Category Archives: Uncategorized

Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders.

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Abstract

“Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ(9)-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca(2+)) increase, etc.), on CBD behavioural effects.”

http://www.ncbi.nlm.nih.gov/pubmed/23108553

Endocannabinoids in nervous system health and disease: the big picture in a nutshell.

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Abstract

“The psychoactive component of the cannabis resin and flowers, delta9-tetrahydrocannabinol (THC), was first isolated in 1964, and at least 70 other structurally related ‘phytocannabinoid’ compounds have since been identified. The serendipitous identification of a G-protein-coupled cannabinoid receptor at which THC is active in the brain heralded an explosion in cannabinoid research. Elements of the endocannabinoid system (ECS) comprise the cannabinoid receptors, a family of nascent lipid ligands, the ‘endocannabinoids’ and the machinery for their biosynthesis and metabolism. The function of the ECS is thus defined by modulation of these receptors, in particular, by two of the best-described ligands, 2-arachidonoyl glycerol and anandamide (arachidonylethanolamide). Research on the ECS has recently aroused enormous interest not only for the physiological functions, but also for the promising therapeutic potentials of drugs interfering with the activity of cannabinoid receptors. Many of the former relate to stress-recovery systems and to the maintenance of homeostatic balance. Among other functions, the ECS is involved in neuroprotection, modulation of nociception, regulation of motor activity, neurogenesis, synaptic plasticity and the control of certain phases of memory processing. In addition, the ECS acts to modulate the immune and inflammatory responses and to maintain a positive energy balance. This theme issue aims to provide the reader with an overview of ECS pharmacology, followed by discussions on the pivotal role of this system in the modulation of neurogenesis in the developing and adult organism, memory processes and synaptic plasticity, as well as in pathological pain and brain ageing. The volume will conclude with discussions that address the proposed therapeutic applications of targeting the ECS for the treatment of neurodegeneration, pain and mental illness.”

http://www.ncbi.nlm.nih.gov/pubmed/23108539

Cannabinoids and innate immunity: taking a toll on neuroinflammation.

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Abstract

“The biologically active components of cannabis have therapeutic potential in neuroinflammatory disorders due to their anti-inflammatory propensity. Cannabinoids influence immune function in both the peripheral and the central nervous system (CNS), and the components of the cannabinoid system, the cannabinoid receptors and their endogenous ligands (endocannabinoids), have been detected on immune cells as well as in brain glia. Neuroinflammation is the complex innate immune response of neural tissue to control infection and eliminate pathogens, and Toll-like receptors (TLRs), a major family of pattern recognition receptors (PRRs) that mediate innate immunity, have emerged as players in the neuroinflammatory processes underpinning various CNS diseases. This review will highlight evidence that cannabinoids interact with the immune system by impacting TLR-mediated signaling events, which may provide cues for devising novel therapeutic approaches for cannabinoid ligands.”

http://www.ncbi.nlm.nih.gov/pubmed/21479354

Cannabinoid receptor signalling in neurodegenerative diseases: a potential role for membrane fluidity disturbance

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Abstract

“Type-1 cannabinoid receptor (CB1) is the most abundant G-protein-coupled receptor (GPCR) in the brain. CB1 and its endogenous agonists, the so-called ‘endocannabinoids (eCBs)’, belong to an ancient neurosignalling system that plays important functions in neurodegenerative and neuroinflammatory disorders like Alzheimer’s disease, Parkinson’s disease, amyotrophic lateral sclerosis and multiple sclerosis. For this reason, research on the therapeutic potential of drugs modulating the endogenous tone of eCBs is very intense. Several GPCRs reside within subdomains of the plasma membranes that contain high concentrations of cholesterol: the lipid rafts. Here, the hypothesis that changes in membrane fluidity alter function of the endocannabinoid system, as well as progression of particular neurodegenerative diseases, is described. To this end, the impact of membrane cholesterol on membrane properties and hence on neurodegenerative diseases, as well as on CB1 signalling in vitro and on CB1-dependent neurotransmission within the striatum, is discussed. Overall, present evidence points to the membrane environment as a critical regulator of signal transduction triggered by CB1, and calls for further studies aimed at better clarifying the contribution of membrane lipids to eCBs signalling. The results of these investigations might be exploited also for the development of novel therapeutics able to combat disorders associated with abnormal activity of CB1.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3165948/

Role of CB1 cannabinoid receptors on GABAergic neurons in brain aging

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“Brain aging is associated with cognitive decline that is accompanied by progressive neuroinflammatory changes. The endocannabinoid system (ECS) is involved in the regulation of glial activity and influences the progression of age-related learning and memory deficits.

Mice lacking the Cnr1 gene (Cnr1−/−), which encodes the cannabinoid receptor 1 (CB1), showed an accelerated age-dependent deficit in spatial learning accompanied by a loss of principal neurons in the hippocampus. The age-dependent decrease in neuronal numbers in Cnr1−/− mice was not related to decreased neurogenesis or to epileptic seizures. However, enhanced neuroinflammation characterized by an increased density of astrocytes and activated microglia as well as an enhanced expression of the inflammatory cytokine IL-6 during aging was present in the hippocampus of Cnr1−/− mice. The ongoing process of pyramidal cell degeneration and neuroinflammation can exacerbate each other and both contribute to the cognitive deficits. Deletion of CB1 receptors from the forebrain GABAergic, but not from the glutamatergic neurons, led to a similar neuronal loss and increased neuroinflammation in the hippocampus as observed in animals lacking CB1 receptors in all cells.

Our results suggest that CB1 receptor activity on hippocampal GABAergic neurons protects against age-dependent cognitive decline by reducing pyramidal cell degeneration and neuroinflammation.”

Regulatory Role of Cannabinoid Receptor 1 in Stress-Induced Excitotoxicity and Neuroinflammation

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 “Exposure to stress elicits excitoxicity and neuroinflammation in the brain, contributing to cell death and damage in stress-related neurological and neuropsychiatric diseases. The endocannabinoid system is present in stress-responsive neural circuits and has been proposed as an endogenous neuroprotective system activated in some neuropathological scenarios to restore homeostasis. To elucidate the possible regulatory role of cannabinoid receptor 1 (CB1) in stress-induced excitotoxicity and neuroinflammation, both genetic and pharmacological approaches were used alternatively… These multifaceted neuroprotective effects suggest that CB1 activation could be a new therapeutic strategy against neurological/neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.”

“Antiinflammatory Effects Elicited by CB1 Activation. Mechanisms Involved”

“In general, ECS has been proposed as an endogenous protective system against excessive inflammatory/immune responses in multiple CNS pathologies. Our following studies were aimed at clarifying the particular role of CB1 as a possible regulator of stress-induced inflammatory response.”

“In summary, the multifaceted neuroprotective effects described here suggest that CB1 activation is an attractive therapeutic strategy against diverse neuropsychiatric pathologies with HPA axis dysregulation and an excitotoxic/neuroinflammatory component in their pathophysiology.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC3055736/

The endocannabinoid system in peripheral lymphocytes as a mirror of neuroinflammatory diseases.

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Abstract

“During immuno-mediated attack of the brain, activation of endocannabinoids represents a protective mechanism, aimed at reducing both neurodegenerative and inflammatory damage through various and partially converging mechanisms that involve neuronal and immune cells. Here, we review the main alterations of the endocannabinoid system (ECS) within the central nervous system and in peripheral blood mononuclear cells, in order to discuss the intriguing observation that elements of the peripheral ECS mirror central dysfunctions of endocannabinoid signaling. As a consequence, elements of blood ECS might serve as novel, non-invasive diagnostic tools of several neurological disorders, and targeting the ECS might be useful for therapeutic purposes. In addition, we discuss the appealing working hypothesis that the presence of type-1 cannabinoid receptors on the luminal side, and that of type-2 cannabinoid receptors on the abluminal side of the blood-brain barrier, could drive a unidirectional transport of AEA in the luminal –> abluminal direction (i.e., from blood to brain), thus implying that blood may be a reservoir of AEA for the brain. On this basis, it can be expected that an unbalance of the endogenous tone of AEA in the blood may sustain a similar unbalance of its level within the brain, as demonstrated in Huntington’s disease, Parkinson’s disease, multiple sclerosis, attention-deficit/hyperactivity disorder, schizophrenia, depression and headache.”

http://www.ncbi.nlm.nih.gov/pubmed/18781987

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

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/