinol, cannabidiol, 3-nitropropionic acid, CB1 receptor, CB2 receptor, calpain, superoxide dismutase 1, GABA deficiency, neuroinflammation, antioxidant activity, cannabis-based medicines
- MeSH terms
- Animals, Cannabidiol, Cannabinoids, Caudate Nucleus, Cells, Cultured, Disease Models, Animal, Drug Combinations, Huntington Disease, Male, Phytotherapy, Plant Extracts, Putamen, Dronabinol, Neostriatum, Rats, Sprague-Dawley, Disease Progression, Neuroprotective Agents, Rats
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