Therapeutic potential of cannabinoids as neuroprotective agents for damaged cells conducing to movement disorders

Antonazzo, Mario; Botta, María Florencia; Bengoetxea, Harkaitz; Ruiz-Ortega, José Ángel; Morera-Herreras, Teresa

doi:10.1016/bs.irn.2019.06.012

Cited by 21 publications

(13 citation statements)

References 146 publications

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“…The number of registered clinical trials indicated in https://clinicaltrials.gov/ for testing cannabidiol in a variety of pathological conditions is 321 (date: 1 July 2021). As commented in the introduction, the CB 2 R is, also, an attractive target to afford neuroprotection in Parkinson's disease [3,[7][8][9][10][11][12][13][14].…”

Section: Discussionmentioning

confidence: 99%

“…The CB 2 R is considered a target for neuroprotection, especially in diseases coursing with neuroinflammation. For instance, cannabinoids acting on the CB 2 R in striatal neural cells reduce the neuronal loss in synucleinopathies such as Parkinson's disease [8][9][10][11][12][13]. The underlying mechanism is mainly related to the reduction of inflammation, but the CB 2 R expressed in some striatal neurons may also have a relevant role [3,7,[14][15][16].…”

Section: Introductionmentioning

confidence: 99%

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Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

Lillo

Zafra

et al. 2021

IJMS

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Cannabinoids have been reported as orexigenic, i.e., as promoting food intake that, among others, is controlled by the so-called “hunger” hormone, ghrelin. The aim of this paper was to look for functional and/or molecular interactions between ghrelin GHSR1a and cannabinoid CB2 receptors at the central nervous system (CNS) level. In a heterologous system we identified CB2-GHSR1a receptor complexes with a particular heteromer print consisting of impairment of CB2 receptor/Gi-mediated signaling. The blockade was due to allosteric interactions within the heteromeric complex as it was reverted by antagonists of the GHSR1a receptor. Cannabinoids acting on the CB2 receptor did not affect cytosolic increases of calcium ions induced by ghrelin acting on the GHSR1a receptor. In situ proximity ligation imaging assays confirmed the expression of CB2-GHSR1a receptor complexes in both heterologous cells and primary striatal neurons. We tested heteromer expression in neurons from offspring of high-fat-diet mouse mothers as they have more risk to be obese. Interestingly, there was a marked upregulation of those complexes in striatal neurons from siblings of pregnant female mice under a high-fat diet.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

Lillo

Zafra

et al. 2021

IJMS

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“…Recently, growing evidences showed that cannabinoids have neuroprotective and motor symptom-modulating properties, and clinical studies have observed a reduction in LID in patients with PD after smoking medical marijuana. Therefore, cannabinoids may be a promising candidate for the treatment of PD ( Antonazzo et al, 2019 ; Cristino et al, 2020 ).…”

Section: Introductionmentioning

confidence: 99%

Roles of the Cannabinoid System in the Basal Ganglia in Parkinson’s Disease

Wang

Liu

2022

Front. Cell. Neurosci.

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Parkinson’s disease (PD) is a neurodegenerative disease usually caused by neuroinflammation, oxidative stress and other etiologies. Recent studies have found that the cannabinoid system present in the basal ganglia has a strong influence on the progression of PD. Altering the cannabinoid receptor activation status by modulating endogenous cannabinoid (eCB) levels can exert an anti-movement disorder effect. Therefore, the development of drugs that modulate the endocannabinoid system may be a novel strategy for the treatment of PD. However, eCB regulation is complex, with diverse cannabinoid receptor functions and the presence of dopaminergic, glutamatergic, and γ-aminobutyric signals interacting with cannabinoid signaling in the basal ganglia region. Therefore, the study of eCB is challenging. Here, we have described the function of the cannabinoid system in the basal ganglia and its association with PD in three parts (eCBs, cannabinoid receptors, and factors regulating the cannabinoid metabolism) and summarized the mechanisms of action related to the cannabinoid analogs currently aimed at treating PD. The shortcomings identified from previous studies and the directions that should be explored in the future will provide insights into new approaches and ideas for the future development of cannabinoid-based drugs and the treatment of PD.

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“…Such neuroprotective potential has been preclinically investigated in accidental brain damage (e.g., stroke, brain trauma, spinal injury) and, in particular, in chronic progressive disorders (e.g., Alzheimer’s disease, amyotrophic lateral sclerosis, Huntington’s disease, and others) [ 2 ]. This also includes Parkinson’s disease (PD), which is one of the disorders that has attracted to date most of the research with cannabinoids, aimed at exploring neuroprotective therapies to delay or arrest disease progression and also alleviate specific parkinsonian symptoms (reviewed in [ 2 , 3 , 4 , 5 ]). Some of these studies have concentrated on compounds targeting the cannabinoid type-1 (CB 1 ) receptor, demonstrating neuroprotective properties in some experimental models of PD [ 6 , 7 ].…”

Section: Introductionmentioning

confidence: 99%

Neuroprotection with the Cannabidiol Quinone Derivative VCE-004.8 (EHP-101) against 6-Hydroxydopamine in Cell and Murine Models of Parkinson’s Disease

et al. 2021

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The 3-hydroxyquinone derivative of the non-psychotrophic phytocannabinoid cannabigerol, so-called VCE-003.2, and some other derivatives have been recently investigated for neuroprotective properties in experimental models of Parkinson’s disease (PD) in mice. The pharmacological effects in those models were related to the activity on the peroxisome proliferator-activated receptor-γ (PPAR-γ) and possibly other pathways. In the present study, we investigated VCE-004.8 (formulated as EHP-101 for oral administration), the 3-hydroxyquinone derivative of cannabidiol (CBD), with agonist activity at the cannabinoid receptor type-2 (CB2) receptor in addition to its activity at the PPAR-γ receptor. Studies were conducted in both in vivo (lesioned-mice) and in vitro (SH-SY5Y cells) models using the classic parkinsonian neurotoxin 6-hydroxydopamine (6-OHDA). Our data confirmed that the treatment with VCE-004.8 partially reduced the loss of tyrosine hydroxylase (TH)-positive neurons measured in the substantia nigra of 6-OHDA-lesioned mice, in parallel with an almost complete reversal of the astroglial (GFAP) and microglial (CD68) reactivity occurring in this structure. Such neuroprotective effects attenuated the motor deficiencies shown by 6-OHDA-lesioned mice in the cylinder rearing test, but not in the pole test. Next, we explored the mechanism involved in the beneficial effect of VCE-004.8 in vivo, by analyzing cell survival in cultured SH-SY5Y cells exposed to 6-OHDA. We found an important cytoprotective effect of VCE-004.8 at a concentration of 10 µM, which was completely reversed by the addition of antagonists, T0070907 and SR144528, aimed at blocking PPAR-γ and CB2 receptors, respectively. The treatment with T0070907 alone only caused a partial reversal, whereas SR144528 alone had no effect, indicating a major contribution of PPAR-γ receptors in the cytoprotective effect of VCE-004.8 at 10 µM. In summary, our data confirmed the neuroprotective potential of VCE-004.8 in 6-OHDA-lesioned mice, and in vitro studies confirmed a greater relevance for PPAR-γ receptors rather than CB2 receptors in these effects.

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Therapeutic potential of cannabinoids as neuroprotective agents for damaged cells conducing to movement disorders

Cited by 21 publications

References 146 publications

Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

Identification of the Ghrelin and Cannabinoid CB2 Receptor Heteromer Functionality and Marked Upregulation in Striatal Neurons from Offspring of Mice under a High-Fat Diet

Roles of the Cannabinoid System in the Basal Ganglia in Parkinson’s Disease

Neuroprotection with the Cannabidiol Quinone Derivative VCE-004.8 (EHP-101) against 6-Hydroxydopamine in Cell and Murine Models of Parkinson’s Disease

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