“Both the kynurenine and the endocannabinoid systems are involved in several neurological disorders, such as migraine and there are increasing number of reports demonstrating that there are interactions of two systems. Although their cooperation has not yet been implicated in migraine, there are reports suggesting this possibility. Additionally, the individual role of the endocannabinoid and kynurenine system in migraine is reviewed here first, focusing on endocannabinoids, kynurenine metabolites, in particular kynurenic acid. Finally, the function of NMDA and cannabinoid receptors in the trigeminal system-which has a crucial role in the pathomechanisms of migraine-will also be discussed. The interaction of the endocannabinoid and kynurenine system has been demonstrated to be therapeutically relevant in a number of pathological conditions, such as cannabis addiction, psychosis, schizophrenia and epilepsy. Accordingly, the cross-talk of these two systems may imply potential mechanisms related to migraine, and may offer new approaches to manage the treatment of this neurological disorder.” https://www.ncbi.nlm.nih.gov/pubmed/28758944 http://www.mdpi.com/1422-0067/18/8/1617]]>
Tag Archives: endocannabinoid system
Could Cannabidiol be a Treatment Option for Intractable Childhood and Adolescent Epilepsy?
“Epilepsy is an important disease that affects brain function, particularly in those under 3 years old. Uncontrolled seizures can affect cognitive function and quality of life. For these reasons, many trials have been conducted to investigate treatments for pediatric epilepsy. Currently, many antiepileptic drugs are available for the treatment of epilepsy, but cases of intractable epilepsy continue to exist.
In the past, cannabis has been tested as a potential treatment of intractable epilepsy.
Since 2013, 10 epilepsy centers in America have conducted research regarding the efficacy of cannabis to treat epilepsy. Cannabis has many components, including cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC). THC has psychoactive properties exerted through its binding of the cannabinoid receptor (CBR) whereas CBD is a CBR antagonist. The inhibition of epilepsy by CBD may therefore be caused by various mechanisms, although the detailed mechanisms of CBD actions have not yet been well defined. In most studies, trial doses of CBD were 2-5 mg/kg/day.
Several such studies have shown that CBD does have efficacy for treatment of epilepsy.
Reported adverse effects of CBD were mostly mild, including drowsiness, diarrhea, and decreased appetite. Severe adverse reactions requiring treatment, such as status epilepticus, have also been reported but it is not clear that this is related to CBD. Furthermore, many previous studies have been limited by an open-label or survey design. In future, double-blind, controlled trials are required and the use of CBD to treat other neurological problems should also be investigated.” https://www.ncbi.nlm.nih.gov/pubmed/28775950
“Most studies suggest anticonvulsant effects of CBD, and consider most adverse effects to be mild. It must be borne in mind that CBD is still illegal in many contexts. However, it has the potential to treat various neurological problems, including epilepsy.” http://www.j-epilepsy.org/journal/view.php?doi=10.14581/jer.17003
Modeling Neurodegenerative Disorders for Developing Cannabinoid-Based Neuroprotective Therapies.
“The increase in lifespan during the last 50 years, mainly in developed countries, has originated a progressive elevation in the incidence of chronic neurodegenerative disorders, for which aging is the key risk factor. This fact will definitively become the major biomedical challenge during the present century, in part because the expectation of a persisting elevation in the population older than 65 years over the whole population and, on the other hand, because the current lack of efficacious therapies to control these disorders despite years of intense research. This chapter will address this question and will stress the urgency of developing better neuroprotective and neurorepair strategies that may delay/arrest the progression of these disorders, reviewing the major needs to solve the causes proposed for the permanent failures experienced in recent years, e.g., to develop multitarget strategies, to use more predictive experimental models, and to identify early disease biomarkers. This chapter will propose the cannabinoids and their classic (e.g., endocannabinoid receptors and enzymes) and nonclassic (e.g., peroxisome proliferator-activated receptors, transcription factors) targets as a useful strategy for developing novel therapies for these disorders, based on their broad-spectrum neuroprotective profile, their activity as an endogenous protective system, the location of the endocannabinoid targets in cell substrates critical for neuronal survival, and their ability to serve for preservation and rescue, but also for repair and/or replacement, of neurons and glial cells against cytotoxic insults.” https://www.ncbi.nlm.nih.gov/pubmed/28750802 http://www.sciencedirect.com/science/article/pii/S0076687917301787?via%3Dihub]]>
Endocannabinoid Transport Proteins: Discovery of Tools to Study Sterol Carrier Protein-2.
“The endocannabinoid (eCB) neurotransmitter system regulates diverse neurological functions including stress and anxiety, pain, mood, and reward. Understanding the mechanisms underlying eCB regulation is critical for developing targeted pharmacotherapies to treat these and other neurologic disorders. Cellular studies suggest that the arachidonate eCBs, N-arachidonoylethanolamine (AEA) and 2-arachidonoylglycerol (2-AG), are substrates for intracellular binding and transport proteins, and several candidate proteins have been identified. Initial evidence from our laboratory indicates that the lipid transport protein, sterol carrier protein 2 (SCP-2), binds to the eCBs and can regulate their cellular concentrations. Here, we present methods for evaluating SCP-2 binding of eCBs and their application to the discovery of the first inhibitor lead molecules. Using a fluorescent probe displacement assay, we found SCP-2 binds the eCBs, AEA (Ki=0.68±0.05μM) and 2-AG (Ki=0.37±0.02μM), with moderate affinity. A series of structurally diverse arachidonate analogues also bind SCP-2 with Ki values between 0.82 and 2.95μM, suggesting a high degree of tolerance for arachidonic acid head group modifications in this region of the protein. We also report initial structure-activity relationships surrounding previously reported inhibitors of Aedis aegypti SCP-2, and the results of an in silico high-throughput screen that identified structurally novel SCP-2 inhibitor leads. The methods and results reported here provide the basis for a robust probe discovery effort to fully elucidate the role of facilitated transport mediated by SCP-2 in eCB regulation and function.” https://www.ncbi.nlm.nih.gov/pubmed/28750817 http://www.sciencedirect.com/science/article/pii/S007668791730174X?via%3Dihub ]]>
Combined deficiency of the Cnr1 and Cnr2 receptors protects against age-related bone loss by osteoclast inhibition.
“The endocannabinoid system plays a role in regulating bone mass and bone cell activity and inactivation of the type 1 (Cnr1) or type 2 (Cnr2) cannabinoid receptors influences peak bone mass and age-related bone loss. As the Cnr1 and Cnr2 receptors have limited homology and are activated by different ligands, we have evaluated the effects of combined deficiency of Cnr1 and 2 receptors (Cnr1/2-/- ) on bone development from birth to old age and studied ovariectomy induced bone loss in female mice. The Cnr1/2-/- mice had accelerated bone accrual at birth when compared with wild type littermates, and by 3 months of age, they had higher trabecular bone mass. They were also significantly protected against ovariectomy-induced bone loss due to a reduction in osteoclast number. The Cnr1/2-/- mice had reduced age-related bone loss when compared with wild-type due to a reduction in osteoclast number. Although bone formation was reduced and bone marrow adiposity increased in Cnr1/2-/- mice, the osteoclast defect outweighed the reduction in bone formation causing preservation of bone mass with aging. This contrasts with the situation previously reported in mice with inactivation of the Cnr1 or Cnr2 receptors individually where aged-related bone loss was greater than in wild-type. We conclude that the Cnr1 and Cnr2 receptors have overlapping but nonredundant roles in regulating osteoclast and osteoblast activities. These observations indicate that combined inhibition of Cnr1 and Cnr2 receptors may be beneficial in preventing age-related bone loss, whereas blockade of individual receptors may be detrimental.” https://www.ncbi.nlm.nih.gov/pubmed/28752643 http://onlinelibrary.wiley.com/doi/10.1111/acel.12638/abstract]]>
The endocannabinoid system expression in the female reproductive tract is modulated by estrogen.
“The endocannabinoid system (ECS) is involved in several physiological events that resulted in a growing interest in its modulation. Moreover, the uterine levels of anandamide (AEA), the major endocannabinoid, must be tightly regulated to create proper embryo implantation conditions. However, there are no evidences about the regulation of AEA in uterus by estrogen. Thus, the aim of this study is to elucidate whether estradiol benzoate (EB) and tamoxifen (TAM) administration to ovariectomized (OVX) rats can induce changes in the expression of cannabinoid receptors and AEA-metabolic enzymes in uterus by evaluating gene transcription and protein levels by qPCR, Western blot and immunohistochemistry. In summary, these data collectively indicate that the expression of ECS components, as well as, the AEA and PGE2 levels in rat uterus is modulated by EB. Thus, estradiol may have a direct regulatory role in the modulation of ECS in female reproductive tissues.” https://www.ncbi.nlm.nih.gov/pubmed/28743542 http://linkinghub.elsevier.com/retrieve/pii/S0960076017301887]]>
Endocannabinoids in arthritis: current views and perspective.
“Preclinical and clinical studies using cannabis-based therapy have been shown to provide both analgesia and anti-inflammatory effects, with an overall alleviation of clinical symptoms in animal models of arthritis, highlighting its promising therapeutic application for humans. Despite this, the development of cannabis-based therapeutics remains in its infancy, with further investigation into its efficacy and safety profile in patients still required. This synopsis reviews the various components of the endocannabinoid system in health and disease and their potential as therapeutic targets.” https://www.ncbi.nlm.nih.gov/pubmed/28736968 http://onlinelibrary.wiley.com/doi/10.1111/1756-185X.13146/abstract]]>
Neuroprotection by (endo)cannabinoids in glaucoma and retinal neurodegenerative diseases.
“Emerging neuroprotective strategies are being explored to preserve the retina from degeneration, that occurs in eye pathologies like glaucoma, diabetic retinopathy, age-related macular degeneration, and retinitis pigmentosa. Incidentally, neuroprotection of retina is a defending mechanism designed to prevent or delay neuronal cell death, and to maintain neural function following an initial insult, thus avoiding loss of vision. Numerous studies have investigated potential neuroprotective properties of plant-derived phytocannabinoids, as well as of their endogenous counterparts collectively termed endocannabinoids (eCBs), in several degenerative diseases of the retina. eCBs are a group of neuromodulators that, mainly by activating G protein-coupled type-1 and type-2 cannabinoid (CB1 and CB2) receptors, trigger multiple signal transduction cascades that modulate central and peripheral cell functions. A fine balance between biosynthetic and degrading enzymes that control the right concentration of eCBs has been shown to provide neuroprotection in traumatic, ischemic, inflammatory and neurotoxic damage of the brain. Since the existence of eCBs and their binding receptors was documented in the retina of numerous species (from fishes to primates), their involvement in the visual processing has been demonstrated, more recently with a focus on retinal neurodegeneration and neuroprotection. The aim of this review is to present a modern view of the endocannabinoid system, in order to discuss in a better perspective available data from preclinical studies on the use of eCBs as new neuroprotective agents, potentially useful to prevent glaucoma and retinal neurodegenerative diseases.” https://www.ncbi.nlm.nih.gov/pubmed/28738764 http://www.eurekaselect.com/154386/article]]>
Alleviation of Neuropathology by Inhibition of Monoacylglycerol Lipase in APP Transgenic Mice Lacking CB2 Receptors.
“Inhibition of monoacylglycerol lipase (MAGL), the primary enzyme that hydrolyzes the endocannabinoid 2-arachidonoylglycerol (2-AG) in the brain, produces profound anti-inflammatory and neuroprotective effects and improves synaptic and cognitive functions in animal models of Alzheimer’s disease (AD). However, the molecular mechanisms underlying the beneficial effects produced by inhibition of 2-AG metabolism are still not clear.
The cannabinoid receptor type 2 (CB2R) has been thought to be a therapeutic target for AD. Here, we provide evidence, however, that CB2R does not play a role in ameliorating AD neuropathology produced by inactivation of MAGL in 5XFAD APP transgenic mice, an animal model of AD.
Our results suggest that CB2R is not required in ameliorating neuropathology and preventing cognitive decline by inhibition of 2-AG metabolism in AD model animals.”