Tag Archives: CB(1) and CB(2) receptors

Contrasting protective effects of cannabinoids against oxidative stress and amyloid-β evoked neurotoxicity in vitro.

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“Cannabinoids have been widely reported to have neuroprotective properties in vitro and in vivo. In this study we compared the effects of CB1 and CB2 receptor-selective ligands, the endocannabinoid anandamide and the phytocannabinoid cannabidiol, against oxidative stress and the toxic hallmark Alzheimer’s protein, β-amyloid (Aβ)…

 …the endocannabinoid anandamide protects neuronal cells from Aβ exposure via a pathway unrelated to CB1 or CB2 receptor activation…protective effect of cannabidiol against oxidative stress…

…divergent pathways for neuroprotection of these two cannabinoids.”

http://www.ncbi.nlm.nih.gov/pubmed/22233683

Prevention of Alzheimer’s Disease Pathology by Cannabinoids: Neuroprotection Mediated by Blockade of Microglial Activation

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“Cannabinoids are neuroprotective agents against excitotoxicity in vitro and acute brain damage in vivo. This background prompted us to study the localization, expression, and function of cannabinoid receptors in AD and the possible protective role of cannabinoids after betaA treatment, both in vivo and in vitro. Here, we show that senile plaques in AD patients express cannabinoid receptors CB1 and CB2……

…Our results indicate that cannabinoid receptors are important in the pathology of AD and that cannabinoids succeed in preventing the neurodegenerative process occurring in the disease.”

Free full text: http://www.jneurosci.org/content/25/8/1904.long

Cannabinoid Treatments: Amyotrophic Lateral Sclerosis (ALS)

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“Amyotrophic lateral sclerosis (ALS), also known as Lou Gehrig’s disease, is a fatal neurodegenerative disorder that is characterized by the selective loss of motor neurons in the spinal cord, brain stem, and motor cortex. An estimated 30,000 Americans are living with ALS, which often arises spontaneously and afflicts otherwise healthy adults. More than half of ALS patients die within 2.5 years following the onset of symptoms.

A review of the scientific literature reveals an absence of clinical trials investigating the use of cannabinoids for ALS treatment. However, recent preclinical findings indicate that cannabinoids can delay ALS progression, lending support to anecdotal reports by patients that cannabinoids may be efficacious in moderating the disease’s development and in alleviating certain ALS-related symptoms such as pain, appetite loss, depression and drooling.

Writing in the March 2004 issue of the journal Amyotrophic Lateral Sclerosis & Other Motor Neuron Disorders, investigators at the California Pacific Medical Center in San Francisco reported that the administration of THC both before and after the onset of ALS symptoms staved disease progression and prolonged survival in animals compared to untreated controls.

Additional trials in animal models of ALS have shown that the administration of other naturally occurring and synthetic cannabinoids can also moderate ALS progression but not necessarily impact survival. One recent study demonstrated that blocking the CB1 cannabinoid receptor did extend life span in an ALS mouse model, suggesting that cannabinoids’ beneficial effects on ALS may be mediated by non-CB1 receptor mechanisms.

As a result, experts are calling for clinical trials to assess cannabinoids for the treatment of ALS. Writing in the American Journal of Hospice & Palliative Medicine in 2010, a team of investigators reported, “Based on the currently available scientific data, it is reasonable to think that cannabis might significantly slow the progression of ALS, potentially extending life expectancy and substantially reducing the overall burden of the disease.” They concluded, “There is an overwhelming amount of preclinical and clinical evidence to warrant initiating a multicenter randomized, double-blind, placebo-controlled trial of cannabis as a disease-modifying compound in ALS.”

By braatahon December 25, 2012| From braatah.com
 
 
 
 

Increasing cannabinoid levels by pharmacological and genetic manipulation delay disease progression in SOD1 mice.

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“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disorder characterized by the selective loss of motoneurons in the spinal cord, brain stem, and motor cortex. However, despite intensive research, an effective treatment for this disease remains elusive. In this study we show that treatment of postsymptomatic, 90-day-old SOD1G93A mice with a synthetic cannabinoid, WIN55,212-2, significantly delays disease progression…

Increasing evidence suggests that cannabinoids might have therapeutic potential in neurodegenerative conditions. In a variety of in vivo and in vitro models, cannabinoids exert neuroprotective effects under excitotoxic, ischemic, and inflammatory conditions. This combination of neuroprotective actions might be particularly relevant to ALS and suggests that cannabinoids might have a greater impact on disease progression than the established therapy that targets excitotoxicity alone.

… the neuroprotective effects observed following pharmacological and genetic augmentation of cannabinoid levels are not necessarily mediated by the CB1 receptor, and indeed inhibition of the CB1 receptor might actually be neuroprotective. Therefore, in contrast to previous studies that have suggested that cannabinoids exert neuroprotection via the CB1 receptor, the present results suggest that activation of CB2 receptors might underlie the beneficial effects of cannabinoids at least in SOD1G93A mice .”

Together these results show that cannabinoids have significant neuroprotective effects in this model of ALS and suggest that these beneficial effects may be mediated by non-CB1 receptor mechanisms.”

http://www.fasebj.org/content/20/7/1003.long

The CB2 cannabinoid agonist AM-1241 prolongs survival in a transgenic mouse model of amyotrophic lateral sclerosis when initiated at symptom onset.

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“Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disease characterized by progressive motor neuron loss, paralysis and death within 2-5 years of diagnosis. Currently, no effective pharmacological agents exist for the treatment of this devastating disease. Neuroinflammation may accelerate the progression of ALS. Cannabinoids produce anti-inflammatory actions via cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2), and delay the progression of neuroinflammatory diseases…

 …treatment with non-selective cannabinoid partial agonists prior to, or upon, symptom appearance minimally delays disease onset and prolongs survival through undefined mechanisms…

…Δ9-Tetrahydrocannabinol (Δ9-THC) is the main psychoactive constituent in the plant Cannabis sativa (marijuana) and produces its effects by activation of cannabinoid receptor 1 (CB1) and cannabinoid receptor 2 (CB2) cannabinoid receptors. CB1 receptors are expressed throughout the CNS, while CB2 receptors are expressed predominantly in immune cells and non-neuronal tissues. Therapeutic agents which modulate the cann-abinoid system are effective in treating a wide variety of disorders characterized by inflammation. More specifically, drugs which activate CB2 receptors successfully improve the symptoms of several inflammatory diseases…

More importantly, daily injections of the selective CB2 agonist AM-1241, initiated at symptom onset, increase the survival interval after disease onset by 56%. Therefore, CB2 agonists may slow motor neuron degeneration and preserve motor function, and represent a novel therapeutic modality for treatment of ALS.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2819701/

 

Identification of receptors and enzymes for endocannabinoids in NSC-34 cells: relevance for in vitro studies with cannabinoids in motor neuron diseases.

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“NSC-34 cells, a hybridoma cell line derived from the fusion of neuroblastoma cells with mice spinal cord cells, have been widely used as an in vitro model for the study of motor neuron diseases [i.e. amyotrophic lateral sclerosis (ALS)]. In the present study, they were used to characterize different elements of the cannabinoid signaling system, which have been reported to serve as targets for the neuroprotective action of different natural and synthetic cannabinoid compounds…

Assuming that glutamate toxicity is one of the major causes of neuronal damage in ALS and other motor neurons diseases, the differentiated NSC-34 cells might serve as a useful model for studying neuroprotection with cannabinoids in conditions of excitotoxic injury, mitochondrial malfunctioning and oxidative stress.”

http://www.ncbi.nlm.nih.gov/pubmed/22206832

Symptom-relieving and neuroprotective effects of the phytocannabinoid Δ9-THCV in animal models of Parkinson’s disease

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“Previous findings have indicated that a cannabinoid, such as Δ(9)-THCV, which has antioxidant properties and the ability to activate CB(2) receptors but to block CB(1) , might be a promising therapy for alleviating symptoms and delaying neurodegeneration in Parkinson’s disease (PD).

…Given its antioxidant properties and its ability to activate CB(2) but to block CB(1) receptors, Δ(9)-THCV has a promising pharmacological profile for delaying disease progression in PD and also for ameliorating parkinsonian symptoms…

Conclusion

In summary, given its antioxidant properties and its ability to activate CB2 but block CB1 receptors at a dose of 2 mg·kg−1, Δ9-THCV seems to have an interesting and therapeutically promising pharmacological profile. Thus, in contrast to other phytocannabinoids that have been investigated to date, it shows promise both for the treatment of disease progression in PD and for the relief of PD symptoms. This represents an important advance in the search for potential novel anti-parkinsonian agents, since Δ9-THCV administered alone or in combination with CBD may provide a much needed improved treatment for PD.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165958/

Evaluation of the neuroprotective effect of cannabinoids in a rat model of Parkinson’s disease: importance of antioxidant and cannabinoid receptor-independent properties.

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Abstract

“We have recently demonstrated that two plant-derived cannabinoids, Delta9-tetrahydrocannabinol and cannabidiol (CBD), are neuroprotective in an animal model of Parkinson’s disease (PD), presumably because of their antioxidant properties. To further explore this issue, we examined the neuroprotective effects of a series of cannabinoid-based compounds, with more selectivity for different elements of the cannabinoid signalling system, in rats with unilateral lesions of nigrostriatal dopaminergic neurons caused by local application of 6-hydroxydopamine. We used the CB1 receptor agonist arachidonyl-2-chloroethylamide (ACEA), the CB2 receptor agonist HU-308, the non-selective agonist WIN55,212-2, and the inhibitors of the endocannabinoid inactivation AM404 and UCM707, all of them administered i.p. Daily administration of ACEA or WIN55,212-2 did not reverse 6-hydroxydopamine-induced dopamine (DA) depletion in the lesioned side, whereas HU-308 produced a small recovery that supports a possible involvement of CB2 but not CB1 receptors. AM404 produced a marked recovery of 6-hydroxydopamine-induced DA depletion and tyrosine hydroxylase deficit in the lesioned side. Possibly, this is caused by the antioxidant properties of AM404, which are derived from the presence of a phenolic group in its structure, rather than by the capability of AM404 to block the endocannabinoid transporter, because UCM707, another transporter inhibitor devoid of antioxidant properties, did not produce the same effect. None of these effects were observed in non-lesioned contralateral structures. We also examined the timing for the effect of CBD to provide neuroprotection in this rat model of PD. We found that CBD, as expected, was able to recover 6-hydroxydopamine-induced DA depletion when it was administered immediately after the lesion, but it failed to do that when the treatment started 1 week later. In addition, the effect of CBD implied an upregulation of mRNA levels for Cu,Zn-superoxide dismutase, a key enzyme in endogenous defenses against oxidative stress. In summary, our results indicate that those cannabinoids having antioxidant cannabinoid receptor-independent properties provide neuroprotection against the progressive degeneration of nigrostriatal dopaminergic neurons occurring in PD. In addition, the activation of CB2 (but not CB1) receptors, or other additional mechanisms, might also contribute to some extent to the potential of cannabinoids in this disease.”

http://www.ncbi.nlm.nih.gov/pubmed/17196181

Cannabinoids and Parkinson’s disease.

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Abstract

“Cannabinoid-based medicines have been proposed as clinically promising therapies in Parkinson’s disease (PD), given the prominent modulatory function played by the cannabinoid signaling system in the basal ganglia. Supporting this pharmacological potential, the cannabinoid signaling system experiences a biphasic pattern of changes during the progression of PD. Thus, early and presymptomatic stages, characterized by neuronal malfunctioning but little evidence of neuronal death, are associated with desensitization/downregulation of CB(1) receptors. It was proposed that these losses may be part of the pathogenesis itself, since they can aggravate different cytotoxic insults which are controlled in part by cannabinoid signals, mainly excitotoxicity but also oxidative stress and glial activation. By contrast, intermediate and, in particular, advanced stages of parkinsonism characterized by a profound nigral degeneration and occurrence of major parkinsonian symptoms (e.g. bradykinesia), are associated with upregulatory responses of CB(1) receptors, possibly CB(2) receptors too, and the endocannabinoid ligands for both receptor types. This would explain the motor inhibition typical of this disease and the potential proposed for CB(1) receptor antagonists in attenuating the bradykinesia typical of PD. In addition, certain cannabinoid agonists have been proposed to serve as neuroprotective molecules in PD, given their well-demonstrated capability to reduce excitotoxicity, calcium influx, glial activation and, in particular, oxidative injury that cooperatively contribute to the degeneration of nigral neurons. However, the potential of cannabinoid-based medicines in PD have been still scarcely studied at the clinical level despite the existence of solid and promising preclinical evidence. Considering the relevance of these preclinical data, the need for finding treatments for motor symptoms that may be alternative to classic dopaminergic replacement therapy, and the lack of efficient neuroprotective strategies in PD, we believe it is of major interest to develop further studies that allow the promising expectations generated for these molecules to progress from the present preclinical evidence towards a real clinical application.”

http://www.ncbi.nlm.nih.gov/pubmed/19839934

An overview of Parkinson’s disease and the cannabinoid system and possible benefits of cannabinoid-based treatments.

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Abstract

“Parkinson’s disease (PD) is a slowly progressive neurodegenerative disorder with a heterogeneous clinical picture and a variable rate of progression. PD is characterized by degeneration of the pigmented neuromelanin bearing cells of the pars compacta of the substantia nigra that leads to a severe dopaminergic denervation of the striatum. Current treatments for PD rely on dopamine replacement therapy, most commonly with the dopamine precursor levodopa. Despite the many recent advances in the symptomatic treatment of PD, there is still no realistic prospect for a cure. In recent years, new data support the idea of a relevant role for the cannabinoid system in PD. As cannabinoids have neuroprotective properties, they have been proposed as potentially useful neuroprotective substances in PD, as well as to alleviate some symptoms in specific circumstances (i.e. parkinsonian tremor associated with overactivity to the subthalamic nucleus; levodopa-induced dyskinesia). By contrast, CB(1) receptor antagonists might be useful to reduce bradykinesia in patients refractory to classic levodopa treatment. The present article will review all data about the relationship between PD and the cannabinoid system including: i) the usefulness of cannabinoid-related compounds to alleviate some PD symptoms; ii) that cannabinoid-based compounds might provide protection against the progression of neuronal injury characteristic of this disease; iii) the influence of cannabinoids on local inflammatory events associated with the pathogenesis in PD. Collectively, all these evidence support that the management of the cannabinoid system might represent a new approach to the treatment of PD.”

http://www.ncbi.nlm.nih.gov/pubmed/17168732