The endocannabinoid system in the regulation of emotions throughout lifespan: a discussion on therapeutic perspectives

Alterations in emotion regulation processes may form the basis of psychopathologies. The endocannabinoid (eCB) system, composed of endogenous ligands, the enzymatic machinery in charge of their metabolism and the specific metabotropic receptors, has emerged as a major neuromodulatory system critically involved in the control of emotional homeostasis and stress responsiveness. Data from animal models indicate that the eCB system plays a key role in brain development, and is probably involved in the control of emotional states from early developmental stages. The present review summarizes the latest information on the role of the eCB system in emotionality and anxiety-related disorders throughout the lifespan. Putative therapeutic strategies based on the pharmacological modulation of this system will be discussed. Given the fact that the pharmacological modulation of the eCB system has recently arisen as a promising strategy in the management of anxiety and mood disorders, the potential efficacy of this pharmacological approach (i.e. blockers of the catabolic pathway) will be discussed, as well as pharmacological alternatives such as modulators of cannabinoid receptors other than the classical CB1 receptor, or administration of other plant-derived compounds (e.g. cannabidiol).     

Targeting the endocannabinoid system: future therapeutic strategies

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The endocannabinoid system and cancer: therapeutic implication

The endocannabinoid system is implicated in a variety of physiological and pathological conditions (inflammation, immunomodulation, analgesia, cancer and others). The main active ingredient of cannabis, Δ(9) -tetrahydrocannabinol (Δ(9) -THC), produces its effects through activation of CB(1) and CB(2) receptors. CB(1) receptors are expressed at high levels in the central nervous system (CNS), whereas CB(2) receptors are concentrated predominantly, although not exclusively, in cells of the immune system. Endocannabinoids are endogenous lipid-signalling molecules that are generated in the cell membrane from phospholipid precursors. The two best characterized endocannabinoids identified to date are anandamide (AEA) and 2-arachidonoylglycerol (2-AG). Here we review the relationship between the endocannabinoid system and anti-tumour actions (inhibition of cell proliferation and migration, induction of apoptosis, reduction of tumour growth) of the cannabinoids in different types of cancer. This review will focus on examining how activation of the endocannabinoid system impacts breast, prostate and bone cancers in both in vitro and in vivo systems. The therapeutic potential of cannabinoids for cancer, as identified in clinical trials, is also discussed. Identification of safe and effective treatments to manage and improve cancer therapy is critical to improve quality of life and reduce unnecessary suffering in cancer patients. In this regard, cannabis-like compounds offer therapeutic potential for the treatment of breast, prostate and bone cancer in patients. Further basic research on anti-cancer properties of cannabinoids as well as clinical trials of cannabinoid therapeutic efficacy in breast, prostate and bone cancer is therefore warranted.     

Interactions between central cholinergic agents and amphetamine in mice

Summary Central cholinergic blockade produced by the administration of scopolamine hydrobromide significantly increased the toxicity of amphetamine in aggregated mice. Stimulation of the central cholinergic system by Tremorine, on the other hand, afforded protection against the lethal effect of amphetamine in aggregated mice, reduced spontaneous motor activity, and antagonized the effect of amphetamine on motor activity.     

The endocannabinoid signaling system: pharmacological and therapeutic aspects

Since the discovery of anandamide in 1992, our knowledge of the endocannabinoid system and its physiological effects has increased greatly, not the least as a result of the availability of compounds affecting endocannabinoid function. In the present review, the pharmacology of the endocannabinoid system is discussed. At present, there are no compounds selectively inhibiting the synthesis of anandamide, and the mechanisms by which anandamide release and reuptake are blocked are a matter for current debate. In contrast, selective agonists and inverse agonists at the CB1 and CB2 receptors have been well characterised, as have inhibitors of the metabolism of anandamide by fatty acid amide hydrolase. Accumulating evidence has suggested that such compounds may be useful for the treatment of a number of disorders. With respect to the treatment of pain, topical CB1 agonists and CB2 agonists may prove therapeutically useful, and there is evidence that the non-steroidal inflammatory agent indomethacin produces effects secondary to activation of the endocannabinoid system. Modulation of the endocannabionid system may also produce neuroprotective effects, although present data would suggest that the observed effects are highly dependent upon the nature of the neurotoxic insult.     

Interactions between phencyclidine and cholinergic excitation of hippocampal pyramidal neurons

The interaction between phencyclidine and acetylcholine-evoked responses of hippocampal pyramidal neurons was investigated in normal and catecholamine-depleted rats. Phencyclidine antagonized the acetylcholine-induced excitations in both preparations. However, in the majority of cases, this effect was observed only at doses of phencyclidine which also manifested nonspecific membrane stabilization. In contrast, phencyclidine-induced decreases in firing rate, which have been shown to be mediated by catecholamines, occurred at doses of phencyclidine which do not cause local anesthesia. Taken together, these data suggest that the catecholaminergically-mediated effects of phencyclidine may be more important in the hippocampus.     

Muscarinic and nicotinic cholinergic agonists: structural analogies and discrepancies

Acetylcholine, the first identified neurotransmitter acts on both types of cholinergic receptors. Both rigid and flexible derivatives of acetylcholine could either be selective muscarinic or selective nicotinic agonists while some compounds show activity at both receptor subclasses. Earlier structure-activity considerations are revisited. Ligand and receptor based calculations have been applied in the hope to identify characteristic geometrical and steric requirements for the activity on the receptor subtypes. Results are treated critically and applied cautiously for predicting selective structural requirements by the cholinergic receptor subclasses.     

The endocannabinoid system and its therapeutic exploitation

The term 'endocannabinoid' - originally coined in the mid-1990s after the discovery of membrane receptors for the psychoactive principle in Cannabis, Delta9-tetrahydrocannabinol and their endogenous ligands - now indicates a whole signalling system that comprises cannabinoid receptors, endogenous ligands and enzymes for ligand biosynthesis and inactivation. This system seems to be involved in an ever-increasing number of pathological conditions. With novel products already being aimed at the pharmaceutical market little more than a decade since the discovery of cannabinoid receptors, the endocannabinoid system seems to hold even more promise for the future development of therapeutic drugs. We explore the conditions under which the potential of targeting the endocannabinoid system might be realized in the years to come.     

The endocannabinoid system: current pharmacological research and therapeutic possibilities

In the relatively short period of time since the discovery of cannabinoid receptors and their endogenous ligands, the endocannabinoids, an intensive research effort has resulted in the identification of agents that affect all aspects of the endocannabinoid system. The cannabinoid(1) receptor antagonist rimonabant is in phase III clinical trials for the treatment of obesity and as an aid to smoking cessation, and cannabinoid(2) receptor agonists are promising in animal models of inflammatory and neuropathic pain. In the present MiniReview, the endocannabinoid system is described from a pharmacological perspective. The main topics covered are: the mechanism of action of cannabinoid(2) receptor agonists; identification of the endocannabinoid(s) involved in retrograde signalling; the elusive mechanism(s) of endocannabinoid uptake; therapeutic possibilities for fatty acid amide hydrolase inhibitors; and the cyclooxygenase-2 and lipoxygenase-derived biologically active metabolites of the endocannabinoids.     

COPD: preclinical models and emerging therapeutic targets

ABSTRACT

Introduction: Chronic obstructive pulmonary disease (COPD) is a leading cause of morbidity and mortality worldwide. Preclinical models of COPD have recently been developed. In those models, COPD/emphysema has been commonly induced using different toxic agents such as elastase, proteolytic enzymes and chronic exposure to cigarette smoke (CS).

Areas covered: The most relevant features of preclinical models of COPD, namely chronic exposure to CS and other agents (proteases and microorganisms), cardiovascular effects, surfactant protein-D, airway remodeling and inflammation, lung regeneration potential and mesenchymal stromal cell therapy are described. The most relevant publications on the topic of interest were selected from Pubmed.

Expert opinion: Preclinical models of COPD are key for understanding the underlying biology and pathophysiology of the disease and for the discovery of therapeutic targets. Enhanced biological insights will help discover therapeutic targets for the treatment of COPD. This will enable health caregivers and doctors to improve treatment where a more holistic approach will be used. This will benefit the patients and society because the use of resources should be significantly lowered.     

New perspectives in the studies on endocannabinoid and cannabis: abnormal behaviors associate with CB1 cannabinoid receptor and development of therapeutic application

Delta9-tetrahydrocannabinol (Delta9-THC), the major psychoactive component of marijuana, induces catalepsy-like immobilization and impairment of spatial memory in rats. Delta9-THC also induces aggressive behavior in isolated housing stress. These abnormal behaviors could be counteracted by SR141716A, a CB1 cannabinoid receptor antagonist. Also Delta9-THC inhibited release of glutamate in the dorsal hippocampus, but this inhibition could be antagonized by SR141716A in an in vivo microdialysis study. Moreover, NMDA and AMPA-type glutamate receptor enhancers improved the Delta9-THC-induced impairment of spatial memory. On the other hand, Delta9-THC markedly inhibited the neurodegeneration in experimental allergic encephalomyelitis (EAE), an animal model of multiple sclerosis and reduced the elevated glutamate level of cerebrospinal fluid induced by EAE. These therapeutic effects on EAE were reversed by SR141716A. Taken together, our results demonstrate that the inhibition of glutamate release via activation of the CB1-cannabinoid receptor is one mechanism involved in Delta9-THC-induced impairment of spatial memory, and the therapeutic effect of Delta9-THC on EAE, and a Delta9-THC analog might provide an effective treatment for psychosis and neurodegenerative diseases.     

New perspectives in the studies on endocannabinoid and cannabis: cannabinoid receptors and schizophrenia

Cannabis consumption may induce psychotic states in normal individuals, worsen psychotic symptoms of schizophrenic patients, and may facilitate precipitation of schizophrenia in vulnerable individuals. Recent studies provide additional biological and genetic evidence for the cannabinoid hypothesis of schizophrenia. Examinations using [3H]CP-55940 or [3H]SR141716A revealed that the density of CB1 receptors, a central type of cannabinoid receptor, is increased in subregions of the prefrontal cortex in schizophrenia. Anandamide, an endogenous cannabinoid, is also increased in the CSF in schizophrenia. A genetic study revealed that the CNR1 gene, which encodes CB1 receptors, is associated with schizophrenia, especially the hebephrenic type. Individuals with a 9-repeat allele of an AAT-repeat polymorphism of the gene may have a 2.3-fold higher susceptibility to schizophrenia. Recent findings consistently indicate that hyperactivity of the central cannabinoid system is involved in the pathogenesis of schizophrenia or the neural mechanisms of negative symptoms.     

Targeting the endocannabinoid system for gastrointestinal diseases: future therapeutic strategies

Cannabinoids extracted from the marijuana plant (Cannabis sativa) and synthetic cannabinoids have numerous effects on gastrointestinal (GI) functions. Recent experimental data support an important role for cannabinoids in GI diseases. Genetic studies in humans have proven that defects in endocannabinoid metabolism underlie functional GI disorders. Mammalian cells have machinery, the so-called endocannabinoid system (ECS), to produce and metabolize their own cannabinoids in order to control homeostasis of the gut in a rapidly adapting manner. Pharmacological manipulation of the ECS by cannabinoids, or by drugs that raise the levels of endogenous cannabinoids, have shown beneficial effects on GI pathophysiology. This review gives an introduction into the functions of the ECS in the GI tract, highlights the role of the ECS in GI diseases and addresses its potential pharmacological exploitation.     

Targeting the endocannabinoid system for gastrointestinal diseases: future therapeutic strategies

Cannabinoids extracted from the marijuana plant (Cannabis sativa) and synthetic cannabinoids have numerous effects on gastrointestinal (GI) functions. Recent experimental data support an important role for cannabinoids in GI diseases. Genetic studies in humans have proven that defects in endocannabinoid metabolism underlie functional GI disorders. Mammalian cells have machinery, the so-called endocannabinoid system (ECS), to produce and metabolize their own cannabinoids in order to control homeostasis of the gut in a rapidly adapting manner. Pharmacological manipulation of the ECS by cannabinoids, or by drugs that raise the levels of endogenous cannabinoids, have shown beneficial effects on GI pathophysiology. This review gives an introduction into the functions of the ECS in the GI tract, highlights the role of the ECS in GI diseases and addresses its potential pharmacological exploitation.     

Phytoestrogens: pharmacological and therapeutic perspectives

Phytoestrogens exert different estrogen receptor-dependent and -independent pharmacological actions. They share with estrogens several structural features and show greater affinity for the newly described estrogen receptor-beta. Many hope that phytoestrogens can exert the cardioprotective, anti-osteoporotic and other beneficial effects of the estrogens used in hormone replacement therapy in postmenopausal women without adversely affecting the risk of thrombosis and the incidence of breast and uterine cancers. Although there are many positive indications that phytoestrogens can fulfil this role, it remains to be proven: controlled interventional studies are lacking, and many questions remain unanswered. This review analyzes, on the basis of available experimental and epidemiological studies, the pros and cons of phytoestrogen use and describes the potential tissue targets and mechanisms of action of phytoestrogens.     

Robust preclinical evidence in somatic cell genome editing: A key driver of responsible and efficient therapeutic innovations

Somatic cell genome editing (SCGE) is highly promising for therapeutic innovation. This study demonstrates that the majority of 46 preclinical SCGE studies discussed in reviews as particularly promising for clinical translation do not report on key elements for robust and confirmatory research practices: randomization, blinding, sample size calculation, data handling, pre-registration, multi-centric study design, and independent confirmation. We present the here-examined reporting standards and the new National Institutes of Health (NIH) funding criteria for SCGE research as a viable solution to protect this promising field from backlashes. We argue that the implementation of the novel methodological standards provides the opportunity for SCGE research to become a lighthouse example for trustworthy and useful translational research.     

Interactions between atropine and etomidate in cortical and spinal networks during cholinergic crisis

General anaesthesia is an important measure in the treatment of patients suffering from organophosphorus intoxication. The intravenous anaesthetic etomidate seems to be well suited for this purpose because of its stable haemodynamics. Here we raise the question whether the anaesthetic properties of etomidate are altered by cholinergic overstimulation and by the cholinergic antagonist atropine.