Category Archives: Endocannabinoid System
The Endocannabinoid System Controls Key Epileptogenic Circuits in the Hippocampus
“Balanced control of neuronal activity is central in maintaining function and viability of neuronal circuits. The endocannabinoid system tightly controls neuronal excitability. Here, we show that endocannabinoids directly target hippocampal glutamatergic neurons to provide protection against acute epileptiform seizures in mice. Functional CB1 cannabinoid receptors are present on glutamatergic terminals of the hippocampal formation, colocalizing with vesicular glutamate transporter 1 (VGluT1). Conditional deletion of the CB1 gene either in cortical glutamatergic neurons or in forebrain GABAergic neurons, as well as virally induced deletion of the CB1 gene in the hippocampus, demonstrate that the presence of CB1 receptors in glutamatergic hippocampal neurons is both necessary and sufficient to provide substantial endogenous protection against kainic acid (KA)-induced seizures. The direct endocannabinoid-mediated control of hippocampal glutamatergic neurotransmission may constitute a promising therapeutic target for the treatment of disorders associated with excessive excitatory neuronal activity.”
“In conclusion, our study reveals a mechanism through which the endocannabinoid system is able to provide on-demand protection against acute behavioral seizures. CB1 expression on hippocampal glutamatergic circuits accounts for this protection and might represent a suitable target for the treatment of neurological disorders associated with excessive neuronal excitation.”
Endocannabinoids and Their Implications for Epilepsy
“This review covers the main features of a newly discovered intercellular signaling system in which endogenous ligands of the brain’s cannabinoid receptors, or endocannabinoids, serve as retrograde messengers that enable a cell to control the strength of its own synaptic inputs. Endocannabinoids are released by bursts of action potentials, including events resembling interictal spikes, and probably by seizures as well. Activation of cannabinoid receptors has been implicated in neuroprotection against excitotoxicity and can help explain the anticonvulsant properties of cannabinoids that have been known since antiquity.”
“Cannabis in its various forms, including marijuana and hashish, is produced from the flowers and leaves of the hemp plant, Cannabis sativa. Through their primary psychoactive ingredient, Δ9-tetrahydrocannabinol (THC), these drugs affect the central nervous system by activating specific membrane-bound receptors. The primary brain receptors, cannabinoid receptors type 1 (CB1), are G protein–coupled, seven-transmembrane domain proteins that share numerous similarities with heterotrimeric G protein–coupled receptors for conventional neurotransmitters such as γ-aminobutyric acid (GABA) and glutamate. The CB1s bind THC with a high degree of selectivity and are heterogeneously distributed throughout the brain. Inasmuch as THC is a plant-derived compound not produced in mammals, endogenous ligands must exist for the cannabinoid receptor, that is, endocannabinoids. Indeed, several endogenous ligands for CB1 have been discovered, with anandamide being the first. Anandamide and 2-arachidonoyl glycerol (2-AG), are thought to be the major brain endocannabinoids, with regional differences in which one or the other predominates. Endocannabinoids have been strongly implicated in a growing variety of physiologic phenomena, including regulation of eating, anxiety, pain, extinction of aversive memories, and neuroprotection. Potent agonists and antagonists for CB1 exist and may serve as the foundation of new therapeutic strategies for treating pathologies. The voluminous work summarized here has been extensively covered in recent reviews on cannabinoid neurochemistry and pharmacology as well as neurophysiology. This review focuses on the neurophysiology of the endocannabinoid systems.”
“Conclusion
From what is known about their synthesis and release, endocannabinoids should be produced under many conditions of increased neuronal excitability and specific intercellular signaling. For example, an epileptic seizure, with its large swings in transmembrane voltage, increases in intracellular calcium, and marked release of neurotransmitters, such as acetylcholine and glutamate, should prominently release endocannabinoids. Indeed, seizures induced by kainic acid (a glutamate agonist) increase hippocampal levels of anandamide in normal and wild-type mice. Intriguingly, CB1 knockout mice and normal mice treated with a CB1 antagonist had more pronounced seizures and more severe excitotoxic cell death than untreated normal mice. Although the detailed mechanisms of neuroprotection have not been worked out, the rapid increases in expression of the immediate early genes, c-fos and zipf268, and subsequent increase in brain-derived neurotrophic factor (BDNF) normally induced by kainic acid, were absent in the CB1 knockout mice. The results complement previous evidence that exogenous cannabinoids can be neuroprotective and show that CB1 activation by seizure-induced release of endocannabinoids also is normally neuroprotective.”
“The important new directions being opened by investigations of endocannabinoids underscore the prescient opinion of Robert Christison, who, in 1848, noting its various beneficial effects, argued that cannabis “is a remedy which deserves a more extensive inquiry…””
The Endogenous Cannabinoid System Regulates Seizure Frequency and Duration in a Model of Temporal Lobe Epilepsy
“Several lines of evidence suggest that cannabinoid compounds are anticonvulsant. However, the anticonvulsant potential of cannabinoids and, moreover, the role of the endogenous cannabinoid system in regulating seizure activity has not been tested in an in vivo model of epilepsy that is characterized by spontaneous, recurrent seizures. Here, using the rat pilocarpine model of epilepsy, we show that the marijuana extract Δ9-tetrahydrocannabinol (10 mg/kg) as well as the cannabimimetic, 4,5-dihydro-2-methyl-4(4-morpholinylmethyl)-1-(1-naphthalenyl-carbonyl)-6H-pyrrolo[3,2,1-i,j]quinolin-6-one [R(+)WIN55,212 (5 mg/kg)], completely abolished spontaneous epileptic seizures. Conversely, application of the cannabinoid CB1 receptor (CB1) antagonist, N-(piperidin-1-yl-5-(4-chlorophenyl)-1-(2,4-dichlorophenyl)-4-methyl-1H-pyrazole-3-carboxamidehydrochloride (SR141716A), significantly increased both seizure duration and frequency. In some animals, CB1 receptor antagonism resulted in seizure durations that were protracted to a level consistent with the clinical condition status epilepticus… These data indicate not only anticonvulsant activity of exogenously applied cannabinoids but also suggest that endogenous cannabinoid tone modulates seizure termination and duration through activation of the CB1 receptor… By demonstrating a role for the endogenous cannabinoid system in regulating seizure activity, these studies define a role for the endogenous cannabinoid system in modulating neuroexcitation and suggest that plasticity of the CB1 receptor occurs with epilepsy.”
“Characterized by spontaneously recurrent seizures, epilepsy is one of the most common neurological conditions. Understanding the factors that contribute to seizure initiation and termination has important implications for our ability to treat epilepsy and for the potential development of novel anticonvulsant agents. Previous evidence has suggested that the endogenous cannabinoid system may be a novel locus of anticonvulsant activity in the brain. Using the maximal electroshock model of short-term seizure, our laboratory determined that cannabinoid compounds block seizure spread via a cannabinoid CB1 receptor-dependent mechanism. Further study revealed that application of a CB1 receptor antagonist lowered the electroshock seizure threshold, indicating that elimination of endogenous cannabinoid tone at the CB1 receptor may increase seizure susceptibility.”
“The CB1 receptor is the most highly expressed G-protein-coupled receptor in brain and has been implicated in regulation of neuronal excitability. The endogenous cannabinoids, arachidonylethanolamine and 2-arachidonylglycerol (2-AG), are synthesized “on demand” in response to sustained neuronal depolarization and elevated intracellular calcium levels; both of these events occur with seizure activity. The neuronal hyperexcitability that accompanies seizure discharge may stimulate endogenous cannabinoid synthesis and subsequently result in CB1 receptor activation. In light of cannabinoid effects on neurotransmission, increased CB1 receptor activation could influence seizure activity. However, no studies have evaluated the role of the endogenous cannabinoid system in an intact model of epilepsy.”
“This study was initiated to evaluate the role of the CB1 receptor and the endogenous cannabinoid system in regulating seizure activity in a long-term model of epilepsy. We used the pilocarpine model of temporal lobe, partial-complex epilepsy; a rat model of acquired, refractory epilepsy that produces spontaneous recurrent seizures for the lifetime of the animal. The pilocarpine model has been shown to closely resemble human refractory partial-complex epilepsy. In this study, seizure frequency and duration were determined by continuous electrographic and video recording of each epileptic animal. The CB1 receptor agonists R(+)WIN55,212 and Δ9-tetrahydrocannabinol (THC) were evaluated for anticonvulsant efficacy. In addition to agonist effects on seizure activity, the effect of CB1 receptor antagonism on seizure frequency and duration was evaluated using the specific antagonist SR141716A. Hippocampal levels of 2-AG during short-term, pilocarpine-induced seizures were measured to determine whether a correlation exists between endogenous cannabinoid synthesis and seizure activity. In addition, Western blot and immunohistochemical analyses were used to evaluate hippocampal CB1 receptor protein expression in the brains of chronically epileptic and sham control rats. The findings presented suggest an anticonvulsant role for the endogenous cannabinoid system and demonstrate that long-term plasticity of the CB1 receptor occurs with epilepsy.”
“Therapeutic Implications for Cannabinoids in the Treatment of Epilepsy. Seizures in patients with refractory, partial-complex epilepsy can be difficult to control despite the use of currently available anticonvulsant medications and surgical interventions. Therefore, there is a clear need for the development of more effective anticonvulsant agents. Some epilepsy patients, seeking alternative treatments, have perceived improvement with marijuana. This has prompted several countries to consider the legalization of marijuana for epilepsy treatment. The pilocarpine model represents a refractory epileptic condition that is not readily treated by conventional anticonvulsants. Our results demonstrate that activation of the CB1 receptor by cannabinoid drugs and possibly endogenous ligands significantly alters seizure activity and is more effective than conventional anticonvulsants in treating the refractory seizures produced in the pilocarpine model. Although the dose dependence and long-term effects of cannabinoid administration on epilepsy must be further investigated, the results presented here provide evidence that warrants a comprehensive assessment of cannabinoid use in the control of refractory epilepsy via the use of animal models and placebo-controlled clinical trials. Although the psychoactive side effects of cannabinoids make their use in the treatment of epilepsy impractical, understanding the mechanisms of endogenous cannabinoid-mediated anticonvulsant action may lead to the development of novel compounds that do not manifest behavioral toxicity. Further investigation of the cannabinoid anticonvulsant phenomenon may illuminate novel therapeutic targets for the treatment of temporal lobe epilepsy as well as more clearly define the physiological function of the endogenous cannabinoid system in brain.”
Marijuana, endocannabinoids, and epilepsy: Potential and challenges for improved therapeutic intervention.
Abstract
“Phytocannabinoids isolated from the cannabis plant have broad potential in medicine that has been well recognized for many centuries. It is presumed that these lipid soluble signaling molecules exert their effects in both the central and peripheral nervous system in large part through direct interaction with metabotropic cannabinoid receptors. These same receptors are also targeted by a variety of endogenous cannabinoids including 2-arachidonoyl glycerol and anandamide. Significant effort over the last decade has produced an enormous advance in our understanding of both the cellular and the synaptic physiology of endogenous lipid signaling systems. This increase in knowledge has left us better prepared to carefully evaluate the potential for both natural and synthetic cannabinoids in the treatment of a variety of neurological disorders. In the case of epilepsy, long standing interest in therapeutic approaches that target endogenous cannabinoid signaling systems are, for the most part, not well justified by available clinical data from human epileptics. Nevertheless, basic science experiments have clearly indicated a key role for endogenous cannabinoid signaling systems in moment to moment regulation of neuronal excitability. Further it has become clear that these systems can both alter and be altered by epileptiform activity in a wide range of in vitro and in vivo models of epilepsy. Collectively these observations suggest clear potential for effective therapeutic modulation of endogenous cannabinoid signaling systems in the treatment of human epilepsy, and in fact, further highlight key obstacles that would need to be addressed to reach that goal.”
Marijuana-Derived Compound Targets Pain, Inflammation
“Researchers are developing a marijuana-derived synthetic compound to relieve pain and inflammation without the mood-altering side effects associated with other marijuana based drugs.
They say the compound could improve treatment of a variety of conditions, including chronic pain, arthritis and multiple sclerosis. Their findings were presented at the 224th national meeting of the American Chemical Society, the world’s largest scientific society.
The compound, called ajulemic acid, has produced encouraging results in animal studies of pain and inflammation. It is undergoing tests in a group of people with chronic pain and could be available by prescription within two to three years, the researchers say.
“We believe that [the compound] will replace aspirin and similar drugs in most applications primarily because of a lack of toxic side effects,” says Sumner Burstein, Ph.D., lead investigator in the study and a professor in the department of biochemistry and molecular pharmacology at the University of Massachusetts Medical School in Worcester. “The indications so far are that it’s safe and effective,” he added.”
Read more: http://www.sciencedaily.com/releases/2002/08/020822071026.htm
The cannabinoid acids: nonpsychoactive derivatives with therapeutic potential.
Abstract
“The discovery of carboxylic acid metabolites of the cannabinoids (CBs) dates back more than three decades. Their lack of psychotropic activity was noted early on, and this resulted in a total absence of further research on their possible role in the actions of the CBs. More recent studies have revealed that the acids possess both analgesic and anti-inflammatory properties and may contribute to the actions of the parent drug. A synthetic analog showed similar actions at considerably lower doses. In this review, a brief survey of the extensive literature on metabolism of delta 9-tetrahydrocannabinol to the acids is presented, while more emphasis is given to the recent findings on the biological actions of this class of CBs. A possible mechanism involving effects on eicosanoids for some of these actions is also suggested. Finally, an analogy with a putative metabolite of anandamide, an endogenous CB, is discussed.”
Inhibitory effect of cannabichromene, a major non-psychotropic cannabinoid extracted from Cannabis sativa, on inflammation-induced hypermotility in mice.
“BACKGROUND AND PURPOSE:
Cannabichromene (CBC) is a major non-psychotropic phytocannabinoid that inhibits endocannabinoid inactivation and activates the transient receptor potential ankyrin-1 (TRPA1). Both endocannabinoids and TRPA1 may modulate gastrointestinal motility. Here, we investigated the effect of CBC on mouse intestinal motility in physiological and pathological states.”
“CONCLUSION AND IMPLICATIONS:
CBC selectively reduces inflammation-induced hypermotility in vivo in a manner that is not dependent on cannabinoid receptors or TRPA1.”
Cannabinoid receptor type 2 activation induces a microglial anti-inflammatory phenotype and reduces migration via MKP induction and ERK dephosphorylation
“Cannabinoid receptor type 2 (CBR2) inhibits microglial reactivity through a molecular mechanism yet to be elucidated. We hypothesized that CBR2 activation induces an anti-inflammatory phenotype in microglia by inhibiting extracellular signal-regulated kinase (ERK) pathway, via mitogen-activated protein kinase-phosphatase (MKP) induction. MKPs regulate mitogen activated protein kinases, but their role in the modulation of microglial phenotype is not fully understood.”
“Our results uncover a cellular microglial pathway triggered by CBR2 activation. These data suggest that the reduction of pro-inflammatory factors and microglial migration via MKP-3 induction is part of the mechanism of action of CBR2 agonists. These findings may have clinical implications for further drug development.”
“In summary, our current results uncovered a cellular mechanism of action of CBR2 agonists that produces a microglial anti-inflammatory phenotype, which may modulate microglial motility in vivo. We identified MKP-3 and microglial migration as potential new targets for drug development. The clinical utility of CBR2 agonists is supported by their analgesic efficacy and their lack of neurological side effects in animal models of postoperative or neuropathic pain.”
The anti-inflammatory activities of cannabinoid receptor ligands in mouse peritonitis models.
“The present results add to the body of literature indicating that cannabinoid receptor ligands have diverse anti-inflammatory properties.” http://www.ncbi.nlm.nih.gov/pubmed/11734194