Tag Archives: cannabinoid receptors

Amyotrophic lateral sclerosis: delayed disease progression in mice by treatment with a cannabinoid.

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Abstract

“Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Two of the primary hypotheses underlying motor neuron vulnerability are susceptibility to excitotoxicity and oxidative damage. There is rapidly emerging evidence that the cannabinoid receptor system has the potential to reduce both excitotoxic and oxidative cell damage. Here we report that treatment with Delta(9)-tetrahydrocannabinol (Delta(9)-THC) was effective if administered either before or after onset of signs in the ALS mouse model (hSOD(G93A) transgenic mice). Administration at the onset of tremors delayed motor impairment and prolonged survival in Delta(9)-THC treated mice when compared to vehicle controls. In addition, we present an improved method for the analysis of disease progression in the ALS mouse model. This logistic model provides an estimate of the age at which muscle endurance has declined by 50% with much greater accuracy than could be attained for any other measure of decline. In vitro, Delta(9)-THC was extremely effective at reducing oxidative damage in spinal cord cultures. Additionally, Delta(9)-THC is anti-excitotoxic in vitro. These cellular mechanisms may underlie the presumed neuroprotective effect in ALS. As Delta(9)-THC is well tolerated, it and other cannabinoids may prove to be novel therapeutic targets for the treatment of ALS.”

http://www.ncbi.nlm.nih.gov/pubmed/15204022

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/

 

AM1241, a cannabinoid CB2 receptor selective compound, delays disease progression in a mouse model of amyotrophic lateral sclerosis.

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“Effective treatment for amyotrophic lateral sclerosis (ALS) remains elusive. Motor neuron degeneration is the primary pathology in ALS; however non-neuronal cells contribute to the disease process. In particular, inflammatory processes have been shown to play an important role. AM1241 is a cannabinoid CB2 receptor selective agonist that has been shown to be effective in models of inflammation and hyperalgesia. Here we report that treatment with AM1241 was effective at slowing signs of disease progression when administered after onset of signs in an ALS mouse model (hSOD1(G93A) transgenic mice)…. As AM1241 was well tolerated by the animals, cannabinoid CB2 receptor-selective compounds may be the basis for developing new drugs for the treatment of ALS and other chronic neurodegenerative diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/16781706

Abnormal sensitivity of cannabinoid CB1 receptors in the striatum of mice with experimental amyotrophic lateral sclerosis.

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“Amyotrophic lateral sclerosis (ALS) is a fatal neurodegenerative disease that primarily affects motor neurons.

The sensitivity of cannabinoid CB1 receptors controlling both glutamate and GABA transmission was remarkably potentiated in ALS mice, indicating that adaptations of the endocannabinoid system might be involved in the pathophysiology of ALS. In conclusion, our data identify possible physiological correlates of striatal dysfunction in ALS mice, and suggest that cannabinoid CB1 receptors might be potential therapeutic targets for this dramatic disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19452308

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

The endocannabinoid system in the inflammatory and neurodegenerative processes of multiple sclerosis and of amyotrophic lateral sclerosis.

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Abstract

“Multiple sclerosis (MS) and amyotrophic lateral sclerosis (ALS) are chronic diseases of the central nervous system (CNS), featured by a complex interplay between inflammation and neurodegeneration. Increasing evidence supports the involvement of the endocannabinoid system (ECS) in both inflammatory and neurodegenerative processes typical of these pathological conditions. Exogenous or endogenous cannabinoids regulate the function of immune system by limiting immune response. On the other hand, by preventing excitotoxic damage, cannabinoids protect neuronal integrity and function. Of note, the ECS not only plays a role as modulator of disease processes, but it can also be disrupted by the same diseases. Agents modulating cannabinoid receptors or endocannabinoid tone provide promising therapeutic opportunities in the treatment of inflammatory neurodegenerative disorders of the CNS.”

http://www.ncbi.nlm.nih.gov/pubmed/20353778

The (endo)cannabinoid system in multiple sclerosis and amyotrophic lateral sclerosis.

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“Alterations of the endocannabinoid system (ECS) have been recently implicated in a number of neuroinflammatory and neurodegenerative conditions so that the pharmacological modulation of cannabinoid (CB) receptors and/or of the enzymes controlling synthesis, transport, and degradation of these substances has emerged as a valuable option to treat neurological diseases.

Here, we describe the current knowledge concerning the rearrangement of ECS in a primarily inflammatory disorder of the central nervous system such as multiple sclerosis (MS), and in a primarily degenerative condition such as amyotrophic lateral sclerosis (ALS).

 Furthermore, the data supporting a therapeutic role of agents modulating CB receptors or endocannabinoid tone in these disorders will also be reviewed. Complex changes of ECS take place in both diseases, influencing crucial aspects of their pathophysiology and clinical manifestations. Neuroinflammation, microglial activation, oxidative stress, and excitotoxicity are variably combined in MS and in ALS and can be modulated by endocannabinoids or by drugs targeting the ECS.”

http://www.ncbi.nlm.nih.gov/pubmed/17678961

Δ⁹-tetrahydrocannabinol (Δ⁹-THC) exerts a direct neuroprotective effect in a human cell culture model of Parkinson’s disease.

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Neuropathology and Applied Neurobiology

“Δ⁹-tetrahydrocannabinol (Δ⁹-THC) is neuroprotective in models of Parkinson’s disease (PD).

Although CB1 receptors are increased within the basal ganglia of PD patients and animal models, current evidence suggests a role for CB1 receptor-independent mechanisms.

Here, we utilized a human neuronal cell culture PD model to further investigate the protective properties of Δ⁹-THC.

We found CB1 receptor up-regulation in response to MPP+, lactacystin and paraquat and a protective effect of Δ⁹-THC against all three toxins. This neuroprotective effect was not reproduced by the CB1 receptor agonist WIN55,212-2 or blocked by the CB1 antagonist AM251. Furthermore, the antioxidants α-tocopherol and butylhydroxytoluene as well as the antioxidant cannabinoids, nabilone and cannabidiol were unable to elicit the same neuroprotection as Δ⁹-THC.

 

We have demonstrated up-regulation of the CB1 receptor in direct response to neuronal injury in a human PD cell culture model, and a direct neuronal protective effect of Δ⁹-THC that may be mediated through PPARγ activation.”

https://www.ncbi.nlm.nih.gov/pubmed/22236282

“In conclusion, we have demonstrated up-regulation of the CB1 receptor in a human cell culture model of PD, as well as a direct neuroprotective effect of the phytocannabinoid, Δ9-THC, not mediated by the CB2 receptor. Although a CB1 receptor-mediated effect cannot totally be excluded, we propose that activation of PPARγ leading to antioxidant effects is highly relevant in mediating the neuroprotection afforded by Δ9-THC in our model.”

http://onlinelibrary.wiley.com/doi/10.1111/j.1365-2990.2011.01248.x/full

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/