Tag Archives: neuroprotective

Biological bases for a possible effect of cannabidiol in Parkinson’s disease.

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 SciELO - Scientific Electronic Library Online“Current pharmacotherapy of Parkinson’s disease (PD) is palliative and unable to modify the progression of neurodegeneration. Treatments that can improve patients’ quality of life with fewer side effects are needed, but not yet available.

Cannabidiol (CBD), the major non-psychotomimetic constituent of cannabis, has received considerable research attention in the last decade. In this context, we aimed to critically review the literature on potential therapeutic effects of CBD in PD and discuss clinical and preclinical evidence supporting the putative neuroprotective mechanisms of CBD.

RESULTS:

Few studies addressed the biological bases for the purported effects of CBD on PD. Six preclinical studies showed neuroprotective effects, while three targeted the antidyskinetic effects of CBD. Three human studies have tested CBD in patients with PD: an open-label study, a case series, and a randomized controlled trial. These studies reported therapeutic effects of CBD on non-motor symptoms.

CONCLUSIONS:

Additional research is needed to elucidate the potential effectiveness of CBD in PD and the underlying mechanisms involved.”

https://www.ncbi.nlm.nih.gov/pubmed/31314869

http://www.scielo.br/scielo.php?script=sci_arttext&pid=S1516-44462019005012104&tlng=en

Endogenous and synthetic cannabinoids induce the downregulation of cannabinoid CB1 receptor in retina.

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Experimental Eye Research

“Endogenous and synthetic cannabinoids have been shown to provide neuroprotection to retinal neurons in acute animal models of retinopathy.

Chronic exposure to cannabinoid receptor (CB1R) agonists has been reported to induce downregulation of the CB1R in brain and behavioral tolerance.

The aim of this study was to investigate the effect of subchronic/chronic cannabinoid administration on CB1R downregulation in normal rat retina, its downstream prosurvival signaling and subsequent effect on retinal neuroprotection against AMPA excitotoxicity.

This study provides novel information regarding agonist-induced CB1R downregulation in rat retina after subchronic/chronic cannabinoid treatment, and its effect on downstream prosurvival signaling and neuroprotection.”

https://www.ncbi.nlm.nih.gov/pubmed/31199905

https://www.sciencedirect.com/science/article/pii/S0014483519301216?via%3Dihub

Efficacy of Cannabinoids in a Pre-Clinical Drug-Screening Platform for Alzheimer’s Disease.

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“Finding a therapy for Alzheimer’s disease (AD) is perhaps the greatest challenge for modern medicine. The chemical scaffolds of many drugs in the clinic today are based upon natural products from plants, yet Cannabis has not been extensively examined as a source of potential AD drug candidates.

Here, we determine if a number of non-psychoactive cannabinoids are neuroprotective in a novel pre-clinical AD and neurodegeneration drug-screening platform that is based upon toxicities associated with the aging brain.

This drug discovery paradigm has yielded several compounds in or approaching clinical trials for AD. Eleven cannabinoids were assayed for neuroprotection in assays that recapitulate proteotoxicity, loss of trophic support, oxidative stress, energy loss, and inflammation. These compounds were also assayed for their ability to remove intraneuronal amyloid and subjected to a structure-activity relationship analysis. Pairwise combinations were assayed for their ability to synergize to produce neuroprotective effects that were greater than additive.

Nine of the 11 cannabinoids have the ability to protect cells in four distinct phenotypic neurodegeneration screening assays, including those using neurons that lack CB1 and CB2 receptors. They are able to remove intraneuronal Aβ, reduce oxidative damage, and protect from the loss of energy or trophic support. Structure-activity relationship (SAR) data show that functional antioxidant groups such as aromatic hydroxyls are necessary but not sufficient for neuroprotection. Therefore, there is a need to focus upon CB1 agonists that have these functionalities if neuroprotection is the goal.

Pairwise combinations of THC and CBN lead to a synergistic neuroprotective interaction.

Together, these results significantly extend the published data by showing that non-psychoactive cannabinoids are potential lead drug candidates for AD and other neurodegenerative diseases.”

https://www.ncbi.nlm.nih.gov/pubmed/31104297

https://link.springer.com/article/10.1007%2Fs12035-019-1637-8

Cannabidiol Enhances the Therapeutic Effects of TRAIL by Upregulating DR5 in Colorectal Cancer.

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“Cannabidiol, a major non-psychotomimetic compound derived from Cannabis sativa, is a potential therapeutic agent for a variety of diseases such as inflammatory diseases, chronic neurodegenerative diseases, and cancers.

Here, we found that the combination of cannabidiol and TNF-related apoptosis-inducing ligand (TRAIL) produces synergistic antitumor effects in vitro. However, this synergistic effect was not observed in normal colonic cells. The levels of ER stress-related proteins, including C/EBP homologous protein (CHOP) and phosphorylated protein kinase RNA-like ER kinase (PERK) were increased in treatment of cannabidiol.

Cannabidiol enhanced significantly DR5 expression by ER stress. Knockdown of DR5 decreased the combined effect of cannabidioland TRAIL. Additionally, the combination of TRAIL and cannabidiol decreased tumor growth in xenograft models.

Our studies demonstrate that cannabidiol enhances TRAIL-induced apoptosis by upregulating DR5 and suggests that cannabidiol is a novel agent for increasing sensitivity to TRAIL.”

https://www.ncbi.nlm.nih.gov/pubmed/31075907

Endocannabinoid System in Spinocerebellar Ataxia Type-3 and Other Autosomal-Dominant Cerebellar Ataxias: Potential Role in Pathogenesis and Expected Relevance as Neuroprotective Targets.

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“Spinocerebellar ataxias (SCAs) are a group of hereditary and progressive neurological disorders characterized by a loss of balance and motor coordination. SCAs have no cure and effective symptom-alleviating and disease-modifying therapies are not currently available. However, based on results obtained in studies conducted in murine models and information derived from analyses in post-mortem tissue samples from patients, which show notably higher levels of CB1 receptors found in different cerebellar neuronal subpopulations, the blockade of these receptors has been proposed for acutely modulating motor incoordination in cerebellar ataxias, whereas their chronic activation has been proposed for preserving specific neuronal losses. Additional studies in post-mortem tissues from SCA patients have also demonstrated elevated levels of CB2 receptors in Purkinje neurons as well as in glial elements in the granular layer and in the cerebellar white matter, with a similar profile found for endocannabinoid hydrolyzing enzymes, then suggesting that activating CB2 receptors and/or inhibiting these enzymes may also serve to develop cannabinoid-based neuroprotective therapies.”
https://www.ncbi.nlm.nih.gov/pubmed/31068788
“Dysregulation of the endocannabinoid signaling system in the cerebellum and brainstem in a transgenic mouse model of spinocerebellar ataxia type-3.” https://www.ncbi.nlm.nih.gov/pubmed/27717809

Marijuana for Parkinson’s Disease?

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“Marijuana is popular in the United States and is being widely legalized for recreational and medicinal purposes. It remains a Schedule 1 substance without fully proven risks and benefits; yet, it is increasingly available in many US states and territories.

Cannabis might have medicinal efficacy in Parkinson’s disease as a form of medical marijuana. Endocannabinoid receptors exist throughout the nervous system and are documented to influence receptors affecting a wide variety of areas. Neuroprotective aspects might be induced by cannabis exposure that might yield benefit against the nigrostriatal degeneration of patients with Parkinson’s disease.

Animal investigations support suggestions of improvement in bradykinesia and/or tremors, but this is unsubstantiated in human studies. However, some patient surveys and anecdotal or case reports indicate that marijuana attenuates some motor manifestations of parkinsonism and also of non-motor, mood and/or cognitive symptoms. Medical marijuana might benefit motor and nonmotor aspects of Parkinson’s disease patients. Currently, these assertions are not substantiated in human investigations and cannabis can also induce side effects. Until studies clarify the safety and efficacy of pharmacotherapy with cannabis products, medical marijuana remains largely without scientific endorsement. Research has yet to document the full benefits, risks, and clinical applications of marijuana as a treatment for patients with Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/31037227

Use of Cannabidiol in the Treatment of Epilepsy: Efficacy and Security in Clinical Trials.

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“Cannabidiol (CBD) is one of the cannabinoids with non-psychotropic action, extracted from Cannabis sativa. CBD is a terpenophenol and it has received a great scientific interest thanks to its medical applications. This compound showed efficacy as anti-seizure, antipsychotic, neuroprotective, antidepressant and anxiolytic. The neuroprotective activity appears linked to its excellent anti-inflammatory and antioxidant properties. The purpose of this paper is to evaluate the use of CBD, in addition to common anti-epileptic drugs, in the severe treatment-resistant epilepsy through an overview of recent literature and clinical trials aimed to study the effects of the CBD treatment in different forms of epilepsy. The results of scientific studies obtained so far the use of CBD in clinical applications could represent hope for patients who are resistant to all conventional anti-epileptic drugs.”

https://www.ncbi.nlm.nih.gov/pubmed/31013866

https://www.mdpi.com/1420-3049/24/8/1459

Cannabinoid Actions on Neural Stem Cells: Implications for Pathophysiology.

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“With the increase of life expectancy, neurodegenerative disorders are becoming not only a health but also a social burden worldwide. However, due to the multitude of pathophysiological disease states, current treatments fail to meet the desired outcomes. Therefore, there is a need for new therapeutic strategies focusing on more integrated, personalized and effective approaches. The prospect of using neural stem cells (NSC) as regenerative therapies is very promising, however several issues still need to be addressed. In particular, the potential actions of pharmacological agents used to modulate NSC activity are highly relevant. With the ongoing discussion of cannabinoid usage for medical purposes and reports drawing attention to the effects of cannabinoids on NSC regulation, there is an enormous, and yet, uncovered potential for cannabinoids as treatment options for several neurological disorders, specifically when combined with stem cell therapy. In this manuscript, we review in detail how cannabinoids act as potent regulators of NSC biology and their potential to modulate several neurogenic features in the context of pathophysiology.”

https://www.ncbi.nlm.nih.gov/pubmed/30959794

https://www.mdpi.com/1420-3049/24/7/1350

Astroglial monoacylglycerol lipase controls mutant huntingtin-induced damage of striatal neurons.

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Neuropharmacology

“Cannabinoids exert neuroprotection in a wide array of preclinical models. A number of these studies has focused on cannabinoid CB1receptors in striatal medium spiny neurons (MSNs) and the most characteristic MSN-degenerative disease, Huntington’s disease (HD). Accruing evidence supports that astrocytes contribute to drive HD progression, and that they express CB1 receptors, degrade endocannabinoids, and modulate endocannabinergic transmission. However, the possible role of the astroglial endocannabinoidsystem in controlling MSN integrity remains unknown. Here, we show that JZL-184, a selective inhibitor of monoacylglycerol lipase (MGL), the key enzyme that deactivates the endocannabinoid 2-arachidonoylglycerol, prevented the mutant huntingtin-induced up-regulation of the pro-inflammatory cytokine tumor necrosis factor-α in primary mouse striatal astrocytes via CB1 receptors. To study the role of astroglial MGL in vivo, we injected stereotactically into the mouse dorsal striatum viral vectors that encode mutant or normal huntingtin under the control of the glial fibrillary acidic protein promoter. We observed that, in wild-type mice, pharmacological blockade of MGL with JZL-184 (8 mg/kg/day, i.p.) conferred neuroprotection against mutant huntingtin-induced striatal damage, as evidenced by the prevention of MSN loss, astrogliosis, and motor coordination impairment. We next found that conditional mutant mice bearing a genetic deletion of MGL selectively in astroglial cells (MGLfloxed/floxed;GFAP-Cre/+ mice) were resistant to mutant huntingtin-induced MSN loss, astrogliosis, and motor coordination impairment. Taken together, these data support that astroglial MGL controls the availability of a 2-arachidonoylglycerol pool that ensues protection of MSNs in the mouse striatum in vivo, thus providing a potential druggable target for reducing striatal neurodegeneration.”

https://www.ncbi.nlm.nih.gov/pubmed/30914306

https://www.sciencedirect.com/science/article/pii/S0028390819301066?via%3Dihub

Oral administration of the cannabigerol derivative VCE-003.2 promotes subventricular zone neurogenesis and protects against mutant huntingtin-induced neurodegeneration.

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 “The administration of certain cannabinoids provides neuroprotection in models of neurodegenerative diseases by acting through various cellular and molecular mechanisms. Many cannabinoid actions in the nervous system are mediated by CB1receptors, which can elicit psychotropic effects, but other targets devoid of psychotropic activity, including CB2 and nuclear PPARγ receptors, can also be the target of specific cannabinoids.

METHODS:

We investigated the pro-neurogenic potential of the synthetic cannabigerol derivative, VCE-003.2, in striatal neurodegeneration by using adeno-associated viral expression of mutant huntingtin in vivo and mouse embryonic stem cell differentiation in vitro.

RESULTS:

Oral administration of VCE-003.2 protected striatal medium spiny neurons from mutant huntingtin-induced damage, attenuated neuroinflammation and improved motor performance. VCE-003.2 bioavailability was characterized and the potential undesired side effects were evaluated by analyzing hepatotoxicity after chronic treatment. VCE-003.2 promoted subventricular zone progenitor mobilization, increased doublecortin-positive migrating neuroblasts towards the injured area, and enhanced effective neurogenesis. Moreover, we demonstrated the proneurogenic activity of VCE-003.2 in embryonic stem cells. VCE-003.2 was able to increase neuroblast formation and striatal-like CTIP2-mediated neurogenesis.

CONCLUSIONS:

The cannabigerol derivative VCE-003.2 improves subventricular zone-derived neurogenesis in response to mutant huntingtin-induced neurodegeneration, and is neuroprotective by oral administration.”

https://www.ncbi.nlm.nih.gov/pubmed/30899454

https://translationalneurodegeneration.biomedcentral.com/articles/10.1186/s40035-019-0148-x