Category Archives: Endocannabinoid System

CNS immune surveillance and neuroinflammation: endocannabinoids keep control.

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Abstract

“To avoid inflammatory escalation, the central nervous system (CNS) harbors an impressive arsenal of cellular and molecular mechanisms enabling strict control of immune reactions. We here summarize studies suggesting that the old paradigm of the “CNS immune privilege” is overly simplistic. The immune system is allowed to keep the CNS under surveillance, but in a strictly controlled, limited and well-regulated manner. The first line of defense lies outside the brain parenchyma to spare neuronal tissue from the detrimental effects of an inflammatory immune response. As a second line of defense neuroinflammation is unavoidable when pathogens infiltrate the brain or the CNS-immune-homeostasis fails. Inflammation in the CNS is often accompanied by divers brain pathologies. We here review recent strategies to maintain brain homeostasis and modulate neuroinflammation. We focus on Multiple Sclerosis as an example of a complex neuroinflammatory disease. In the past years, several in vitro, in vivo and clinical studies suggested that the endocannabinoid system participates crucially in the immune control and protection of the CNS. We discuss here the endocannabinoid system as a key regulator mechanism of the cross talk between brain and the immune system as well as its potential as a therapeutic target.”

http://www.ncbi.nlm.nih.gov/pubmed/18781977

Endocannabinoids in neuroimmunology and stress.

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Abstract

“Two topics are presented in this review. In the first section, we review data regarding the effects of the endocannabinoids (eCBs) and cannabinoid receptors on neuroimmune function. The function of eCBs in the interaction between the immune system and the central nervous system (CNS) is of particular interest, since the CNS itself is a rich source of eCBs while being exquisitely sensitive to inflammation. There are several sites at which cannabinoids can influence neuroinflammation. Microglial cells express both CB receptors and make eCBs. Activation of CB receptors on these cells seems to promote migration and proliferation but to reduce activation to macrophages. In several neurodegenerative diseases, up-regulation of microglial CB2 receptors have been observed. It is our hypothesis that microglial CB receptor activity is anti-inflammatory and could be exploited to manipulate neuroinflammatory processes with a minimum of unwanted effects. The second topic discussed suggests that the eCB/CB1 receptor pair is involved in the responses of animals to acute, repeated and variable stress. The roles of this pair are complex and dependent upon previous stress, among other things. Dysfunctional responding to stress is a component of several human neuropsychiatric disorders, including anxiety and panic disorders, post-traumatic stress disorders, premenstrual dysphoria and quite possibly, drug abuse. While it is too early to say with certainty, it is very possible that either inhibition or potentiation of endocannabinoid signaling will be an efficacious novel therapeutic approach to more than one human psychiatric disease.”

http://www.ncbi.nlm.nih.gov/pubmed/16375683

Nonpsychotropic Cannabinoid Receptors Regulate Microglial Cell Migration

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“During neuroinflammation, activated microglial cells migrate toward dying neurons, where they exacerbate local cell damage. The signaling molecules that trigger microglial cell migration are poorly understood. In this paper, we show that pathological overstimulation of neurons by glutamate plus carbachol dramatically increases the production of the endocannabinoid 2-arachidonylglycerol (2-AG) but only slightly increases the production of anandamide and does not affect the production of two putative endocannabinoids, homo-γ-linolenylethanolamide and docosatetraenylethanolamide. We further show that pathological stimulation of microglial cells with ATP also increases the production of 2-AG without affecting the amount of other endocannabinoids. Using a Boyden chamber assay, we provide evidence that 2-AG triggers microglial cell migration. This effect of 2-AG occurs through CB2 and abnormal-cannabidiol-sensitive receptors, with subsequent activation of the extracellular signal-regulated kinase 1/2 signal transduction pathway. It is important to note that cannabinol and cannabidiol, two nonpsychotropic ingredients present in the marijuana plant, prevent the 2-AG-induced cell migration by antagonizing the CB2 and abnormal-cannabidiol-sensitive receptors, respectively. Finally, we show that microglial cells express CB2 receptors at the leading edge of lamellipodia, which is consistent with the involvement of microglial cells in cell migration. Our study identifies a cannabinoid signaling system regulating microglial cell migration. Because this signaling system is likely to be involved in recruiting microglial cells toward dying neurons, we propose that cannabinol and cannabidiol are promising nonpsychotropic therapeutics to prevent the recruitment of these cells at neuroinflammatory lesion sites.”

“Because marijuana produces remarkable beneficial effects, patients with multiple sclerosis, for example, commonly use this plant as a therapeutic agent; however, we still lack essential information on the mechanistic basis of these beneficial effects.”

“The marijuana plant, Cannabis sativa, contains >60 cannabinoid compounds, the best known being Δ9-tetrahydrocannabinol (THC), cannabinol (CBN), and cannabidiol (CBD) (for review, see. Cannabinoid compounds produce their biological effects by acting through at least three cannabinoid receptors (see Table1). These include the cloned cannabinoid CB1 receptors, which are expressed predominately in the CNS, the cloned cannabinoid CB2 receptors, which are expressed predominately by immune cells, and the abnormal-cannabidiol-sensitive receptors (hereafter referred to as abn-CBD receptors). The latter receptors have not been cloned yet, but they have been pinpointed pharmacologically in mice lacking CB1 and CB2 receptors and are also known as anandamide (AEA) receptors.”

“We also show that CBN and CBD, two nonpsychotropic bioactive compounds of marijuana, may antagonize the 2-AG-induced recruitment of microglial cells. This is in agreement with the fact that nabilone, a synthetic analog of THC, produces minimal palliative effects against multiple sclerosis symptoms, whereas smoking cannabis is reported to be beneficial. Therefore, our results suggest that bioactive cannabinoids present in the marijuana plant, such as CBN and CBD, are likely to underlie the increased efficacy of cannabis versus nabilone and therefore hold promise as nonpsychotropic therapeutics to treat neuroinflammation.”

http://www.jneurosci.org/content/23/4/1398.long

Cannabinoids and neuroinflammation

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Abstract

“Growing evidence suggests that a major physiological function of the cannabinoid signaling system is to modulate neuroinflammation. This review discusses the anti-inflammatory properties of cannabinoid compounds at molecular, cellular and whole animal levels, first by examining the evidence for anti-inflammatory effects of cannabinoids obtained using in vivo animal models of clinical neuroinflammatory conditions, specifically rodent models of multiple sclerosis, and second by describing the endogenous cannabinoid (endocannabinoid) system components in immune cells. Our aim is to identify immune functions modulated by cannabinoids that could account for their anti-inflammatory effects in these animal models.”

Conclusion

“Cells involved in neuroinflammation express functional cannabinoid receptors and produce and degrade endocannabinoids, suggesting that the endocannabinoid signaling system has a regulatory function in the inflammatory response. Specifically, during neuroinflammation, there is an upregulation of components involved in the cannabinoid signaling system. This suggests that the cannabinoid signaling system participates in the complex development of this disease, which includes a tight orchestration of the various immune cells involved. If this is the case, the cannabinoid signaling machinery may provide ideal targets, since these would be more susceptible to pharmacological effects than those in the same system under healthy conditions. In line with this, cannabinoid compounds alter the functions of these cells, generally by eliciting anti-inflammatory effects. In the case of MS, neuroinflammation is accompanied by autoimmunity and suppressing the immune response may halt or even prevent associated symptoms. As seen in rodent models of MS, cannabinoids ameliorate the progression of and symptoms associated with neuroinflammation. Future experiments into the components that alter endocannabinoid production and degradation, cannabinoid receptor expression, and effects of cannabinoid receptor agonists on immune cells will provide the necessary information to design more effective treatments for neuroinflammation.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1574256/

The endocannabinoid system in normal and pathological brain ageing.

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Abstract

“The role of endocannabinoids as inhibitory retrograde transmitters is now widely known and intensively studied. However, endocannabinoids also influence neuronal activity by exerting neuroprotective effects and regulating glial responses. This review centres around this less-studied area, focusing on the cellular and molecular mechanisms underlying the protective effect of the cannabinoid system in brain ageing. The progression of ageing is largely determined by the balance between detrimental, pro-ageing, largely stochastic processes, and the activity of the homeostatic defence system. Experimental evidence suggests that the cannabinoid system is part of the latter system. Cannabinoids as regulators of mitochondrial activity, as anti-oxidants and as modulators of clearance processes protect neurons on the molecular level. On the cellular level, the cannabinoid system regulates the expression of brain-derived neurotrophic factor and neurogenesis. Neuroinflammatory processes contributing to the progression of normal brain ageing and to the pathogenesis of neurodegenerative diseases are suppressed by cannabinoids, suggesting that they may also influence the ageing process on the system level. In good agreement with the hypothesized beneficial role of cannabinoid system activity against brain ageing, it was shown that animals lacking CB1 receptors show early onset of learning deficits associated with age-related histological and molecular changes. In preclinical models of neurodegenerative disorders, cannabinoids show beneficial effects, but the clinical evidence regarding their efficacy as therapeutic tools is either inconclusive or still missing.”

http://www.ncbi.nlm.nih.gov/pubmed/23108550

Can the benefits of cannabinoid receptor stimulation on neuroinflammation, neurogenesis and memory during normal aging be useful in AD prevention?

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Abstract

“Background

Alzheimer’s disease has become a growing socio-economical concern in developing countries where increased life expectancy is leading to large aged populations. While curing Alzheimer’s disease or stopping its progression does not appear within reach in a foreseeable future, new therapies capable of delaying the pathogenesis would represent major breakthroughs.

Presentation of the hypothesis

The growing number of medical benefits of cannabinoids, such as their ability to regulate age-related processes like neuroinflammation, neurogenesis and memory, raise the question of their potential role as a preventive treatment of AD.

Testing the hypothesis

To test this hypothesis, epidemiological studies on long term, chronic cannabinoid users could enlighten us on the potential benefits of these compounds in normal and pathological ageing processes. Systematic pharmacological (and thus more mechanistic) investigations using animal models of Alzheimer’s disease that have been developed would also allow a thorough investigation of the benefits of cannabinoid pharmacotherapy in the pathogenesis of Alzheimer’s disease.

Implications of the hypothesis

The chronic administration of non-selective cannabinoids may delay the onset of cognitive deficits in AD patients; this will dramatically reduce the socio-economic burden of AD and improve the quality of life of the patients and their families.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3284401/

Cannabinoid agonist WIN-55,212-2 partially restores neurogenesis in the aged rat brain

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“A decline in neurogenesis in the hippocampus may underlie age-related memory impairment in rats and humans. We now show that WIN 55,212-2 administration for 3 weeks can partially restore neurogenesis in the hippocampus of aged rats. Cannabinoid receptor stimulation therapy may thus provide clinical benefit for humans with age-associated memory impairment.”

“This report shows for the first time the potential therapeutic efficacy of endocannabinoid receptor stimulation in stimulating neurogenesis from proliferation to engraftment during normal aging in vivo. The current results, coupled with our previous observations regarding the role of endocannabinoid receptors, underscores the potential clinical benefits of cannabinoid pharmacotherapies during normal and pathological brain aging.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3011092/

Anti-inflammatory property of the cannabinoid agonist WIN-55212-2 in a rodent model of chronic brain inflammation

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“Cannabinoid receptors (CBr) stimulation induces numerous central and peripheral effects. A growing interest in the beneficial properties of manipulating the endocannabinoid system has lead to the possible involvement of CBr in the control of brain inflammation… Our results emphasize the potential use of CBr agonists in the regulation of inflammatory processes within the brain; this knowledge may lead to the use of CBr agonists in the treatment of neurodegenerative diseases associated with chronic neuroinflammation, such as Alzheimer disease.”

“The current report is the first to our knowledge to demonstrate the modulatory role of cannabinoids in an animal model of chronic neuroinflammation, pointing out the effectiveness of a CBr agonist on the consequences of LPS mediated neuroinflammation at a dose (0.5 mg/kg/day i.p. of WIN-55212-2) that does not impair performance in a patial memory task. These results further advocate for the manipulation of the endocannabinoid system to diminish the consequences of neuroinflammation in progression of AD and others inflammation-related diseases.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1852513/

Regulation of neuroinflammation by herbal medicine and its implications for neurodegenerative diseases. A focus on traditional medicines and flavonoids.

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Abstract

“Herbal medicine has long been used to treat neural symptoms. Although the precise mechanisms of action of herbal drugs have yet to be determined, some of them have been shown to exert anti-inflammatory and/or anti-oxidant effects in a variety of peripheral systems. Now, as increasing evidence indicates that neuroglia-derived chronic inflammatory responses play a pathological role in the central nervous system, anti-inflammatory herbal medicine and its constituents are being proved to be a potent neuroprotector against various brain pathologies. Structural diversity of medicinal herbs makes them valuable source of novel lead compounds against therapeutic targets that are newly discovered by genomics, proteomics, and high-throughput screening.”

http://www.ncbi.nlm.nih.gov/pubmed/15956812

Cannabinoid receptors and endocannabinoids: role in neuroinflammatory and neurodegenerative disorders.

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Abstract

“The G-protein coupled receptors for Δ⁹-tetrahydrocannabinol, the major psychoactive principle of marijuana, are known as cannabinoid receptors of type 1 (CB₁) and 2 (CB₂) and play important functions in degenerative and inflammatory disorders of the central nervous system. Whilst CB₁ receptors are mostly expressed in neurons, where they regulate neurotransmitter release and synaptic strength, CB₂ receptors are found mostly in glial cells and microglia, which become activated and over-express these receptors during disorders such as Alzheimer’s disease, multiple sclerosis, amyotropic lateral sclerosis, Parkinson’s disease, and Huntington’s chorea. The neuromodulatory actions at CB₁ receptors by endogenous agonists (‘endocannabinoids’), of which anandamide and 2-arachidonoylglycerol are the two most studied representatives, allows them to counteract the neurochemical unbalances arising during these disorders. In contrast, the immunomodulatory effects of these lipophilic mediators at CB₂ receptors regulate the activity and function of glia and microglia. Indeed, the level of expression of CB₁ and CB₂ receptors or of enzymes controlling endocannabinoid levels, and hence the concentrations of endocannabinoids, undergo time- and brain region-specific changes during neurodegenerative and neuroinflammatory disorders, with the initial attempt to counteract excitotoxicity and inflammation. Here we discuss this plasticity of the endocannabinoid system during the aforementioned central nervous system disorders, as well as its dysregulation, both of which have opened the way to the use of either direct and indirect activators or blockers of CB₁ and CB₂ receptors for the treatment of the symptoms or progression of these diseases.”

http://www.ncbi.nlm.nih.gov/pubmed/20632970