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Cited by 407Cannabis and Cannabinoid ResearchParkinson's Disease Mechanisms and TreatmentsAlzheimer's disease research and treatments

Cannabinoids provide neuroprotection against 6-hydroxydopamine toxicity in vivo and in vitro: relevance to Parkinson's disease

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Lastres-Becker, Isabel, Molina-Holgado, Francisco, Ramos, José A., Mechoulam, Raphael, Fernández-Ruiz, Javier·2005·Neurobiology of Disease
DOI 10.1016/j.nbd.2004.11.009
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Abstract

Cannabinoids have been reported to provide neuroprotection in acute and chronic neurodegeneration. In this study, we examined whether they are also effective against the toxicity caused by 6-hydroxydopamine, both in vivo and in vitro, which may be relevant to Parkinson's disease (PD). First, we evaluated whether the administration of cannabinoids in vivo reduces the neurodegeneration produced by a unilateral injection of 6-hydroxydopamine into the medial forebrain bundle. As expected, 2 weeks after the application of this toxin, a significant depletion of dopamine contents and a reduction of tyrosine hydroxylase activity in the lesioned striatum were noted, and were accompanied by a reduction in tyrosine hydroxylase-mRNA levels in the substantia nigra. None of these events occurred in the contralateral structures. Daily administration of delta9-tetrahydrocannabinol (delta9-THC) during these 2 weeks produced a significant waning in the magnitude of these reductions, whereas it failed to affect dopaminergic parameters in the contralateral structures. This effect of delta9-THC appeared to be irreversible since interruption of the daily administration of this cannabinoid after the 2-week period did not lead to the re-initiation of the 6-hydroxydopamine-induced neurodegeneration. In addition, the fact that the same neuroprotective effect was also produced by cannabidiol (CBD), another plant-derived cannabinoid with negligible affinity for cannabinoid CB1 receptors, suggests that the antioxidant properties of both compounds, which are cannabinoid receptor-independent, might be involved in these in vivo effects, although an alternative might be that the neuroprotection exerted by both compounds might be due to their anti-inflammatory potential. As a second objective, we examined whether cannabinoids also provide neuroprotection against the in vitro toxicity of 6-hydroxydopamine. We found that the non-selective cannabinoid agonist HU-210 increased cell survival in cultures of mouse cerebellar granule cells exposed to this toxin. However, this effect was significantly lesser when the cannabinoid was directly added to neuronal cultures than when these cultures were exposed to conditioned medium obtained from mixed glial cell cultures treated with HU-210, suggesting that the cannabinoid exerted its major protective effect by regulating glial influence to neurons. In summary, our results support the view of a potential neuroprotective action of cannabinoids against the in vivo and in vitro toxicity of 6-hydroxydopamine, which might be relevant for PD. Our data indicated that these neuroprotective effects might be due, among others, to the antioxidant properties of certain plant-derived cannabinoids, or exerted through the capability of cannabinoid agonists to modulate glial function, or produced by a combination of both mechanisms.

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  • In animal models of Parkinson's disease, CBD protects neurons by preventing tyrosine hydroxylase activity reduction and dopamine depletion in the substantia nigra.

    “In animal models of Parkinson's disease, CBD protects neurons by preventing the tyrosine hydroxylase activity reduction and the dopamine depletion in the substantia nigra (119, 129).”

    From Translational investigation of the therapeutic potential of Cannabidiol (CBD): Toward a new age (2018) · cites this paper as [129]

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Authors
Lastres-Becker, I., Molina-Holgado, F., Ramos, J. A., Mechoulam, R., & Fernández-Ruiz, J.
Affiliations
  • Universidad Complutense de Madrid (ES)
  • Hebrew University of Jerusalem (IL)
ORCID
Venue
Neurobiology of Disease
Publisher
Elsevier BV
Published
2005-06
Volume
19
Issue
1-2
Pages
96-107
ISSN
0969-9961 (ISSN-L)
DOI
10.1016/j.nbd.2004.11.009
OpenAlex
W2110514788
Cited by
407
References
108
Citations by year
2026: 8 · 2025: 13 · 2024: 23 · 2023: 25 · 2022: 23 · 2021: 30 · 2020: 29 · 2019: 26 · 2018: 15 · 2017: 26 · 2016: 20 · 2015: 13 · 2014: 13 · 2013: 14 · 2012: 16
FWCI
12.12
Type
journal article
Language
en
Open access
Licence
Locations
  • Neurobiology of Disease (publishedVersion)
  • PubMed (publishedVersion)
  • DOAJ (DOAJ: Directory of Open Access Journals) (submittedVersion, cc-by-sa)
  • Research Portal (King's College London) (submittedVersion)
Funders
Deakin University
Topics
  • Health Sciences › Medicine › Pharmacology › Cannabis and Cannabinoid Research
  • Health Sciences › Medicine › Neurology › Parkinson's Disease Mechanisms and Treatments
  • Health Sciences › Medicine › Physiology › Alzheimer's disease research and treatments
Keywords
cannabinoids, neuroprotection, 6-hydroxydopamine, Parkinson's disease, delta-9-tetrahydrocannabinol, cannabidiol, HU-210, dopamine depletion, tyrosine hydroxylase, substantia nigra, striatum, neuron-glia interactions, cerebellar granule cells
MeSH terms
Animals, Cannabinoids, Cell Survival, Cells, Cultured, Dopamine, Male, Mice, Inbred C57BL, Parkinson Disease, Oxidopamine, Rats, Sprague-Dawley, Neuroprotective Agents, Mice, Rats

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