Category Archives: Endocannabinoid System

Therapeutic potential of endocannabinoid-hydrolysing enzyme inhibitors.

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Abstract

“The specific protein target of delta9-tetrahydrocannabinol (delta9-THC), the main active ingredient of Cannabis sativa L., was characterized from rat brain nearly 20 years ago, and several endogenous compounds and proteins comprising the endocannabinoid (eCB) system have since been discovered. It has become evident that the eCB system consists of at least two cannabinoid receptors (i.e. the CB1 and CB2 receptors), in addition to their endogenous ligands (the eCBs) and several enzymes involved in the biosynthesis and catabolism of the eCBs. The two well-established eCBs, N-arachidonoylethanolamide (AEA) and 2-arachidonoylglycerol (2-AG), are produced by neurons on demand, act near their sites of synthesis and are effectively metabolized by fatty acid amide hydrolase (FAAH) and monoglyceride lipase (MGL), respectively. Inhibitors specifically targeting these enzymes could offer novel therapeutic approaches (e.g. for the treatment of pain and movement disorders). This MiniReview summarizes the literature concerning the potential therapeutic potential of FAAH and MGL inhibitors.”

http://www.ncbi.nlm.nih.gov/pubmed/17910610

A new strategy to block tumor growth by inhibiting endocannabinoid inactivation.

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“Endocannabinoid signaling has been shown to be enhanced in several cancer tissues and malignant cells, and studies in cell lines have shown that this up-regulation might serve the purpose of providing transformed cells with a further means to inhibit their proliferation. Here we investigated the effect of inhibitors of endocannabinoid degradation on the growth of rat thyroid tumor xenografts induced in athymic mice. VDM-11, a selective inhibitor of endocannabinoid cellular re-uptake, and arachidonoyl-serotonin (AA-5-HT), a selective blocker of endocannabinoid enzymatic hydrolysis, both inhibited the growth in vivo of tumor xenografts induced by the subcutaneous injection of rat thyroid transformed (KiMol) cells. This effect was accompanied by significantly enhanced endocannabinoid concentrations in the tumors excised at the end of the in vivo experiments. Endocannabinoids, as well as VDM-11 and AA-5-HT, inhibited the growth in vitro of the transformed rat thyroid cells used to induce the tumors in vivo, and their effect was reversed at least in part by the cannabinoid CB1 receptor antagonist SR141716A. This compound, however, when administered alone, did not enhance, but instead slightly inhibited, the growth of rat thyroid transformed cells both in vitro and in tumor xenografts induced in vivo. These findings indicate that endocannabinoids tonically control tumor growth in vivo by both CB1-mediated and non-CB1-mediated mechanisms and that, irrespective of the molecular mechanism of their anti-proliferative action, inhibitors of their inactivation might be used for the development of novel anti-cancer drugs.”  http://www.ncbi.nlm.nih.gov/pubmed/15289448

“A new strategy to block tumor growth by inhibiting endocannabinoid inactivation”  http://www.fasebj.org/content/early/2004/10/02/fj.04-1754fje.long

A metabolically stable analogue of anandamide, Met-F-AEA, inhibits human thyroid carcinoma cell lines by activation of apoptosis.

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Abstract

  “The active components of Cannabis sativa and their derivatives produce a wide spectrum of effects, some of which may have clinical application. The discovery of specific cannabinoid receptors and a family of endogenous ligands of those receptors has attracted much attention to cannabinoids as agents capable of controlling the decision of cells to survive or die. We analysed the effects exerted by 2-methyl-2′-F-anandamide (Met-F-AEA), a metabolically stable analogue of anandamide, and observed a growth inhibition in cell lines derived from thyroid carcinomas. Growth inhibition was associated with a high level of CB1 receptor expression, suggesting that the cytotoxic effect is due to interaction with the CB1 receptor. This phenomenon was associated with activation of the protein, p53, an increased apoptotic rate, and expression of p21(CIP1/WAF1). This study provides new insights into the mechanism of Met-F-AEA action, and could have significance in providing a basis for the management of thyroid carcinoma.”

http://www.ncbi.nlm.nih.gov/pubmed/19189054

Endogenous cannabinoids and neutrophil chemotaxis.

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Abstract

  “Neutrophils are the earliest inflammatory cell to infiltrate tissue, playing an important role in early phagocytosis. Under pathological conditions, pro-inflammatory actions of neutrophils contribute to the development of various inflammatory diseases. G(i) protein-coupled cell-surface receptors are an essential component of pro-migratory responses in leukocytes; however, few investigations regarding inhibitors of cell migration have been reported. Kurihara et al. (2006) and McHugh et al. (2008) have revealed that certain endogenous cannabinoids and lipids are potent inhibitors of induced human neutrophil migration. McHugh et al. implicate a novel SR141716A-sensitive pharmacological target distinct from cannabinoid CB(1) and CB(2) receptors, which is antagonized by N-arachidonoyl-l-serine; and that the CB(2) receptor exerts negative co-operativity upon this receptor. Kurihara et al. demonstrate that fMLP-induced RhoA activity is decreased following endocannabinoid pretreatment, disrupting the front/rear polarization necessary for neutrophils to engage in chemotaxis.

The therapeutic potential of exploiting endocannabinoids as neutrophilic chemorepellants is plain to see.”

http://www.ncbi.nlm.nih.gov/pubmed/19647118

Inhibition of Human Neutrophil Chemotaxis by Endogenous Cannabinoids and Phytocannabinoids: Evidence for a Site Distinct from CB1 and CB2

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   “Here, we show a novel pharmacology for inhibition of human neutrophil migration by endocannabinoids, phytocannabinoids, and related compounds. The endocannabinoids virodhamine and N-arachidonoyl dopamine are potent inhibitors of N-formyl-l-methionyl-l-leucyl-l-phenylalanine-induced migration of human neutrophils…”

   “This study reveals that certain endogenous lipids, phytocannabinoids and related ligands are potent inhibitors of human neutrophil migration, and it implicates a novel pharmacological target distinct from cannabinoid CB1 and CB2 receptors; this target is antagonized by the endogenous compound N-arachidoloyl l-serine. These findings corroborate the emerging clinical and animal model data demonstrating that the nonpsychoactive phytocannabinoid, CBD and its structural analogs are effective in alleviating arthritis. Furthermore, our findings have implications for the potential pharmacological manipulation of elements of the endocannabinoid system for the treatment of various inflammatory conditions.”

http://molpharm.aspetjournals.org/content/73/2/441.long

Cannabis and endocannabinoid modulators: Therapeutic promises and challenges.

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   “The discovery that botanical cannabinoids such as delta-9 tetrahydrocannabinol exert some of their effect through binding specific cannabinoid receptor sites has led to the discovery of an endocannabinoid signaling system, which in turn has spurred research into the mechanisms of action and addiction potential of cannabis on the one hand, while opening the possibility of developing novel therapeutic agents on the other. This paper reviews current understanding of CB1, CB2, and other possible cannabinoid receptors, their arachidonic acid derived ligands (e.g. anandamide; 2 arachidonoyl glycerol), and their possible physiological roles. CB1 is heavily represented in the central nervous system, but is found in other tissues as well; CB2 tends to be localized to immune cells. Activation of the endocannabinoid system can result in enhanced or dampened activity in various neural circuits depending on their own state of activation. This suggests that one function of the endocannabinoid system may be to maintain steady state. The therapeutic action of botanical cannabis or of synthetic molecules that are agonists, antagonists, or which may otherwise modify endocannabinoid metabolism and activity indicates they may have promise as neuroprotectants, and may be of value in the treatment of certain types of pain, epilepsy, spasticity, eating disorders, inflammation, and possibly blood pressure control.”

“Marijuana and cannabinoids as medicine”

“Although references to potential medicinal properties of cannabis date to ancient times, and despite cannabis being included as a medication in Western pharmacopeias from the nineteenth through the early twentieth centuries, there is still no body of reliable information on possible indications or efficacy. In part, slow progress can be attributed to difficulties in identifying the active ingredients in cannabis; THC was not actually characterized and identified as the main psychoactive substance until 1965. The chemical properties of the cannabinoids, for example their virtual insolubility in water, and the fact that they consist of oily liquids at room temperature has posed further challenges in formulation and administration. Increased governmental concerns about the abuse potential of marijuana and hashish also created a regulatory climate in many Western countries that emphasized the negative properties of these substances and absence of any documented medicinal properties, thus discouraging research into therapeutics.”

“Cultural and attitude changes in the latter half of the twentieth century in many Western countries resulted in large groups of ‘mainstream’ adults and adolescents experimenting with marijuana. The scarcity of obvious acute serious toxic effects, and lack of consistent information on longer-term adverse effects has lead to more recent attitudinal changes in many Western societies that have re-opened the possibility of use of cannabis as a medication.”

http://www.ncbi.nlm.nih.gov/pmc/articles/PMC2544377/

Cannabis and the brain.

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Abstract

“The active compound in herbal cannabis, Delta(9)-tetrahydrocannabinol, exerts all of its known central effects through the CB(1) cannabinoid receptor. Research on cannabinoid mechanisms has been facilitated by the availability of selective antagonists acting at CB(1) receptors and the generation of CB(1) receptor knockout mice. Particularly important classes of neurons that express high levels of CB(1) receptors are GABAergic interneurons in hippocampus, amygdala and cerebral cortex, which also contain the neuropeptides cholecystokinin. Activation of CB(1) receptors leads to inhibition of the release of amino acid and monoamine neurotransmitters. The lipid derivatives anandamide and 2-arachidonylglycerol act as endogenous ligands for CB(1) receptors (endocannabinoids). They may act as retrograde synaptic mediators of the phenomena of depolarization-induced suppression of inhibition or excitation in hippocampus and cerebellum. Central effects of cannabinoids include disruption of psychomotor behaviour, short-term memory impairment, intoxication, stimulation of appetite, antinociceptive actions (particularly against pain of neuropathic origin) and anti-emetic effects. Although there are signs of mild cognitive impairment in chronic cannabis users there is little evidence that such impairments are irreversible, or that they are accompanied by drug-induced neuropathology. A proportion of regular users of cannabis develop tolerance and dependence on the drug. Some studies have linked chronic use of cannabis with an increased risk of psychiatric illness, but there is little evidence for any causal link. The potential medical applications of cannabis in the treatment of painful muscle spasms and other symptoms of multiple sclerosis are currently being tested in clinical trials. Medicines based on drugs that enhance the function of endocannabinoids may offer novel therapeutic approaches in the future.”

http://www.ncbi.nlm.nih.gov/pubmed/12764049

Multiple roles for the endocannabinoid system during the earliest stages of life: pre- and postnatal development.

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Abstract

“The endocannabinoid system, including its receptors (CB(1) and CB(2)), endogenous ligands (‘endocannabinoids’), synthesising and degrading enzymes, as well as transporter molecules, has been detected from the earliest stages of embryonic development and throughout pre- and postnatal development. In addition, the endocannabinoids, notably 2-arachidonyl glycerol, are also present in maternal milk. During three distinct developmental stages (i.e. embryonic implantation, prenatal brain development and postnatal suckling), the endocannabinoid system appears to play an essential role for development and survival. Thus, during early pregnancy, successful embryonic passage through the oviduct and implantation into the uterus both require critical enzymatic control of optimal anandamide levels at the appropriate times and sites. During foetal life, the cannabinoid CB(1) receptor plays a major role in brain development, regulating neural progenitor differentiation into neurones and glia and guiding axonal migration and synaptogenesis. Postnatally, CB(1) receptor blockade interferes with the initiation of milk suckling in mouse pups, by inducing oral motor weakness, which exposes a critical role for CB(1) receptors in the initiation of milk suckling by neonates, possibly by interfering with innervation of the tongue muscles. Manipulating the endocannabinoid system by pre- and/or postnatal administration of cannabinoids or maternal marijuana consumption, has significant, yet subtle effects on the offspring. Thus, alterations in the dopamine, GABA and endocannabinoid systems have been reported while enhanced drug seeking behaviour and impaired executive (prefrontal cortical) function have also been observed. The relatively mild nature of the disruptive effects of prenatal cannabinoids may be understood in the framework of the intricate timing requirements and frequently biphasic effects of the (endo)cannabinoids. In conclusion, the endocannabinoid system plays several key roles in pre- and postnatal development. Future studies should further clarify the mechanisms involved and provide a better understanding of the adverse effects of prenatal exposure, in order to design strategies for the treatment of conditions such as infertility, mental retardation and failure-to-thrive.”

http://www.ncbi.nlm.nih.gov/pubmed/18426504

The endocannabinoid-CB(1) receptor system in pre- and postnatal life.

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Abstract

“Recent research suggests that the endogenous cannabinoids (“endocannabinoids”) and their cannabinoid receptors have a major influence during pre- and postnatal development. First, high levels of the endocannaboid anandamide and cannabinoid receptors are present in the preimplantation embryo and in the uterus, while a temporary reduction of anandamide levels is essential for embryonal implantation. In women accordingly, an inverse association has been reported between fatty acid amide hydrolase (the anandamide degrading enzyme) in human lymphocytes and miscarriage. Second, CB(1) receptors display a transient presence in white matter areas of the pre- and postnatal nervous system, suggesting a role for CB(1) receptors in brain development. Third, endocannabinoids have been detected in maternal milk and activation of CB(1) receptors appears to be critical for milk sucking by newborn mice, apparently activating oral-motor musculature. Fourth, anandamide has neuroprotectant properties in the developing postnatal brain. Finally, prenatal exposure to the active constituent of marihuana (Delta(9)-tetrahydrocannabinol) or to anandamide affects prefrontal cortical functions, memory and motor and addictive behaviors, suggesting a role for the endocannabinoid CB(1) receptor system in the brain structures which control these functions. Further observations suggest that children may be less prone to psychoactive side effects of Delta(9)-tetrahydrocannabinol or endocannabinoids than adults. The medical implications of these novel developments are far reaching and suggest a promising future for cannabinoids in pediatric medicine for conditions including “non-organic failure-to-thrive” and cystic fibrosis.”

http://www.ncbi.nlm.nih.gov/pubmed/15464041

The endocannabinoid-CB receptor system: Importance for development and in pediatric disease.

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Abstract

“Endogenous cannabinoids (endocannabinoids) and their cannabinoid CB1 and CB2 receptors, are present from the early stages of gestation and play a number of vital roles for the developing organism. Although most of these data are collected from animal studies, a role for cannabinoid receptors in the developing human brain has been suggested, based on the detection of “atypically” distributed CB1 receptors in several neural pathways of the fetal brain. In addition, a role for the endocannabinoid system for the human infant is likely, since the endocannabinoid 2-arachidonoyl glycerol has been detected in human milk. Animal research indicates that the Endocannabinoid-CB1 Receptor (‘ECBR’) system fulfills a number of roles in the developing organism: 1. embryonal implantation (requires a temporary and localized reduction in anandamide); 2. in neural development (by the transient presence of CB1 receptors in white matter areas of the nervous system); 3. as a neuroprotectant (anandamide protects the developing brain from trauma-induced neuronal loss); 4. in the initiation of suckling in the newborn (where activation of the CB1 receptors in the neonatal brain is critical for survival). 5. In addition, subtle but definite deficiencies have been described in memory, motor and addictive behaviors and in higher cognitive (‘executive’) function in the human offspring as result of prenatal exposure to marihuana. Therefore, the endocanabinoid-CB1 receptor system may play a role in the development of structures which control these functions, including the nigrostriatal pathway and the prefrontal cortex. From the multitude of roles of the endocannabinoids and their receptors in the developing organism, there are two distinct stages of development, during which proper functioning of the endocannabinoid system seems to be critical for survival: embryonal implantation and neonatal milk sucking. We propose that a dysfunctional Endocannabinoid-CB1 Receptor system in infants with growth failure resulting from an inability to ingest food, may resolve the enigma of “non-organic failure-to-thrive” (NOFTT). Developmental observations suggest further that CB1 receptors develop only gradually during the postnatal period, which correlates with an insensitivity to the psychoactive effects of cannabinoid treatment in the young organism. Therefore, it is suggested that children may respond positively to medicinal applications of cannabinoids without undesirable central effects. Excellent clinical results have previously been reported in pediatric oncology and in case studies of children with severe neurological disease or brain trauma. We suggest cannabinoid treatment for children or young adults with cystic fibrosis in order to achieve an improvement of their health condition including improved food intake and reduced inflammatory exacerbations.”

http://www.ncbi.nlm.nih.gov/pubmed/15159678