Molecular Imaging of the Cannabinoid System in Idiopathic Parkinson’s Disease.

International Review of Neurobiology

“The endocannabinoid system is a modulator of neurotransmitter release and is involved in several physiological functions. Hence, it has been increasingly studied as a potential pharmacologic target of Parkinson’s disease.

Several preclinical and clinical studies evidenced a substantial rearrangement of the endocannabinoid system in the basal ganglia circuit following dopamine depletion. The endocannabinoid system has been additionally implicated in the regulation of neuroinflammation and neuroprotection through the activation of CB2 receptors, suggesting a potential target for disease modifying therapies in Parkinson’s disease.

In this chapter, current pharmacological and physiological knowledge on the role of the endocannabinoid system will be reviewed, focusing on preclinical studies animal models and clinical studies in patients with idiopathic Parkinson’s disease. The main strategies for imaging the brain cannabinoid system will be summarized to finally focus on in vivo imaging of patients with Parkinson’s disease.”

https://www.ncbi.nlm.nih.gov/pubmed/30314601

https://www.sciencedirect.com/science/article/pii/S0074774218300692?via%3Dihub

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A systematic review on the neuroprotective perspectives of beta-caryophyllene.

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“Beta (β)-caryophyllene (BCAR) is a major sesquiterpene of various plant essential oils reported for several important pharmacological activities, including antioxidant, anti-inflammatory, anticancer, cardioprotective, hepatoprotective, gastroprotective, nephroprotective, antimicrobial, and immune-modulatory activity. Recent studies suggest that it also possesses neuroprotective effect.

This study reviews published reports pertaining to the neuropharmacological activities of BCAR. Databases such as PubMed, Scopus, MedLine Plus, and Google Scholar with keywords “beta (β)-caryophyllene” and other neurological keywords were searched. Data were extracted by referring to articles with information about the dose or concentration/route of administration, test system, results and discussion, and proposed mechanism of action.

A total of 545 research articles were recorded, and 41 experimental studies were included in this review, after application of exclusion criterion. Search results suggest that BCAR exhibits a protective role in a number of nervous system-related disorders including pain, anxiety, spasm, convulsion, depression, alcoholism, and Alzheimer’s disease.

Additionally, BCAR has local anesthetic-like activity, which could protect the nervous system from oxidative stress and inflammation and can act as an immunomodulatory agent. Most neurological activities of this natural product have been linked with the cannabinoid receptors (CBRs), especially the CB2R. This review suggests a possible application of BCAR as a neuroprotective agent.”

https://www.ncbi.nlm.nih.gov/pubmed/30281175

“β-caryophyllene (BCP) is a common constitute of the essential oils of numerous spice, food plants and major component in Cannabis.” http://www.ncbi.nlm.nih.gov/pubmed/23138934

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Cannabinoid 1 Receptor Signaling on Hippocampal GABAergic Neurons Influences Microglial Activity.

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“Microglia, the resident immune cells of the brain, play important roles in defending the brain against pathogens and supporting neuronal circuit plasticity. Chronic or excessive pro-inflammatory responses of microglia damage neurons, therefore their activity is tightly regulated.

Pharmacological and genetic studies revealed that cannabinoid type 1 (CB1) receptor activity influences microglial activity, although microglial CB1 receptor expression is very low and activity-dependent. The CB1 receptor is mainly expressed on neurons in the central nervous system (CNS)-with an especially high level on GABAergic interneurons.

Here, we determined whether CB1 signaling on this neuronal cell type plays a role in regulating microglial activity.

Our result suggests that CB1 receptor agonists can modulate microglial activity indirectly, through CB1 receptors on GABAergic neurons.

Altogether, we demonstrated that GABAergic neurons, despite their relatively low density in the hippocampus, have a specific role in the regulation of microglial activity and cannabinoid signaling plays an important role in this arrangement.”

https://www.ncbi.nlm.nih.gov/pubmed/30210289

https://www.frontiersin.org/articles/10.3389/fnmol.2018.00295/full

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Antiapoptotic effects of cannabidiol in an experimental model of cognitive decline induced by brain iron overload.

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“Iron accumulation in the brain has been recognized as a common feature of both normal aging and neurodegenerative diseases. Cognitive dysfunction has been associated to iron excess in brain regions in humans. We have previously described that iron overload leads to severe memory deficits, including spatial, recognition, and emotional memory impairments in adult rats.

In the present study we investigated the effects of neonatal iron overload on proteins involved in apoptotic pathways, such as Caspase 8, Caspase 9, Caspase 3, Cytochrome c, APAF1, and PARP in the hippocampus of adult rats, in an attempt to establish a causative role of iron excess on cell death in the nervous system, leading to memory dysfunction.

Cannabidiol (CBD), the main non-psychotropic component of Cannabis sativa, was examined as a potential drug to reverse iron-induced effects on the parameters analyzed.

These results suggest that iron can trigger cell death pathways by inducing intrinsic apoptotic proteins. The reversal of iron-induced effects by CBD indicates that it has neuroprotective potential through its anti-apoptotic action.”

“In summary, we have shown that iron treatment in the neonatal period disrupts the apoptotic intrinsic pathway. This finding may place iron excess as a central component in neurodegenerative processes since many neurodegenerative disorders are accompanied by iron accumulation in brain regions. Moreover, indiscriminate iron supplementation to toddlers and infants, modeled here by iron overload in the neonatal period, has been considered a potential environmental risk factor for the development of neurodegenerative disorders later in life. Our findings also strongly suggest that CBD has neuroprotective effects, at least in part by blocking iron-induced apoptosis even at later stages, following iron overload, which puts CBD as a potential therapeutic agent in the treatment of neurodegenerative diseases.”
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Cannabis cures the spine.

The Journal of Thoracic and Cardiovascular Surgery Home

“Cannabis cures the spine.” https://www.ncbi.nlm.nih.gov/pubmed/30172587

“Huo and colleagues elegantly demonstrate that the endogenous cannabinoid system can be modulated to provide neuroprotection in ischemic injury of the spine.

Modulation of the endocannabinoid system attenuates ischemic spinal cord injury through CB2-mediated inhibition of the GAPDH/Siah1 signaling cascade, positively influencing neuron survival and function.” https://www.jtcvs.org/article/S0022-5223(18)32080-4/fulltext

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Traditional Uses of Cannabinoids and New Perspectives in the Treatment of Multiple Sclerosis.

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“Recent findings highlight the emerging role of the endocannabinoid system in the control of symptoms and disease progression in multiple sclerosis (MS). MS is a chronic, immune-mediated, demyelinating disorder of the central nervous system with no cure so far. It is widely reported in the literature that cannabinoids might be used to control MS symptoms and that they also might exert neuroprotective effects and slow down disease progression. This review aims to give an overview of the principal cannabinoids(synthetic and endogenous) used for the symptomatic amelioration of MS and their beneficial outcomes, providing new potentially possible perspectives for the treatment of this disease.”

https://www.ncbi.nlm.nih.gov/pubmed/30111755

http://www.mdpi.com/2305-6320/5/3/91

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The enigma of cannabis use in spinal cord injury.

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“Cannabis use in medicine continues to confound practitioners.

There is confusing interpretation of the efficacy and adverse event data, highlighting the complexity of this unique plant.

Cannabis may have a neuroprotective role in SCI.”

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Neuronal preservation and reactive gliosis attenuation following neonatal sciatic nerve axotomy by a fluorinated cannabidiol derivative.

Neuropharmacology

“Immature peripheral nervous system damage, such as the transection of a peripheral nerve, results in the extensive degeneration of motoneurons and dorsal root ganglia (DRG) sensory neurons, mostly due to apoptotic events.

We have previously shown that cannabidiol (CBD), the most abundant non-psychotropic molecule present in the Cannabis sativa plant, exhibits neuroprotective action when administered daily at a dose of 15 mg/kg.

This study shows that use of the fluorinated synthetic version of CBD (4′-fluoro-cannabidiol, HUF-101) significantly improves neuronal survival by 2-fold compared to that achieved with traditional CBD at one-third the dose. Furthermore, we show that HUF-101 administration significantly upregulates anti-apoptotic genes and blocks the expression of pro-apoptotic nuclear factors.

Two-day-old Wistar rats were subjected to unilateral sectioning of the sciatic nerve and treated daily with HUF-101 (1, 2.5, 5 mg/kg/day, i.p.) or a vehicle solution for five days.

The results were evaluated by Nissl staining, immunohistochemistry, and qRT-PCR. Neuronal counting revealed a 47% rescue of spinal motoneurons and a 79% rescue of DRG neurons (HUF-101, 5 mg/kg). Survival was associated with complete depletion of p53 and a 60-fold elevation in BCL2-like 1 gene expression.

Additionally, peroxisome proliferator-activated receptor gamma (PPAR-gamma) gene expression was downregulated by 80%. Neuronal preservation was coupled with a high preservation of synaptic coverage and a reduction in astroglial and microglial reactions that were evaluated in nearby spinal motoneurons present in the ventral horn of the lumbar intumescence.

Overall, these data strongly indicate that HUF-101 exerts potent neuroprotective effects that are related to anti-apoptotic protection and the reduction of glial reactivity.”

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Neuroprotective effects of the cannabigerol quinone derivative VCE-003.2 in SOD1G93A transgenic mice, an experimental model of amyotrophic lateral sclerosis.

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“Antioxidant phytocannabinoids, synthetic compounds targeting the CB2 receptor, and inhibitors of the endocannabinoid inactivation afforded neuroprotection in SOD1G93A mutant mice, a model of ALS. These effects may involve the activation of PPAR-γ too.

Here, we have investigated the neuroprotective effects in SOD1G93A mutant mice of the cannabigerol derivative VCE-003.2, which works as by activating PPAR-γ.

As expected, SOD1G93Atransgenic mice experienced a progressive weight loss and neurological deterioration, which was associated with a marked loss of spinal cholinergic motor neurons, glial reactivity, and elevations in several biochemical markers (cytokines, glutamate transporters) that indirectly reflect the glial proliferation and activation in the spinal cord. The treatment with VCE-003.2 improved most of these neuropathological signs.

It attenuated the weight loss and the anomalies in neurological parameters, preserved spinal cholinergic motor neurons, and reduced astroglial reactivity. VCE-003.2 also reduced the elevations in IL-1β and glial glutamate transporters. Lastly, VCE-003.2 attenuated the LPS-induced generation of TNF-α and IL-1β in cultured astrocytes obtained from SOD1G93Atransgenic newborns, an effect also produced by rosiglitazone, then indicating a probable PPAR-γ activation as responsible of its neuroprotective effects.

In summary, our results showed benefits with VCE-003.2 in SOD1G93A transgenic mice supporting PPAR-γ as an additional neuroprotective target available for cannabinoids in ALS. Such benefits would need to be validated in other ALS models prior to be translated to the clinical level.”

https://www.ncbi.nlm.nih.gov/pubmed/30076846

https://www.sciencedirect.com/science/article/abs/pii/S0006295218303198

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[Should ophtalmologists recommend medical cannabis to patients with glaucoma?]

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“Cannabis has been widely used for various medical purposes since before year 2000 BC. Its effects are mediated by cannabinoids and stimulation of mainly G-protein coupled cannabinoid receptors.

In 1971, subjects who smoked marihuana, showed a decrease in the intraocular pressure.

Later investigations additionally revealed a neuroprotective effect of both ∆-9-tetrahydrocannabinol and cannabidiol (CBD).

Furthermore, CBD was found to promote neurogenesis. The aim of this review is to provide an overview of the potential use of cannabinoids in the treatment of glaucoma.”

https://www.ncbi.nlm.nih.gov/pubmed/30020072

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