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

The anxiolytic effect of cannabidiol on chronically stressed mice depends on hippocampal neurogenesis: involvement of the endocannabinoid system.

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“Cannabidiol (CBD), the main non-psychotomimetic component of the plant Cannabis sativa, exerts therapeutically promising effects on human mental health such as inhibition of psychosis, anxiety and depression. However, the mechanistic bases of CBD action are unclear. Here we investigate the potential involvement of hippocampal neurogenesis in the anxiolytic effect of CBD in mice subjected to 14 d chronic unpredictable stress (CUS). Repeated administration of CBD (30 mg/kg i.p., 2 h after each daily stressor) increased hippocampal progenitor proliferation and neurogenesis in wild-type mice. Ganciclovir administration to GFAP-thymidine kinase (GFAP-TK) transgenic mice, which express thymidine kinase in adult neural progenitor cells, abrogated CBD-induced hippocampal neurogenesis. CBD administration prevented the anxiogenic effect of CUS in wild type but not in GFAP-TK mice as evidenced in the novelty suppressed feeding test and the elevated plus maze. This anxiolytic effect of CBD involved the participation of the CB1 cannabinoid receptor, as CBD administration increased hippocampal anandamide levels and administration of the CB1-selective antagonist AM251 prevented CBD actions. Studies conducted with hippocampal progenitor cells in culture showed that CBD promotes progenitor proliferation and cell cycle progression and mimics the proliferative effect of CB1 and CB2 cannabinoid receptor activation. Moreover, antagonists of these two receptors or endocannabinoid depletion by fatty acid amide hydrolase overexpression prevented CBD-induced cell proliferation.

 These findings support that the anxiolytic effect of chronic CBD administration in stressed mice depends on its proneurogenic action in the adult hippocampus by facilitating endocannabinoid-mediated signalling.”

http://www.ncbi.nlm.nih.gov/pubmed/23298518

Interleukin-1β causes anxiety by interacting with the endocannabinoid system.

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“Interleukin-1β (IL-1β) is involved in mood alterations associated with inflammatory illnesses and with stress. The present investigation identifies a previously unrecognized interaction between a major proinflammatory cytokine and the endocannabinoid system in the pathophysiology of anxiety.”

http://www.ncbi.nlm.nih.gov/pubmed/23035099

Targeting the endocannabinoid system in Alzheimer’s disease.

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“The endocannabinoid system is rapidly emerging as a potential drug target for a variety of immune-mediated central nervous system diseases. There is a growing body of evidence suggesting that endocannabinoid interventions may have particular relevance to Alzheimer’s disease. Here we present a review of endocannabinoid physiology, the evidence that underscores its utility as a potential target for intervention in Alzheimer’s disease, and suggest future pathways of research.

Inflammation and oxidative stress are generally accepted as a critical risk factor for the development of AD, and interventions such as cannabinoids that attenuate these risks without arresting microglial activity and have innate neuroprotective benefits are attractive as potential preventative treatments for AD.

There is a potential for the development of CB1 interventions, whether agonists or antagonists, with applications for a variety of cognitive disorders including neurodegenerative disorders and schizophrenia. The recent discovery of a CB1 receptor Positron Emission Tomography tracer for clinical use may provide the opportunity to evaluate the impact of the regional distribution of CB1 receptors in brain on domain-specific cognitive performance (memory, executive function, praxis) in healthy individuals. Additionally, if AD is a disease of overproduction of eCBs, this may be visualized in case-control CB1receptor binding studies.

The emerging data suggest that the eCB system is a potential target for immune and/or cognitive intervention in AD. A wealth of available chemical compounds capable of intervening in the eCB system at a variety of levels and the success with which these compounds have been used in animal models suggest the potential for human drug development. What is missing is a clear direction for that development based on a concise conceptualization of eCB system function in both health and in neurodegenerative and inflammatory conditions such as AD. Focused experiments are now required to move the field forward.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2889705/

Cannabinoid CB2 receptors and fatty acid amide hydrolase are selectively overexpressed in neuritic plaque-associated glia in Alzheimer’s disease brains.

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.”We have studied the status of some of the components of the endocannabinoid system, fatty acid amide hydrolase and cannabinoid CB1 and CB2 receptors, in postmortem brains from patients with Alzheimer’s disease. Our results show that both fatty acid amide hydrolase and cannabinoid CB2 receptors are abundantly and selectively expressed in neuritic plaque-associated astrocytes and microglia, respectively, whereas the expression of CB1 receptors remains unchanged. In addition, the hydrolase activity seems to be elevated in the plaques and surrounding areas.

Thus, some elements of the endocannabinoid system may be postulated as possible modulators of the inflammatory response associated with this neurodegenerative process and as possible targets for new therapeutic approaches.

To our knowledge, this report is the first evidence for the presence of CB2 receptors in the human CNS. Furthermore, these receptors have recently been reported to play an important role in microglial migration. It is important to note that we detected CB2 receptors only in microglial cells, which is in agreement with the well known immunomodulatory effects of CB2 activation. Thus, many studies have shown that CB2 receptor activation leads to a myriad of changes in the production of inflammation-related substances, although with results that vary depending on the experimental model used and the concentration of cannabinoids used.

 In any case, the selective presence of CB2 receptors in microglial cells opens new perspectives on the role of CB2 receptors in the human CNS and suggests that the modulation of their activity may have therapeutic implications.”

http://www.jneurosci.org/content/23/35/11136.long

The activation of cannabinoid CB2 receptors stimulates in situ and in vitro beta-amyloid removal by human macrophages.

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“The endocannabinoid system is a promising therapeutic target in a wide variety of diseases. However, the non-desirable psychotropic effects of natural and synthetic cannabinoids have largely counteracted their clinical usefulness. These effects are mostly mediated by cannabinoid receptors of the CB(1) type, that exhibit a wide distribution in neuronal elements of the CNS. Thus, the presence of other elements of this system in the CNS, such as CB(2) receptors, may open new possibilities for the development of cannabinoid-based therapies. These receptors are almost absent from the CNS in normal conditions but are up-regulated in glial cells under chronic neuroinflammatory stimuli, as has been described in Alzheimer’s disease. To understand the functional role of these receptors, we tested their role in the process of beta-amyloid removal, that is currently considered as one of the most promising experimental approaches for the treatment of this disease.

Our results show that a CB(2) agonist (JWH-015) is capable of inducing the removal of native beta-amyloid removal from human frozen tissue sections as well as of synthetic pathogenic peptide by a human macrophage cell line (THP-1). Remarkably, this effect was achieved at low doses and was specific for this type of cells, as U373MG astrocytoma cells did not respond to the treatment. The effect was CB(2)-mediated, at least partially, as the selective CB(2) antagonist SR144528 prevented the JWH-015-induced plaque removal in situ.

 These data corroborate the possible therapeutic interest of CB(2) cannabinoid specific chemicals in the treatment of Alzheimer’s disease.”

http://www.ncbi.nlm.nih.gov/pubmed/19505450

CB(2) receptor and amyloid pathology in frontal cortex of Alzheimer’s disease patients.

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“The cannabinoid system seems to play an important role in various neurodegenerative diseases including Alzheimer’s disease (AD). The relationship of cannabinoid receptors (CB(1)R and CB(2)R) to cognitive function and neuropathological markers in AD remains unclear. In the present study, postmortem cortical brain tissues (Brodmann area 10) from a cohort of neuropathologically confirmed AD patients and age-matched controls were used to measure CB(1)R and CB(2)R by immunoblotting. Correlational analyses were performed for the neurochemical and cognitive data. CB(1)R expression was significantly decreased in AD. Levels of CB(1)R correlated with hypophagia, but not with any AD molecular marker or cognitive status (Mini Mental State Examination score). The level of CB(2)R was significantly higher (40%) in AD. Increases in the expression of the glial marker glial fibrillar acidic protein were also found. CB(2)R expression did not correlate with cognitive status. Interestingly, expression levels of CB(2)R correlated with two relevant AD molecular markers, Aβ(42) levels and senile plaque score.

These results may constitute the basis of CB(2)R-based therapies and/or diagnostic approaches.”

http://www.ncbi.nlm.nih.gov/pubmed/22763024

Cannabinoid CB2 receptors in human brain inflammation.

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“CB2 receptors in neuroinflammatory conditions of the human brain.

“CB2 receptors have been found to be present in the CNS, thus offering new opportunities for the pharmacological use of cannabinoid agents. Furthermore, the fact that their expression is increased by inflammatory stimuli suggests that they may be involved in the pathogenesis and/or in the endogenous response to injury. Data obtained in vitro and in animal models show that CB2 receptors may be part of the general neuroprotective action of the ECS…

The anti-inflammatory effects triggered by the activation of the CB2 receptor make it an attractive target for the development of novel anti-inflammatory therapies.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2219537/

Endocannabinoid system: emerging role from neurodevelopment to neurodegeneration.

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“The endocannabinoid system, including endogenous ligands (‘endocannabinoids’ ECs), their receptors, synthesizing and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. ECs are bioactive lipids, which comprise amides, esters and ethers of long chain polyunsaturated fatty acids. Anandamide (N-arachidonoylethanolamine; AEA) and 2-arachidonoylglycerol (2-AG) are the best studied ECs, and act as agonists of cannabinoid receptors.

Thus, AEA and 2-AG mimic several pharmacological effects of the exogenous cannabinoid delta9-tetrahydrocannabinol (Delta(9)-THC), the psychoactive principle of cannabis sativa preparations like hashish and marijuana. Recently, however, several lines of evidence have suggested that the EC system may play an important role in early neuronal development as well as a widespread role in neurodegeneration disorders. Many of the effects of cannabinoids and ECs are mediated by two G protein-coupled receptors (GPCRs), CB1 and CB2, although additional receptors may be implicated. Both CB1 and CB2 couple primarily to inhibitory G proteins and are subject to the same pharmacological influences as other GPCRs. This new system is briefly presented in this review, in order to put in a better perspective the role of the EC pathway from neurodevelopment to neurodegenerative disorders, like Alzheimer’s disease, Parkinson’s disease, Huntington’s disease, and multiple sclerosis.

In addition, the potential exploitation of antagonists of CB1 receptors, or of inhibitors of EC metabolism, as next-generation therapeutics is discussed.”

http://www.ncbi.nlm.nih.gov/pubmed/19356123

Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo: relevance to Alzheimer’s disease.

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“Microglial activation is an invariant feature of Alzheimer’s disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in vitro and in vivo… the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms…

Cannabinoids, whether plant-derived, synthetic, or endocannabinoids, exert their functions through activation of cannabinoid receptors, two of which have been well characterized to date: CB1 and CB2. Cannabinoids are neuroprotective against excitotoxicity and acute brain damage, both in vitro and in vivo. Several mechanisms account for the neuroprotection afforded by this type of drug such as blockade of excitotoxicity, reduction of calcium influx, antioxidant properties of the compounds, or enhanced trophic factor support. A decrease in proinflammatory mediators brought about by cannabinoids may be also involved in their neuroprotection… Cannabidiol (CBD), the major plant-derived nonpsychotropic constituent of marijuana, is of potential therapeutic interest in different disease conditions (e.g., inflammation)…

…this kind of drug with neuroprotective and anti-inflammatory effects may be of interest in the prevention of AD inflammation, in particular CB2-selective agonists, which are devoid of psychoactive effects…

Cannabidiol and other cannabinoids reduce microglial activation in vitro and in vivo…

CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD.

Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3102548/

Cannabinoid CB1 receptor stimulation affords neuroprotection in MPTP-induced neurotoxicity by attenuating S100B up-regulation in vitro.

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 “…the involvement of the endocannabinoid system was investigated by using selective inhibitors of endocannabinoid inactivation (cellular re-uptake or enzymatic hydrolysis) and selective cannabinoid CB1 and CB2 receptor antagonists and by silencing the CB1 receptor…

 Our data suggest that selective activation of CB1 receptors by either exogenous or endogenous cannabinoids might afford neuroprotection…”

http://www.ncbi.nlm.nih.gov/pubmed/17639288