Cannabinoid signaling system

The cannabinoid signaling system is located during brain development in a position concordant with playing a modulatory function in the regulation of neuronal and glial cell proliferation and migration, survival of neural progenitors, axonal elongation and synaptogenesis, and differentiation of oligodendrocytes and formation of myelin. This assumption is based on the fact that CB1 receptors and their ligands emerge early in brain development and are transiently expressed in certain brain regions that play key roles in these processes. We have recently proposed that this modulatory action might be exerted through regulating L1 and other cell adhesion molecules, that are also key elements for those processes. The present commentary will address these two questions trying to summarize all the available evidence and to suggest the future directions for research.     

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

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.     

Neurotransmitters as early signals for central nervous system development

During brain ontogenesis, the temporal and spatial generation of the different types of neuronal and glial cells from precursors occurs as a sequence of successive progenitor stages whose proliferation, survival and cell-fate choice are controlled by environmental and cellular regulatory molecules. Neurotransmitters belong to the chemical microenvironment of neural cells, even at the earliest stages of brain development. It is now established that specific neurotransmitter receptors are present on progenitor cells of the developing central nervous system and could play, during neural development, a role that has remained unsuspected until recently. The present review focuses on the occurrence of neurotransmitters and their corresponding ligand-gated ion channel receptors in immature cells, including neural stem cells of specific embryonic and neonatal brain regions. We summarize in vitro and in vivo data arguing that neurotransmitters could regulate morphogenetic events such as proliferation, growth, migration, differentiation and survival of neural precursor cells. The understanding of neurotransmitter function during early neural maturation could lead to the development of pharmacological tools aimed at improving adult brain repair strategies.     

Adaptations of Striatal Endocannabinoid System During Stress

The endocannabinoid system (ECS) plays a fundamental role in the regulation of synaptic transmission. Exposure to stressful events triggers synaptic adaptations in many brain areas. The activity of the ECS in stress-responsive neural circuits suggests that it may be involved in the behavioral responses and synaptic effects typical of stress. In this review, we discuss evidence demonstrating that striatal ECS is modulated by stress. Chronic stress exposure alters endocannabinoid levels, cannabinoid CB1 receptor binding and cannabinoid CB1 receptor-mediated control of inhibitory synaptic transmission in the striatum. Recent studies have shown that impairment of endocannabinoid signalling is associated with inability to adapt to chronic stress and to the development of maladaptive behaviors. The ECS represents a novel potential pharmacological target to treat stress-associated neuropsychiatric conditions.     

Cannabis, cannabinoids and reproduction

In most countries Cannabis is the most widely used illegal drug. Its use during pregnancy in developed nations is estimated to be approximately 10%. Recent evidence suggests that the endogenous cannabinoid system, now consisting of two receptors and multiple endocannabinoid ligands, may also play an important role in the maintenance and regulation of early pregnancy and fertility. The purpose of this review is therefore twofold, to examine the impact that cannabis use may have on fertility and reproduction, and to review the potential role of the endocannabinoid system in hormonal regulation, embryo implantation and maintenance of pregnancy.     

Biochemistry, pharmacology and physiology of 2-arachidonoylglycerol, an endogenous cannabinoid receptor ligand

2-Arachidonoylglycerol (2-AG) is a unique molecular species of monoacylglycerol isolated in 1995 from rat brain and canine gut as an endogenous ligand for the cannabinoid receptors. 2-AG is rapidly formed from arachidonic acid-containing phospholipids through increased phospholipid metabolism, such as enhanced inositol phospholipid turnover, in various tissues and cells upon stimulation. 2-AG binds to the cannabinoid receptors (CB1 and CB2) and exhibits a variety of cannabimimetic activities in vitro and in vivo. Notably, anandamide, another endogenous ligand for the cannabinoid receptors, often acts as a partial agonist at these cannabinoid receptors, whereas 2-AG acts as a full agonist in most cases. The results of structure-activity relationship studies suggested that 2-AG rather than anandamide is the true natural ligand for both the CB1 and the CB2 receptors. Evidence is gradually accumulating which shows that 2-AG plays physiologically essential roles in diverse biological systems. For example, several lines of evidence indicate that 2-AG plays an important role as a retrograde messenger molecule in the regulation of synaptic transmission. 2-AG has also been shown to be involved in the regulation of various types of inflammatory reactions and immune responses. In this review, we focused on 2-AG, and summarized information concerning its biosynthesis, metabolism, bioactions and physiological significance, including our latest experimental results.     

Endocannabinoids in the immune system and cancer

The present review focuses on the role of the endogenous cannabinoid system in the modulation of immune response and control of cancer cell proliferation. The involvement of cannabinoid receptors, endogenous ligands and enzymes for their biosynthesis and degradation, as well as of cannabinoid receptor-independent events is discussed. The picture arising from the recent literature appears very complex, indicating that the effects elicited by the stimulation of the endocannabinoid system are strictly dependent on the specific compounds and cell types considered. Both the endocannabinoid anandamide and its congener palmitoylethanolamide, exert a negative action in the onset of a variety of parameters of the immune response. However, 2-arachidonoylglycerol appears to be the true endogenous ligand for peripheral cannabinoid receptors, although its action as an immunomodulatory molecule requires further characterization. Modulation of the endocannabinoid system interferes with cancer cell proliferation either by inhibiting mitogenic autocrine/paracrine loops or by directly inducing apoptosis; however, the proapoptotic effect of anandamide is not shared by other endocannabinoids and suggests the involvement of non-cannabinoid receptors, namely the VR1 class of vanilloid receptors. In conclusion, further investigations are needed to elucidate the function of endocannabinoids as immunosuppressant and antiproliferative/cytotoxic agents. The experimental evidence reviewed in this article argues in favor of the therapeutic potential of these compounds in immune disorders and cancer.     

We have got you 'covered': how the meninges control brain development

The meninges have traditionally been viewed as specialized membranes surrounding and protecting the adult brain from injury. However, there is increasing evidence that the fetal meninges play important roles during brain development. Through the release of diffusible factors, the meninges influence the proliferative and migratory behaviors of neural progenitors and neurons in the forebrain and hindbrain. Meningeal cells also secrete and organize the pial basement membrane (BM), a critical anchor point for the radially oriented fibers of neuroepithelial stem cells. With its emerging role in brain development, the potential that defects in meningeal development may underlie certain congenital brain abnormalities in humans should be considered. In this review, we will discuss what is known about assembly of the fetal meninges and review the role of meningeal-derived proteins in mouse and human brain development.     

Comparative biology of the endocannabinoid system possible role in the immune response.

In this review we discuss data showing that the endogenous cannabinoid system, represented by cannabinoid receptors, endogenous cannabinoid receptor ligands and enzymes for the biosynthesis and degradation of these ligands, is conserved throughout evolution from coelenterates to man. This signaling system has been suggested to play several roles in animals, including the regulation of cell development and growth, nervous functions, reproduction and feeding behavior. In this article, however, we shall describe with more detail the possible function of the endogenous cannabinoid system in the modulation of immune response in organisms from the lower to the higher levels of animal evolution.     

Cannabinoid signaling system: Does it play a function in cell proliferation and migration,neuritic elongation and guidance and synaptogenesis during brain ontogenesis?

The cannabinoid signaling system is located during brain development in a position concordant with playing a modulatory function in the regulation of neuronal and glial cell proliferation and migration, survival of neural progenitors, axonal elongation and synaptogenesis and differentiation of oligodendrocytes and formation of myelin. This assumption is based on the fact that CB₁ receptors and their ligands emerge early in brain development and are transiently expressed in certain brain regions that play key roles in these processes. We have recently proposed that this modulatory action might be exerted through regulating L1 and other cell adhesion molecules, that are also key elements for those processes. The present commentary will address these two questions trying to summarize all the available evidence and to suggest the future directions for research.Key words: cannabinoid signaling system, CB₁ receptors, brain development, neural cell proliferation, migration and differentiation, cell adhesion moleculesThe study of the molecular mechanisms underlying the psychoactive effects of Cannabis sativa led to the discovery of the “endogenous cannabinoid system”, an intercellular signaling system that plays modulatory functions in brain synapses and also in the periphery. It consists of multiple endocannabinoid ligands, their membrane receptors (CB₁, CB₂ and others), anabolic and catabolic enzymes, as well as a membrane-transport mechanism. The function(s) of this system has (have) been extensively studied in adult mammals pointing to an important role in the regulation of numerous neurobiological processes. Studies conducted during the last decade, which addressed the ontogeny of this system in the brain, led to the assumption that the endocannabinoid system might also play relevant modulatory functions during brain development. This assumption derived from certain particularities found in the ontogenic pattern of the endocannabinoid system, which mimicked similar results found for neurotransmitters having a neurotrophic function.¹ Thus, the endo cannabinoid signaling system, in particular the CB₁ receptors: (1) emerge early in brain development,^1–5 (2) are particularly abundant in forebrain subventricular zones and cortical structures,^1,4 which play a key role in cell proliferation and migration, respectively, and (3) and are transiently located, during restricted ontogenic periods, in forebrain white matter structures, in particular transverse commissural tracts,^1,2,4 which are essential for cell migration and axonal elongation. The fact that this “atypical” distribution of the CB₁ receptor disappears coinciding with the conclusion of the establishement of synaptic communication and postsynaptic target selection^1,6 is highly suggestive of a specific role of the cannabinoid signaling in these processes.     

Novel Physiologic Functions of Endocannabinoids as Revealed Through the Use of Mutant Mice

The presence in the mammalian brain of specific receptors for marijuana triggered a search for endogenous ligands, several of which have been recently identified. There has been growing in-terest in the possible physiological functions of endocannabinoids, and mutant mice that lack cannabinoid receptors have become an important tool in the search for such functions. To date, studies using CB1 knockout mice have supported the possible role of endocannabinoids in retro-grade synaptic inhibition in the hippocampus, in long-term potentiation and memory, in the de-velopment of opiate dependence, and in the control of appetite and food intake. They also suggested the existence of as yet unidentified cannabinoid receptors in the cardiovascular and central nervous systems. The use of CB2 receptor knockout mice suggested a role for this re-ceptor in macrophage-mediated helper T cell activation. Further studies will undoubtedly reveal many additional roles for this novel signaling system.     

Muscarinic acetylcholine receptors involved in the regulation of neural stem cell proliferation and differentiation in vitro

Neural stem cells (NSCs) are currently considered powerful candidates for cell therapy in neurodegenerative disorders such as Parkinson's disease. However, it is not known when and how NSCs begin to differentiate functionally. Recent reports suggest that classical neurotransmitters such as acetylcholine (Ach) are involved in the proliferation and differentiation of neural progenitor cells, suggesting that neurotransmitters play an important regulatory role in development of the central nervous system (CNS). We have shown by calcium imaging and immunochemistry that proliferation and differentiation are enhanced by M2 muscarinic Ach receptors (mAchR) expressed on the NSC surface and on their neural progeny. Moreover, atropine, an mAchR antagonist, blocks the enhancement and inhibits the subsequent differentiation of NSCs. Further understanding of this neural-nutrition role of Ach might elucidate fetal brain development, the brain's response to injury, and learning and memory.     

Effects of retinoid and thyroid receptors during development of the inner ear

The sensory epithelia of the vertebrate inner ear are comprised of a complex pattern of hair cells and supporting cells. Several different families of signaling molecules have been shown to play a role in the development and maintenance of this structure. In particular, the steroid/thyroid receptor superfamily, and specifically retinoid and thyroid receptors appear to influence the determination, differentiation, maintenance, and possibly regeneration, of the sensory epithelia of the vertebrate inner ear. Clinical and experimental evidence demonstrates that changes in the relative availability of retinoic acid and thyroid hormone, the ligands for retinoid and thyroid receptors, result in perturbations in the development of hair cell sensory epithelia. Retinoic acid and retinoid receptors appear to play a role in early developmental events including cellular proliferation and determination whereas thyroid hormone and thyroid receptors appear to play a role in later events including differentiation and maintenance.     

Cannabinoid receptors and their endogenous ligands

Delta9-Tetrahydrocannabinol, a major psychoactive component of marijuana, has been shown to interact with specific cannabinoid receptors, thereby eliciting a variety of pharmacological responses in experimental animals and human. In 1990, the gene encoding a cannabinoid receptor (CB1) was cloned. This prompted the search for endogenous ligands. In 1992, N-arachidonoylethanolamine (anandamide) was isolated from pig brain as an endogenous ligand, and in 1995, 2-arachidonoylglycerol was isolated from rat brain and canine gut as another endogenous ligand. Both anandamide and 2-arachidonoylglycerol exhibit various cannabimimetic activities. The results of structure-activity relationship experiments, however, revealed that 2-arachidonoylglycerol, but not anandamide, is the intrinsic natural ligand for the cannabinoid receptor. 2-Arachidonoylglycerol is a degradation product of inositol phospholipids that links the function of cannabinoid receptors with the enhanced inositol phospholipid turnover in stimulated tissues and cells. The possible physiological roles of cannabinoid receptors and 2-arachidonoylglycerol in various mammalian tissues such as those of the nervous system are discussed.     

Localization of cannabinoid receptors CB1, CB2, GPR55, and PPARα in the canine gastrointestinal tract

The endocannabinoid system (ECS) is composed of cannabinoid receptors, their endogenous ligands, and the enzymes involved in endocannabinoid turnover. Modulating the activity of the ECS may influence a variety of physiological and pathophysiological processes. A growing body of evidence indicates that activation of cannabinoid receptors by endogenous, plant-derived, or synthetic cannabinoids may exert beneficial effects on gastrointestinal inflammation and visceral pain. The present ex vivo study aimed to investigate immunohistochemically the distribution of cannabinoid receptors CB1, CB2, G protein-coupled receptor 55 (GPR55), and peroxisome proliferation activation receptor alpha (PPARα) in the canine gastrointestinal tract. CB1 receptor immunoreactivity was observed in the lamina propria and epithelial cells. CB2 receptor immunoreactivity was expressed by lamina propria mast cells and immunocytes, blood vessels, and smooth muscle cells. Faint CB2 receptor immunoreactivity was also observed in neurons and glial cells of the submucosal plexus. GPR55 receptor immunoreactivity was expressed by lamina propria macrophages and smooth muscle cells. PPARα receptor immunoreactivity was expressed by blood vessels, smooth muscle cells, and glial cells of the myenteric plexus. Cannabinoid receptors showed a wide distribution in the gastrointestinal tract of the dog. Since cannabinoid receptors have a protective role in inflammatory bowel disease, the present research provides an anatomical basis supporting the therapeutic use of cannabinoid receptor agonists in relieving motility disorders and visceral hypersensitivity in canine acute or chronic enteropathies.     

Integrating information from different senses in the auditory cortex

Multisensory integration was once thought to be the domain of brain areas high in the cortical hierarchy, with early sensory cortical fields devoted to unisensory processing of inputs from their given set of sensory receptors. More recently, a wealth of evidence documenting visual and somatosensory responses in auditory cortex, even as early as the primary fields, has changed this view of cortical processing. These multisensory inputs may serve to enhance responses to sounds that are accompanied by other sensory cues, effectively making them easier to hear, but may also act more selectively to shape the receptive field properties of auditory cortical neurons to the location or identity of these events. We discuss the new, converging evidence that multiplexing of neural signals may play a key role in informatively encoding and integrating signals in auditory cortex across multiple sensory modalities. We highlight some of the many open research questions that exist about the neural mechanisms that give rise to multisensory integration in auditory cortex, which should be addressed in future experimental and theoretical studies.     

肾上腺素受体在大鼠中枢神经系统发育中的作用研究

去甲肾上腺素和肾上腺素受体在大鼠中枢神经系统（CNS）的发育早期开始表达,且受体表达的时空模式与脑发育过程中某些脑区神经元的迁移和分化相一致,这提示去甲肾上腺素在中枢神经系统的发育中具有重要作用。本文论述了胚胎和新出生的大鼠不同脑区肾上腺素受体mRNA的表达模式以及这些受体对体外培养的成熟细胞和相应的前体细胞的调控效应,通过离体和在体研究的实验证据,阐述肾上腺素受体介导了去甲肾上腺素对神经前体细胞的增殖、生长、迁移、分化和存活的调控作用。进一步明确了去甲肾上腺素在CNS发育中所起的作用,使其可作为成体脑修复的助动剂而赋予新的意义。     

神经干细胞迁移的研究进展

神经干细胞的定向迁移是胚胎神经系统发育的先决条件,同时在成体组织的许多生理、病理过程中也起着重要作用;研究发现,许多神经退行性疾病都与神经干细胞迁移的缺陷相关。近年来,越来越多的证据表明,无论是内源性的还是移植的神经干细胞都有向大脑损伤部位迁移的特性,显示出神经干细胞用于神经再生及损伤修复治疗的潜能。该文着重在神经干细胞的基本特性以及神经干细胞定向迁移的细胞与分子机制研究等方面进行了综述。     

New natural noncannabinoid ligands for cannabinoid type-2 (CB2) receptors

Since the discovery that Delta 9-tetrahydrocannabinol and related cannabinoids from Cannabis sativa L. act on specific physiological receptors in the human body and the subsequent elucidation of the mammalian endogenous cannabinoid system, no other natural product class has been reported to mimic the effects of cannabinoids. We recently found that N-alkyl amides from purple coneflower (Echinacea spp.) constitute a new class of cannabinomimetics, which specifically engage and activate the cannabinoid type-2 (CB2) receptors. Cannabinoid type-1 (CB1) and CB2 receptors belong to the family of G protein-coupled receptors and are the primary targets of the endogenous cannabinoids N-arachidonoyl ethanolamine and 2-arachidonoyl glyerol. CB2 receptors are believed to play an important role in distinct pathophysiological processes, including metabolic dysregulation, inflammation, pain, and bone loss. CB2 receptors have, therefore, become of interest as new targets in drug discovery. This review focuses on N-alkyl amide secondary metabolites from plants and underscores that this group of compounds may provide novel lead structures for the development of CB2-directed drugs.