Tag Archives: endocannabinoid system

Functional autoradiography shows unaltered cannabinoid CB1 receptor signalling in hippocampus and cortex of APP/PS1 transgenic mice.

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Abstract

“The cannabinoid CB1-receptor is among the most abundant G-protein-coupled receptors in the mammalian brain. Whereas post-mortem studies in Alzheimer´s disease (AD) brains compared to age-matched controls have reported decreased CB1-receptor binding but no change in their protein levels (immunoreactivity), decreased or increased CB1-receptor protein levels have been reported in APP/PS1 transgenic mice modelling AD. To complete the picture, the present study used functional autoradiography to assess CB1-receptor-dependent Gi protein activation in the hippocampus, entorhinal cortex and medial frontal cortex of 13- to14-month-old female APPswe/PS1dE9 transgenic and wild-type littermate control mice. The mouse brains were processed for [35S]GTPγS autoradiography so that brain sections were analysed in pairs of one transgenic and one control mouse brain. The autoradiography protocol was completed for each pair both in the absence and presence of dithiotreitol (DTT) to reveal possible redox-dependent alterations in CB1 receptor function. Five treatments were used: baseline, incubation with 10 μM GTPγS to assess non-specific binding, and CB1 receptor agonist CP55,940 in three concentrations. By and large we found no statistically significant differences between the APP/PS1 transgenic and control mice in CB1 receptor signalling. The only exception was a modest redox-dependent alteration in entorhinal cortical CB1 receptors between the genotypes. Thus, in accordance with the majority of earlier human AD findings, we did not find evidence for notable changes in the number of functional CB1 receptors in the common APPswe/PS1dE9 mouse model of AD.”

http://www.ncbi.nlm.nih.gov/pubmed/23244427

Effects of cannabinoids on the immune system and central nervous system: therapeutic implications.

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“Cannabinoids possess immunomodulatory activity, are neuroprotective in vivo and in vitro and can modify the production of inflammatory mediators… Cannabinoid-induced immunosuppression may have implications for the treatment of neurological disorders that are associated with excess immunological activity, such as multiple sclerosis and Alzheimer’s disease. There is anecdotal evidence that cannabis use improves the symptoms of multiple sclerosis, and studies with animal models are beginning to provide evidence for the mechanism of such effects. The development of nonpsychotropic cannabinoid analogues and modulators of the metabolism of endogenous cannabinoid ligands may lead to novel approaches to the treatment of neurodegenerative disorders.”

http://www.ncbi.nlm.nih.gov/pubmed/18031185

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

An amyloid β42-dependent deficit in anandamide mobilization is associated with cognitive dysfunction in Alzheimer’s disease.

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“The endocannabinoids and their attending cannabinoid (CB)(1) receptors have been implicated in the control of cognition, but their possible roles in dementias are still unclear.

 The results suggest that an Aβ(42)-dependent impairment in brain anandamide mobilization contributes to cognitive dysfunction in AD.”

http://www.ncbi.nlm.nih.gov/pubmed/21546126

The endocannabinoid, anandamide, augments Notch-1 signaling in cultured cortical neurons exposed to amyloid-β and in the cortex of aged rats.

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“Aberrant Notch signaling has recently emerged as a possible mechanism for the altered neurogenesis, cognitive impairment, and learning and memory deficits associated with Alzheimer disease (AD). Recently, targeting the endocannabinoid system in models of AD has emerged as a potential approach to slow the progression of the disease process. Although studies have identified neuroprotective roles for endocannabinoids, there is a paucity of information on modulation of the pro-survival Notch pathway by endocannabinoids. In this study the influence of the endocannabinoids, anandamide (AEA) and 2-arachidonoylglycerol, on the Notch-1 pathway and on its endogenous regulators were investigated in an in vitro model of AD. We report that AEA up-regulates Notch-1 signaling in cultured neurons… In summary, AEA has the proclivity to enhance Notch-1 signaling in an in vitro model of AD, which may have relevance for restoring neurogenesis and cognition in AD.”

http://www.ncbi.nlm.nih.gov/pubmed/22891244

Role of the endocannabinoid system in Alzheimer’s disease: new perspectives.

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Abstract

“The role of the endocannabinoid system in several diseases is currently under intense study. Among these, Alzheimer’s disease may be a new promising area of research. We have recently reported the existence of profound changes in the location and density of several elements of this system in Alzheimer’s disease tissue samples, indicating that a non-neuronal endocannabinoid system is up-regulated in activated glia. Additional data from other groups suggest that glial cells may be important elements in the regulation of endocannabinoid system activity, both in health as in disease. Some of these aspects are briefly discussed in the present review.”

http://www.ncbi.nlm.nih.gov/pubmed/15306158

The therapeutic potential of the endocannabinoid system for Alzheimer’s disease.

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“Based on the complex pathology of AD, a preventative, multimodal drug approach targeting a combination of pathological AD symptoms appears ideal. Importantly, cannabinoids show anti-inflammatory, neuroprotective and antioxidant properties and have immunosuppressive effects. Thus, the cannabinoid system should be a prime target for AD therapy. The cannabinoid receptor 2 appears to be a promising candidate but its role in AD has to be investigated cautiously. Furthermore, the phytocannabinoid cannabidiol is of particular interest as it lacks the psychoactive and cognition-impairing properties of other cannabinoids. In conclusion, future research should focus on the evaluation of the effects of manipulations to the endocannabinoid system in established animal models for AD, combined with early-phase studies in humans.”

http://www.ncbi.nlm.nih.gov/pubmed/22448595

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

Endocannabinoids accumulate in spinal cord of SOD1 G93A transgenic mice.

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Abstract

“Approximately 2% of amyotrophic lateral sclerosis (ALS) cases are caused by mutations in the super oxide dismutase 1 (SOD1) gene and transgenic mice for these mutations recapitulate many features of this devastating neurodegenerative disease. Here we show that the amount of anandamide (AEA) and 2-arachidonoylglycerol (2-AG), two endocannabinoids that have neuroprotective properties, increase in spinal cord of SOD1(G93A) transgenic mice. This increase occurs in the lumbar section of spinal cords, the first section to undergo neurodegeneration, and is significant before overt motor impairment. Our results show that chronic neurodegeneration induced by a genetic mutation increases endocannabinoid production possibly as part of an endogenous defense mechanism.”

http://www.ncbi.nlm.nih.gov/pubmed/15189359

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/