In vitro comparison of mouse and rat liver crude microsome preparations | The in vitro biotransformations of cannabidiol (CBD) and Δ9-tetrahydrocannabinol. Cannabidiol and δ9-tetrahydrocannabinol metabolism: In vitro comparison of mouse and rat liver crude microsome preparations. Author links. In vitro comparison of mouse and rat liver crude microsome preparations. of interactions between cannabidiol and Δ(9) -tetrahydrocannabinol in mice: Siemens AJ, Kalant H. Metabolism of delta1-tetrahydrocannabinol by rats tolerant .
rat mouse vitro of metabolism: Cannabidiol and δ9-tetrahydrocannabinol and In liver crude comparison
Similar to systemic administration, this treatment reduced catalepsy induced by haloperidol. Altogether, these results suggest that CBD acts in the dorsal striatum to improve haloperidol-induced catalepsy via postsynaptic 5-HT1A receptors. Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT 1A receptors without diminishing nervous system function or chemotherapy efficacy.
Paclitaxel PAC is associated with chemotherapy-induced neuropathic pain CIPN that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. We previously reported that chronic administration of the non-psychoactive cannabinoid cannabidiol CBD prevents PAC-induced mechanical and thermal sensitivity in mice.
The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task. CBD produced no conditioned rewarding effects and did not affect conditioned learning and memory. Furthermore, CBD treatment was devoid of conditioned rewarding effects or cognitive impairment and did not attenuate PAC-induced inhibition of breast cancer cell viability.
Cannabidiol inhibits paclitaxel-induced neuropathic pain through 5-HT1A receptors without diminishing nervous system function or chemotherapy efficacy. Background and Purpose Paclitaxel PAC is associated with chemotherapy-induced neuropathic pain CIPN that can lead to the cessation of treatment in cancer patients even in the absence of alternate therapies. Experimental Approach The ability of acute CBD pretreatment to prevent PAC-induced mechanical sensitivity was assessed, as was the effect of CBD on place conditioning and on an operant-conditioned learning and memory task.
The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical neuron cultures exposed to toxic levels of the excitatory neurotransmitter glutamate. Cannabinoids protected equally well against neurotoxicity mediated by N-methyl-d-aspartate receptors , 2-amino 4-butylhydroxyisoxazolyl propionic acid receptors , or kainate receptors.
The neuroprotection observed with cannabidiol and THC was unaffected by cannabinoid receptor antagonist, indicating it to be cannabinoid receptor independent. Previous studies have shown that glutamate toxicity may be prevented by antioxidants. Cannabidiol , THC and several synthetic cannabinoids all were demonstrated to be antioxidants by cyclic voltametry. Cannabidiol and THC also were shown to prevent hydroperoxide-induced oxidative damage as well as or better than other antioxidants in a chemical Fenton reaction system and neuronal cultures.
These data also suggest that the naturally occurring, nonpsychotropic cannabinoid, cannabidiol , may be a potentially useful therapeutic agent for the treatment of oxidative neurological disorders such as cerebral ischemia. Epilepsy is the most common neurological disorder, with over 50 million people worldwide affected. Recent evidence suggests that the transient receptor potential cation channel subfamily V member 1 TRPV1 may contribute to the onset and progression of some forms of epilepsy.
Since the two nonpsychotropic cannabinoids cannabidivarin CBDV and cannabidiol CBD exert anticonvulsant activity in vivo and produce TRPV1-mediated intracellular calcium elevation in vitro, we evaluated the effects of these two compounds on TRPV1 channel activation and desensitization and in an in vitro model of epileptiform activity. The prototypical TRPV1 agonist, capsaicin, produced similar, although not identical effects.
Molecular targets for cannabidiol and its synthetic analogues: Little is known on the possible molecular targets of this compound. We investigated whether CBD and some of its derivatives interact with vanilloid receptor type 1 VR1 , the receptor for capsaicin, or with proteins that inactivate the endogenous cannabinoid, anandamide AEA.
The effects of maximal doses of the two compounds were not additive. These findings suggest that VR1 receptors , or increased levels of endogenous AEA, might mediate some of the pharmacological effects of CBD and its analogues. In view of the facile high yield. The aim of this review is to present some of the recent publications on cannabidiol CBD; 2 , a major non-psychoactive constituent of Cannabis, and to give a general overview. Special emphasis is laid on biochemical and pharmacological advances, and on novel mechanisms recently put forward, to shed light on some of the pharmacological effects that can possibly be rationalized through these mechanisms.
The plethora of positive pharmacological effects observed with CBD make this compound a highly attractive therapeutic entity. Cannabidiol , extracted from Cannabis sativa, selectively inhibits inflammatory hypermotility in mice. Cannabidiol is a Cannabis-derived non-psychotropic compound that exerts a plethora of pharmacological actions, including anti-inflammatory, neuroprotective and antitumour effects, with potential therapeutic interest.
However, the actions of cannabidiol in the digestive tract are largely unexplored. In the present study, we investigated the effect of cannabidiol on intestinal motility in normal control mice and in mice with intestinal inflammation.
Motility in vivo was measured by evaluating the distribution of an orally administered fluorescent marker along the small intestine; intestinal inflammation was induced by the irritant croton oil; contractility in vitro was evaluated by stimulating the isolated ileum, in an organ bath, with ACh. In vivo, cannabidiol did not affect motility in control mice, but normalized croton oil-induced hypermotility. The inhibitory effect of cannabidiol was counteracted by the cannabinoid CB1 receptor antagonist rimonabant, but not by the cannabinoid CB2 receptor antagonist SR N-[-1S-endo-1,3,3-trimethyl bicyclo [2.
Cannabidiol did not reduce motility in animals treated with the fatty acid amide hydrolase FAAH inhibitor N-arachidonoylhydroxytryptamine, whereas loperamide was still effective. In vitro, cannabidiol inhibited ACh-induced contractions in the isolated ileum from both control and croton oil-treated mice. Cannabidiol selectively reduces croton oil-induced hypermotility in mice in vivo and this effect involves cannabinoid CB1 receptors and FAAH.
In view of its low toxicity in humans, cannabidiol may represent a good candidate to normalize motility in patients with inflammatory bowel disease. Over the past few years, considerable attention has focused on cannabidiol CBD , a major nonpsychotropic constituent of cannabis.
The authors present a review on the chemistry of CBD and discuss the anticonvulsive, antianxiety, antipsychotic, antinausea, and antirheumatoid arthritic properties of CBD. CBD does not bind to the known cannabinoid receptors , and its mechanism of action is yet unknown. It is possible that, in part at least, its effects are due to its recently discovered inhibition of anandamide uptake and hydrolysis and to its antioxidative effect.
Over the past few years, increasing public and political pressure has supported legalization of medical marijuana. One of the main thrusts in this effort has related to the treatment of refractory epilepsy-especially in children with Dravet syndrome-using cannabidiol CBD.
Despite initiatives in numerous states to at least legalize possession of CBD oil for treating epilepsy, little published evidence is available to prove or disprove the efficacy and safety of CBD in patients with epilepsy.
This review highlights some of the basic science theory behind the use of CBD, summarizes published data on clinical use of CBD for epilepsy, and highlights issues related to the use of currently available CBD products. Cannabidiol is the major nonpsychoactive component of Cannabis sativa.
Over the centuries, a number of medicinal preparations derived from C. These preparations were widely employed as analgesics by Western medical practitioners in the 19 th century 1.
More recently, there is clinical evidence suggesting efficacy in HIV-associated neuropathic pain, as well as spasms associated with multiple sclerosis 1.
Cannabidiol -induced apoptosis in human leukemia cells: A novel role of cannabidiol in the regulation of p22phox and Nox4 expression. In the current study, we examined the effects of the nonpsychoactive cannabinoid, cannabidiol , on the induction of apoptosis in leukemia cells. Exposure of leukemia cells to cannabidiol led to cannabinoid receptor 2 CB2 -mediated reduction in cell viability and induction in apoptosis. Furthermore, cannabidiol treatment led to a significant decrease in tumor burden and an increase in apoptotic tumors in vivo.
From a mechanistic standpoint, cannabidiol exposure resulted in activation of caspase-8, caspase-9, and caspase-3, cleavage of poly ADP-ribose polymerase, and a decrease in full-length Bid, suggesting possible cross-talk between the intrinsic and extrinsic apoptotic pathways. The role of the mitochondria was further suggested as exposure to cannabidiol led to loss of mitochondrial membrane potential and release of cytochrome c.
It is noteworthy that cannabidiol exposure led to an increase in reactive oxygen species ROS production as well as an increase in the expression of the NAD P H oxidases Nox4 and p22 phox.
Finally, cannabidiol exposure led to a decrease in the levels of p-p38 mitogen-activated protein kinase, which could be blocked by treatment with a CB2-selective antagonist or ROS scavenger. Together, the results from this study reveal that cannabidiol , acting through CB2 and regulation of Nox4 and p22 phox expression, may be a novel and highly selective treatment for leukemia.
Cannabidiol CBD is a non-psychoactive constituent of Cannabis sativa with potential to treat neurodegenerative diseases.
Its neuroprotection has been mainly associated with anti-inflammatory and antioxidant events; however, other mechanisms might be involved. CBD increased cell viability, differentiation, and the expression of axonal GAP and synaptic synaptophysin and synapsin I proteins. Its neuritogenic effect was not dependent or additive to NGF, but it was inhibited by Ka trkA inhibitor. CBD did not induce neuritogenesis in this cellular model, which supports the involvement of trkA receptors.
This is the first study to report the involvement of neuronal proteins and trkA in the neuroprotection of CBD. Cannabidiol CBD is a natural non-psychotropic cannabinoid from marijuana Cannabis sativa with anti-epileptic and anti-inflammatory properties.
CBD being a major component of Cannabis, our study indicates that marijuana may modulate or dysregulate the immune system by mobilizing MDSC. The Dravet syndrome is a complex childhood epilepsy disorder that is associated with drug-resistant seizures and a high mortality rate.
We studied cannabidiol for the treatment of drug-resistant seizures in the Dravet syndrome. In this double-blind, placebo-controlled trial, we randomly assigned children and young adults with the Dravet syndrome and drug-resistant seizures to receive either cannabidiol oral solution at a dose of 20 mg per kilogram of body weight per day or placebo, in addition to standard antiepileptic treatment.
The primary end point was the change in convulsive-seizure frequency over a week treatment period, as compared with a 4-week baseline period. The median frequency of convulsive seizures per month decreased from Adverse events that occurred more frequently in the cannabidiol group than in the placebo group included diarrhea, vomiting, fatigue, pyrexia, somnolence, and abnormal results on liver-function tests.
There were more withdrawals from the trial in the cannabidiol group. The effects of leptin in combination with a cannabinoid receptor 1 antagonist, AM , or cannabidiol on food intake and body weight in rats fed a high-fat or a free-choice high sugar diet.
High intake of fats and sugars has prompted a rapid growth in the number of obese individuals worldwide. The hormone had no significant effects, however, on either caloric intake, body weight or food preferences in rats fed an FC diet. This drug combination, however, had no effect on the consumption of high-sucrose chow. None of the drug combinations affected water consumption. It is concluded that the concomitant treatment with leptin and AM attenuated markedly body weight gain in rats maintained on high-calorie diets rich in fat and carbohydrates but did not affect preferences for sweet food.
We describe the varied clinical features and mutations in nine patients examined at the National Institutes of Health who were compound heterozygotes for XPD mutations but had different clinical phenotypes: The vitamin D stimulation ratio of CYP24 and osteopontin was associated with specific pairs of mutations reduced in 5, elevated in 1 but not correlated with distinct clinical phenotypes.
Thyroid receptor stimulation ratio for KLF9 was not significantly different from normal. Potential protective effects of cannabidiol on neuroanatomical alterations in cannabis users and psychosis: Cannabis use and the development of schizophrenic psychoses share a variety of similarities. Both start during late adolescence; go along with neuropsychological deficits, reduced activity, motivation deficits, and hallucinations suggesting impairment of similar brain structures.
In cannabis heavy users diminished regional gray and white matter volume was reported. Similar alterations were observed in the large literature addressing structural abnormalities in schizophrenia. Furthermore, in cannabis using schizophrenic patients, these brain alterations were especially pronounced.
Close relatives of schizophrenic patients showed greater cannabis-associated brain tissue loss than non-relatives indicating a genetically mediated particular sensitivity to brain tissue loss. Possible mechanisms for the induction of structural brain alterations are here discussed including impairments of neurogenesis, disturbance of endocannabinoids and diminished neuroplasticity.
Especially direct THC effects or via endocannabinoids may mediate diminished glutamatergic neurotransmission usually driving neuroplasticity. Correspondingly, alterations of the kynurenic acid blocking NMDA receptors may contribute to brain structure alterations. However, different cannabis compounds may exert opposite effects on the neuroanatomical changes underlying psychosis. This finding is further supported by several animal experiments supporting neuroprotective properties of CBD mainly via anti-oxidative effects, CB2 receptors or adenosine receptors.
We will discuss here the mechanisms by which CBD may reduce brain volume loss, including antagonism of THC, interactions with endocannabinoids, and mechanisms that specifically underlie antipsychotic properties of CBD. Prenatal exposure to phencyclidine produces abnormal behaviour and NMDA receptor expression in postpubertal mice. Several studies have shown the disruptive effects of non-competitive N-methyl-d-aspartate NMDA receptor antagonists on neurobehavioural development.
Based on the neurodevelopment hypothesis of schizophrenia, there is growing interest in animal models treated with NMDA antagonists at developing stages to investigate the pathogenesis of psychological disturbances in humans.
Previous studies have reported that perinatal treatment with phencyclidine PCP impairs the development of neuronal systems and induces schizophrenia-like behaviour.
This study investigated the long-term effects of prenatal exposure to PCP in mice. The prenatal PCP-treated mice showed hypersensitivity to a low dose of PCP in locomotor activity and impairment of recognition memory in the novel object recognition test at age 7 wk.
Meanwhile, the prenatal exposure reduced the phosphorylation of NR1, although it increased the expression of NR1 itself. Furthermore, these behavioural changes were attenuated by atypical antipsychotic treatment. Taken together, prenatal exposure to PCP produced long-lasting behavioural deficits, accompanied by the abnormal expression and dysfunction of NMDA receptors in postpubertal mice.
It is worth investigating the influences of disrupted NMDA receptors during the prenatal period on behaviour in later life. The novel endocannabinoid receptor GPR55 is activated by atypical cannabinoids but does not mediate their vasodilator effects. The purpose of the present study was to test the hypothesis that human recombinant GPR55 is activated by atypical cannabinoids and mediates vasodilator responses to these agents.
In GPRdeficient and wild-type littermate control mice, in vivo blood pressure measurement and isolated resistance artery myography were used to determine GPR55 dependence of atypical cannabinoid-induced haemodynamic and vasodilator responses. The abnormal cannabidiol vasodilator response was antagonized equivalently by O in both strains. These results demonstrate that while GPR55 is activated by atypical cannabinoids, it does not appear to mediate the vasodilator effects of these agents.
Cannabidiol improves brain and liver function in a fulminant hepatic failure-induced model of hepatic encephalopathy in mice. We investigated the effects of cannabidiol , a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT1A, on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide.
Neurological and motor functions were evaluated 2 and 3 days, respectively, after induction of hepatic failure, after which brains and livers were removed for histopathological analysis and blood was drawn for analysis of plasma liver enzymes.
In a separate group of animals, cognitive function was tested after 8 days and brain 5-HT levels were measured 12 days after induction of hepatic failure. Similarly, decreased motor activity in thioacetamide-treated mice was partially restored by cannabidiol. Increased plasma levels of ammonia, bilirubin and liver enzymes, as well as enhanced 5-HT levels in thioacetamide-treated mice were normalized following cannabidiol administration.
Likewise, astrogliosis in the brains of thioacetamide-treated mice was moderated after cannabidiol treatment. Therefore, the effects of cannabidiol may result from a combination of its actions in the liver and brain. Hepatic encephalopathy is a neuropsychiatric disorder of complex pathogenesis caused by acute or chronic liver failure.
We investigated the effects of cannabidiol , a non-psychoactive constituent of Cannabis sativa with anti-inflammatory properties that activates the 5-hydroxytryptamine receptor 5-HT 1A , on brain and liver functions in a model of hepatic encephalopathy associated with fulminant hepatic failure induced in mice by thioacetamide.
Female Sabra mice were injected with either saline or thioacetamide and were treated with either vehicle or cannabidiol. Neurological and cognitive functions were severely impaired in thioacetamide-treated mice and were restored by cannabidiol.
Cannabidiol restores liver function, normalizes 5-HT levels and improves brain pathology in accordance with normalization of brain function. Cannabidiol as potential anticancer drug. Indeed, cannabinoids possess anti-proliferative and pro-apoptotic effects and they are known to interfere with tumour neovascularization, cancer cell migration, adhesion, invasion and metastasization.
Cannabidiol , neuroprotection and neuropsychiatric disorders. Cannabidiol CBD is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa.
It has possible therapeutic effects over a broad range of neuropsychiatric disorders. It also has positive effects on attenuating psychotic-, anxiety- and depressive-like behaviors. Moreover, CBD affects synaptic plasticity and facilitates neurogenesis. The mechanisms of these effects are still not entirely clear but seem to involve multiple pharmacological targets.
In the present review, we summarized the main biochemical and molecular mechanisms that have been associated with the therapeutic effects of CBD, focusing on their relevance to brain function, neuroprotection and neuropsychiatric disorders.
Published by Elsevier Ltd. Altered localization, abnormal modification and loss of function of Sigma receptor -1 in amyotrophic lateral sclerosis. Intracellular accumulations of mutant, misfolded proteins are major pathological hallmarks of amyotrophic lateral sclerosis ALS and related disorders. In the present study, we found that levels of the SigR1 protein were reduced in lumbar ALS patient spinal cord. SigR1 was abnormally accumulated in enlarged C-terminals and endoplasmic reticulum ER structures of alpha motor neurons.
These accumulations co-localized with the 20s proteasome subunit. Along with the accumulation of SigR1 and several other proteins involved in protein quality control, severe disturbances in the unfolded protein response and impairment of protein degradation pathways were detected in the above-mentioned cell culture systems. Finally, pharmacological activation of SigR1 induced the clearance of mutant protein aggregates in these cells.
Our results support the notion that SigR1 is abnormally modified and contributes to the pathogenesis of ALS. Abstract Cannabidiol CBD , a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. It has been argued that this may occur also after oral administration in humans. However, the experimental conversion of CBD to THC and delta8-THC in simulated gastric fluid SGF is a highly artificial approach that deviates significantly from physiological conditions in the stomach; therefore, SGF does not allow an extrapolation to in vivo conditions.
In addition, the typical spectrum of side effects of THC, or of the very similar synthetic cannabinoid nabilone, as listed in the official Summary of Product Characteristics e.
Cannabidiol CBD , a major cannabinoid of hemp, does not bind to CB1 receptors and is therefore devoid of psychotomimetic properties. Cannabidiol restores intestinal barrier dysfunction and inhibits the apoptotic process induced by Clostridium difficile toxin A in Caco-2 cells. Clostridium difficile toxin A is responsible for colonic damage observed in infected patients.
Drugs able to restore Clostridium difficile toxin A-induced toxicity have the potential to improve the recovery of infected patients. The purpose of this study was to evaluate a the anti-apoptotic effect and b the mechanisms by which cannabidiol protects mucosal integrity in Caco-2 cells exposed to Clostridium difficile toxin A.
Cytotoxicity assay, transepithelial electrical resistence measurements, immunofluorescence analysis and immunoblot analysis were performed in the different experimental conditions. Clostridium difficile toxin A significantly decreased Caco-2 cells' viability and reduced transepithelial electrical resistence values and RhoA guanosine triphosphate GTP , bax, zonula occludens-1 and occludin protein expression, respectively.
All these effects were significantly and concentration-dependently inhibited by cannabidiol , whose effects were completely abolished in the presence of the cannabinoid receptor type 1 CB1 antagonist, AM Cannabidiol improved Clostridium difficile toxin A-induced damage in Caco-2 cells, by inhibiting the apoptotic process and restoring the intestinal barrier integrity, through the involvement of the CB1 receptor.
However, further elucidation of the channel properties and physiological role of TRPV2 have been hindered by the lack of selective pharmacological tools as well as by the species-dependent differences in the activation of this channel. In the present study, we have used cell-based calcium mobilization and electrophysiological assays to identify and characterize several novel cannabinoid TRPV2 agonists.
We also demonstrated that cannabidiol evoked a concentration-dependent release of calcitonin gene-related peptide CGRP from cultured rat dorsal root ganglion neurons in a cannabinoid receptor - and TRPV1-independent manner. Moreover, the cannabidiol -evoked CGRP release depended on extracellular calcium and was blocked by the nonselective TRP channel blocker, ruthenium red.
We further provide evidence through the use of small interfering RNA knockdown and repetitive stimulation studies, to show that cannabidiol -evoked CGRP release is mediated, at least in part, by TRPV2. Together, these data suggest not only that TRPV2 may comprise a mechanism whereby cannabidiol exerts its clinically beneficial effects in vivo, but also that TRPV2 may constitute a viable, new drug target.
Neurological Aspects of Medical Use of Cannabidiol. Cannabidiol CBD is among the major secondary metabolites of Cannabis devoid of the deltatetra-hydrocannabinol psychoactive effects.
It is a resorcinol-based compound with a broad spectrum of potential therapeutic properties, including neuroprotective effects in numerous pathological conditions. CBD neuroprotection is due to its antioxidant and antiinflammatory activities and the modulation of a large number of brain biological targets receptors , channels involved in the development and maintenance of neurodegenerative diseases.
The aim of the present review was to describe the state of art about the pre-clinical research, the potential use and, when existing, the clinical evidence related to CBD in the neurological field. Collection of all the pre-clinical and clinical findings carried out investigating the effects of CBD alone, not in combination with other substances, in the neurological arena with the exclusion of studies on neuropsychiatric disorders.
Pre-clinical evidence largely shows that CBD can produce beneficial effects in AD, PD and MS patients, but its employment for these disorders needs further confirmation from well designed clinical studies.
CBD pre-clinical demonstration of antiepileptic activity is supported by recent clinical studies in human epileptic subjects resistant to standard antiepileptic drugs showing its potential use in children and young adults affected by refractory epilepsy.
Evidence for use of CBD in PD is still not supported by sufficient data whereas only a few studies including a small number of patients are available. Amphetamine-induced augmentation of striatal dopamine and its blunted release in prefrontal cortex PFC is a hallmark of schizophrenia pathophysiology. Here, we report enhanced dopaminomimetic-induced locomotor activity in these mutants, along with bidirectional, site-specific changes in in vivo amphetamine-induced dopamine release: Interestingly, the magnitude and distribution of amphetamine-induced c-Fos expression in dopamine neurons was comparable between genotypes across dopaminergic input subregions in the ventral tegmental area VTA.
Published by Oxford University. Responding was maintained under a fixed ratio 5 schedule of stimulus-shock termination. Results Both training drugs dose-dependently increased the percentage of responses on the respective drug-associated levers.
Cannabidiol up to Moreover, 8-OH-DPAT significantly attenuated the discriminative stimulus effects of rimonabant, whereas cannabidiol did not modify the rimonabant discriminative stimulus.
Both training drugs dose-dependently increased the percentage of responses on the respective drug-associated levers. In the past five years, an increasing number of publications have focused on the discovery of the anti-inflammatory, anti-oxidant, and neuroprotective effects of CBD.
In particular, CBD exerts positive pharmacological effects in ischemic stroke and other chronic diseases, including Parkinson's disease, Alzheimer's disease, and rheumatoid arthritis. Importantly, CBD use does not lead to tolerance. In this review, we will discuss the therapeutic possibility of CBD as a cerebroprotective agent, highlighting recent pharmacological advances, novel mechanisms, and therapeutic time window of CBD in ischemic stroke.
Cannabis contains the psychoactive component delta9-tetrahydrocannabinol delta9-THC , and the non-psychoactive components cannabidiol CBD , cannabinol, and cannabigerol.
It is well-known that delta9-THC and other cannabinoid CB1 receptor agonists are neuroprotective during global and focal ischemic injury. Additionally, delta9-THC also mediates psychological effects through the activation of the CB1 receptor in the central nervous system.
In addition to the CB1 receptor agonists, cannabis also contains therapeutically active components which are CB1 receptor independent. The cerebroprotective action of CBD is CB1 receptor -independent, long-lasting, and has potent anti-oxidant activity.
Abnormal function of NMDA receptors is believed to be a contributing factor to the pathophysiology of schizophrenia. NMDAR subunits and postsynaptic-interacting proteins of these channels are abnormally expressed in some patients with this illness.
In mice, reduced NMDAR expression leads to behaviors analogous to symptoms of schizophrenia, but reports of animals with mutations in core postsynaptic density proteins having similar a phenotype have yet to be reported. SynGAP mutant mice exhibited nonhabituating and persistent hyperactivity that was ameliorated by the antipsychotic clozapine. SynGAP mutants exhibited enhanced startle reactivity and impaired sensory-motor gating. These mice also displayed a complete lack of social memory and a propensity toward social isolation.
Finally, SynGAP mutants had deficits in cued fear conditioning and working memory, indicating abnormal function of circuits that control emotion and choice. Our results demonstrate that SynGAP mutant mice have gross neurological deficits similar to other mouse models of schizophrenia.
Taken together, these data support the idea that schizophrenia may arise from abnormal signaling pathways that are mediated by NMDA receptors. Intact attentional processing but abnormal responding in M1 muscarinic receptor -deficient mice using an automated touchscreen method. However, to better target therapeutically the appropriate receptor subsystems, we need to understand more about the functions of those subsystems.
In addition, we tested these mice on several tasks featuring learning, memory and perceptual challenges. An advantage of the touchscreen method is that each test in the battery is carried out in the same task setting, using the same types of stimuli, responses and feedback, thus providing a high level of control and task comparability. The surprising finding, given the predominance of the M1 receptor in cortex, was the complete lack of effect of M1 deletion on measures of attentional function per se.
They did, however, show clear abnormalities on a variety of response measures: Cannabidiol exerts sebostatic and antiinflammatory effects on human sebocytes. The endocannabinoid system ECS regulates multiple physiological processes, including cutaneous cell growth and differentiation.
Here, we explored the effects of the major nonpsychotropic phytocannabinoid of Cannabis sativa, - - cannabidiol CBD , on human sebaceous gland function and determined that CBD behaves as a highly effective sebostatic agent. Administration of CBD to cultured human sebocytes and human skin organ culture inhibited the lipogenic actions of various compounds, including arachidonic acid and a combination of linoleic acid and testosterone, and suppressed sebocyte proliferation via the activation of transient receptor potential vanilloid-4 TRPV4 ion channels.
Collectively, our findings suggest that, due to the combined lipostatic, antiproliferative, and antiinflammatory effects, CBD has potential as a promising therapeutic agent for the treatment of acne vulgaris.
Molecular Targets of Cannabidiol in Neurological Disorders. Cannabis has a long history of anecdotal medicinal use and limited licensed medicinal use. Until recently, alleged clinical effects from anecdotal reports and the use of licensed cannabinoid medicines are most likely mediated by tetrahydrocannabinol by virtue of: However, there has recently been considerable interest in the therapeutic potential for the plant cannabinoid, cannabidiol CBD , in neurological disorders but the current evidence suggests that CBD does not directly interact with the endocannabinoid system except in vitro at supraphysiological concentrations.
Thus, as further evidence for CBD's beneficial effects in neurological disease emerges, there remains an urgent need to establish the molecular targets through which it exerts its therapeutic effects.
Here, we conducted a systematic search of the extant literature for original articles describing the molecular pharmacology of CBD.
We critically appraised the results for the validity of the molecular targets proposed. Thereafter, we considered whether the molecular targets of CBD identified hold therapeutic potential in relevant neurological diseases. The molecular targets identified include numerous classical ion channels, receptors , transporters, and enzymes. Some CBD effects at these targets in in vitro assays only manifest at high concentrations, which may be difficult to achieve in vivo, particularly given CBD's relatively poor bioavailability.
Moreover, several targets were asserted through experimental designs that demonstrate only correlation with a given target rather than a causal proof. When the molecular targets of CBD that were physiologically plausible were considered for their potential for exploitation in neurological therapeutics, the results were variable. Implications for a Role in Epidermal Differentiation. Bermudez, Yira; Benavente, Claudia A. Russell; Jacobson, Myron K.
Background Chronic UV skin exposure leads to epidermal differentiation defects in humans that can be largely restored by pharmacological doses of nicotinic acid. Results Nicotinic acid increases epidermal differentiation in photodamaged human skin as judged by the terminal differentiation markers caspase 14 and filaggrin. Both GPRA and GPRB genes are transcribed in human skin and in epidermal keratinocytes, but expression in dermal fibroblasts is below limits of detection.
Receptor transcripts are greatly over-expressed in squamous cell cancers. Receptor protein in normal skin is prominent from the basal through granular layers of the epidermis, with cellular localization more dispersive in the basal layer but predominantly localized at the plasma membrane in more differentiated epidermal layers.
In normal human primary and immortalized keratinocytes, nicotinic acid receptors show plasma membrane localization and functional Gi-mediated signaling. In contrast, in a squamous cell carcinoma derived cell line, receptor protein shows a more diffuse cellular localization and the receptors are nearly non-functional.
Conclusions The results of these studies justify future genetic and pharmacological intervention studies to define possible specific role s of nicotinic acid receptors in human skin homeostasis. The Developmental Origins of Health and Disease DOHaD Theory proposes that the environment encountered during fetal life and infancy permanently shapes tissue physiology and homeostasis such that damage resulting from maternal stress, poor nutrition or exposure to environmental agents may be at the heart of adult onset disease.
Interference with endogenous developmental functions of the aryl hydrocarbon receptor AHR , either by gene ablation or by exposure in utero to 2,3,7,8-tetrachlorodibenzo-p-dioxin TCDD , a potent AHR ligand, causes structural, molecular and functional cardiac abnormalities and altered heart physiology in mouse embryos. To test if embryonic effects progress into an adult phenotype, we investigated whether Ahr ablation or TCDD exposure in utero resulted in cardiac abnormalities in adult mice long after removal of the agent.
Underlying these effects, genes in signaling networks related to cardiac hypertrophy and mitochondrial function were differentially expressed. The findings reported here underscore the conclusion that AHR signaling in the developing heart is one potential target of environmental factors associated with cardiovascular disease. The anti-cancer effect of the plant-derived cannabinoid, cannabidiol , has been widely demonstrated both in vivo and in vitro. However, this body of preclinical work has not been translated into clinical use.
Key issues around this failure can be related to narrow dose effects, the cell model used and incomplete efficacy. A model of acute lymphoblastic disease, the Jurkat T cell line, has been used extensively to study the cannabinoid system in the immune system and cannabinoid-induced apoptosis. Using these cells, this study sought to investigate the outcome of those remaining viable cells post-treatment with cannabidiol , both in terms of cell size and tracking any subsequent recovery.
The phosphorylation status of the mammalian Target of Rapamycin mTOR signaling pathway and the downstream target ribosomal protein S6, were measured. The ability of cannabidiol to exert its effect on cell viability was also evaluated in physiological oxygen conditions. The remaining population of viable cells that were cultured in nutrient rich conditions post-treatment were able to proliferate, but did not recover to control cell numbers.
However, the proportion of viable cells that were gated as small, increased in response to cannabidiol and normally sized cells decreased. This proportion of small cells persisted in the recovery period and did not return to basal levels.
In conclusion, these results indicate that cannabidiol causes a reduction in cell size, which persists post-treatment. However, resistance to cannabidiol under physiological normoxia for these cells would imply that cannabidiol may not be useful in the clinic as an anti-leukemic agent. Using real-time reverse transcriptase—polymerase chain reaction RT-PCR and immunohistochemical analysis of normal endometrium, endometrial samples demonstrated cycle-regulated expression of GPER, with maximal expression in the proliferative phase.
Eutopic and ectopic endometrium from women with endometriosis overexpressed GPER as compared to eutopic endometrium of normal participants. Decreased expression was seen in Ishikawa cells stably transfected with progesterone receptor A. Together, these data suggest that normal endometrial GPER expression is cyclic and regulated by nuclear estrogen and progesterone receptors , while expression is dysregulated in endometriosis. G protein-coupled estrogen receptor GPER expression in normal and abnormal endometrium.
Considering estrogen's importance in endometrial physiology and endometriosis pathophysiology, we hypothesized that GPER could be involved in both cyclic changes in endometrial estrogen action and that aberrant expression might be seen in the eutopic endometrium of women with endometriosis.
Using real-time reverse transcriptase-polymerase chain reaction RT-PCR and immunohistochemical analysis of normal endometrium, endometrial samples demonstrated cycle-regulated expression of GPER, with maximal expression in the proliferative phase.
Short-term treatment with VEGF receptor inhibitors induces retinopathy of prematurity-like abnormal vascular growth in neonatal rats. Retinal arterial tortuosity and venous dilation are hallmarks of plus disease, which is a severe form of retinopathy of prematurity ROP. In this study, we examined whether short-term interruption of vascular endothelial growth factor VEGF signals leads to the formation of severe ROP-like abnormal retinal blood vessels.
The retinal vasculatures were examined on P9, P14, or P21 in retinal whole-mounts stained with an endothelial cell marker. Prevention of vascular growth and regression of some preformed capillaries were observed on P9 in retinas of rats treated with KRN However, on P14 and P21, density of capillaries, tortuosity index of arterioles, and diameter of veins significantly increased in KRNtreated rats, compared to vehicle 0.
Similar observations were made with axitinib-treated rats. These results suggest that an interruption of normal retinal vascular development in neonatal rats as a result of short-term VEGFR inhibition causes severe ROP-like abnormal retinal vascular growth in a VEGF-dependent manner.
Rats treated postnatally with VEGFR inhibitors could serve as an animal model for studying the mechanisms underlying the development of plus disease. Effects of cannabidiol plus naltrexone on motivation and ethanol consumption. The aim of this study was to explore if the administration of naltrexone NTX together with cannabidiol CBD may improve the efficacy in reducing alcohol consumption and motivation rather than any of the drugs given separately.
The effects of low doses of NTX 0. The combination of low doses of CBD plus NTX resulted more effective to reduce ethanol consumption and motivation to drink. These effects, appears to be mediated, at least in part, by 5-HT 1A receptors.
This article is protected by copyright. Dopamine D3 receptor knockout mice exhibit abnormal nociception in a sex-different manner. Pain is a complex and subjective experience. Previous studies have shown that mice lacking the dopamine D3 receptor D3RKO exhibit hypoalgesia, indicating a role of the D3 receptor in modulation of nociception. Given that there are sex differences in pain perception, there may be differences in responses to nociceptive stimuli between male and female D3RKO mice.
In the current study, we examined the role of the D3 receptor in modulating nociception in male and female D3RKO mice. Acute thermal pain was modeled by hot-plate test. The von Frey hair test was applied to evaluate mechanical pain. And persistent pain produced by peripheral tissue injury and inflammation was modeled by formalin test.
In the hot-plate test, compared with wild-type WT mice, D3RKO mice generally exhibited longer latencies at each of the three temperatures. In the formalin test, the male D3RKO mice displayed a similar nociceptive behavior as their sex-matched WT littermates, whereas significantly depressed late-phase formalin-induced nociceptive behaviors were observed in the female mutants.
These findings indicated that the D3 receptor affects nociceptive behaviors in a sex-specific manner and that its absence induces more analgesic behavior in the female knockout mice.
Cannabidiol for the treatment of cannabis withdrawal syndrome: Cannabis withdrawal in heavy users is commonly followed by increased anxiety, insomnia, loss of appetite, migraine, irritability, restlessness and other physical and psychological signs. Tolerance to cannabis and cannabis withdrawal symptoms are believed to be the result of the desensitization of CB1 receptors by THC.
Daily symptom assessments demonstrated the absence of significant withdrawal, anxiety and dissociative symptoms during the treatment. CBD can be effective for the treatment of cannabis withdrawal syndrome. The astrocytes have gained in recent decades an enormous interest as a potential target for neurotherapies, due to their essential and pleiotropic roles in brain physiology and pathology. The cannabinoid system and its ligands have been shown to interact and affect activities of astrocytes.
Cannabidiol CBD is the main non-psychotomimetic cannabinoid derived from Cannabis. Here, we attempt to sum up the current findings on the effects of CBD on astrocyte activity, and in this way on central nervous system CNS functions, across various tested models and neuropathologies.
The collected data shows that increased astrocyte activity is suppressed in the presence of CBD in models of ischemia, Alzheimer-like and Multiple-Sclerosis-like neurodegenerations, sciatic nerve injury, epilepsy, and schizophrenia. Moreover, CBD has been shown to decrease proinflammatory functions and signaling in astrocytes.
Correlation between dopamine receptor D2 expression and presence of abnormal involuntary movements in Wistar rats with hemiparkinsonism and dyskinesia. Although the pathogenic mechanism of L-DOPA-induced dyskinesia is unclear, the condition has been associated with alterations in dopamine receptors , among which D2 receptors D2R have received little attention.
This study aims to: We allocated 21 male Wistar rats into 3 groups: Sensorimotor impairment was assessed with behavioural tests. Yu, Tian; Taussig, Matthew D. Lipoprotein lipase LPL hydrolyzes triacylglycerides in lipoproteins and regulates lipid metabolism in multiple organs and tissues, including the central nervous system CNS.
We interpret these findings to indicate that LPL regulates the availability of PUFA in the CNS and, this in turn, impacts the strength of synaptic plasticity in the brain of aging mice through the modification of AMPA receptor and its phosphorylation.
Ovarian cancer G protein-coupled receptor 1 OGR1 has been shown to be a proton sensing receptor in vitro. We have shown that OGR1 functions as a tumor metastasis suppressor gene when it is over-expressed in human prostate cancer cells in vivo.
To examine the physiological functions of OGR1, we generated conditional OGR1 deficient mice by homologous recombination. OGR1 deficient mice were viable and upon gross-inspection appeared normal. Consistent with in vitro studies showing that OGR1 is involved in osteoclastogenesis, reduced osteoclasts were detected in OGR1 deficient mice.
A pH-dependent osteoclasts survival effect was also observed. However, overall abnormality in the bones of these animals was not observed. In addition, melanoma cell tumorigenesis was significantly inhibited in OGR1 deficient mice. OGR1 deficient mice in the mixed background produced significantly less peritoneal macrophages when stimulated with thioglycolate.
These macrophages also showed altered extracellular signal-regulated kinases ERK activation and nitric oxide NO production in response to lipopolysaccharide. OGR1-dependent pH responses assessed by cAMP production and cell survival in macrophages or brown fat cells were not observed, presumably due to the presence of other proton sensing receptors in these cells.
Our results indicate that OGR1's role in osteoclastogenesis is not strong enough to affect overall bone development and its role in tumorigenesis warrants further investigation. The mice generated can be potentially used for several disease models, including cancers or osteoclast-related diseases.
Antinociceptive effects of HUF, a fluorinated cannabidiol derivative. Cannabidiol CBD is a phytocannabinoid with multiple pharmacological effects and several potential therapeutic properties. Its low oral bioavailability, however, can limit its clinical use. Preliminary results indicate that fluorination of the CBD molecule increases its pharmacological potency. These drugs were tested in male Swiss mice submitted to the following models predictive to antinociceptive drugs: Whereas the pretreatment with AM did not mitigate the effects induced by any drug in this test, the pretreatment with AM attenuated the effect caused by WIN55, The effects of all compounds were attenuated by the pretreatment with AM and AM Additionally, we evaluated whether HUF would induce the classic cannabinoid CB 1 receptor -mediated tetrad hypolocomotion, catalepsy, hypothermia.
Abnormal norepinephrine clearance and adrenergic receptor sensitivity in idiopathic orthostatic intolerance. Chronic orthostatic intolerance OI is characterized by symptoms of inadequate cerebral perfusion with standing, in the absence of significant orthostatic hypotension. Possible underlying pathophysiologies include hypovolemia, partial dysautonomia, or a primary hyperadrenergic state. We tested the hypothesis that patients with OI have functional abnormalities in autonomic neurons regulating cardiovascular responses.
Thirteen patients with chronic OI and 10 control subjects underwent a battery of autonomic tests. Systemic norepinephrine NE kinetics were determined with the patients supine and standing before and after tyramine administration. In addition, baroreflex sensitivity, hemodynamic responses to bolus injections of adrenergic agonists, and intrinsic heart rate were determined. Resting supine NE spillover and clearance were similar in both groups. At date the major neuroreceptors i.
In particular, MUS induced moderate p abnormal swimming events in fish. Cannabidiol as a potential treatment for psychosis. Although cannabis use is associated with an increased risk of developing psychosis, the cannabis constituent cannabidiol CBD may have antipsychotic properties. This review concisely describes the role of the endocannabinoid system in the development of psychosis and provides an overview of currently available animal, human experimental, imaging, epidemiological and clinical studies that investigated the antipsychotic properties of CBD.
Studies were selected if they described experiments with psychosis models, psychotic symptoms or psychotic disorders as outcome measure and involved the use of CBD as intervention.
Evidence from several research domains suggests that CBD shows potential for antipsychotic treatment. We found that separation of platelet activation, as assessed by platelet aggregation, from that needed to form viscoelastic stable whole blood thrombi, occurred.
In normal human blood, ristocetin and collagen aggregated platelets, but did not induce strong viscoelastic thrombi. However, ADP, arachidonic acid, thrombin, and protease-activated- receptor -1 and -4 agonists, stimulated both processes. During this study, we identified the genetic basis of a very rare double heterozygous GP1b deficiency in a BSS patient, along with a new homozygous GP1b inactivating mutation in another BSS patient.
Further, the platelets of 3 additional GT patients showed very weak whole blood platelet aggregation toward the above agonists and provided whole blood thrombi of very low viscoelastic strength. These results indicate that measurements of platelet counts and platelet aggregability do not necessarily correlate with generation of stable thrombi, a potentially significant feature in patient clinical outcomes.
LPA promotes cell growth and differentiation, and has been shown to be implicated in a variety of developmental and pathophysiological processes. Various strains of "medical marijuana" are found to have a significant variation in the ratios of CBD-to-THC, and are known to contain other non-psychotropic cannabinoids. The Colorado Industrial Hemp Program registers growers of industrial hemp and samples crops to verify that the dry-weight THC concentration does not exceed 0.
Cannabidiol is not scheduled under the Convention on Psychotropic Substances or any other UN drug treaty. In addition, in the Drug Enforcement Administration added "marijuana extracts" to the list of Schedule I drugs , which it defined as "an extract containing one or more cannabinoids that has been derived from any plant of the genus Cannabis , other than the separated resin whether crude or purified obtained from the plant.
In September , following its approval by the FDA for rare types of childhood epilepsy,  Epidiolex was rescheduled by the Drug Enforcement Administration as a Schedule V drug to allow for its prescription use. The Farm Bill  legalized the sale of "non-viable hemp material" grown within states participating in the Hemp Pilot Program.
Prescription medicine Schedule 4 for therapeutic use containing 2 per cent 2. A schedule 4 drug under the SUSMP is Prescription Only Medicine, or Prescription Animal Remedy — Substances, the use or supply of which should be by or on the order of persons permitted by State or Territory legislation to prescribe and should be available from a pharmacist on prescription.
It is also a prescription medicine under the Medicines Act. In the rules were changed so that anyone wanting to use it could go to the Health Ministry for approval. Prior to this, the only way to obtain a prescription was to seek the personal approval of the Minister of Health. Associate Health Minister Peter Dunne said restrictions would be removed, which means a doctor will now be able to prescribe cannabidiol to patients.
On October 17, , cannabidiol became legal for recreational and medical use. Several industrial hemp varieties can be legally cultivated in Western Europe. CBD is classified as a medical product in Sweden. Cannabidiol, in an oral-mucosal spray formulation combined with deltatetrahydrocannabinol, is a product available by prescription only until for relief of severe spasticity due to multiple sclerosis where other anti- spasmodics have not been effective.
Until , products containing cannabidiol marketed for medical purposes were classed as medicines by the UK regulatory body , the Medicines and Healthcare products Regulatory Agency MHRA and could not be marketed without regulatory approval for the medical claims. A literature review indicated that cannabidiol was under basic research to identify its possible neurological effects,  although as of [update] , there was limited high-quality evidence for such effects in people.
From Wikipedia, the free encyclopedia. Not to be confused with Cannabinol or Cannabinodiol. S4 Prescription only UK: Schedule I except Epidiolex, Schedule V.
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Cannabidiol and (−)Δ9-tetrahydrocannabinol are neuroprotective The neuroprotective actions of cannabidiol and other cannabinoids were examined in rat cortical receptors and results in metabolic stress and accumulation of toxic reported to be neuroprotective against glutamate toxicity in vitro (7). Irinotecan and Δ9-Tetrahydrocannabinol Interactions in Rat Liver: A Preliminary .. Since THC has a somewhat higher bioavailability if consumed in an oil .. in the liver of CDF1 mice administered IRI i.p. at mg/kg for six days . . the metabolic differences between the rat and human metabolism. Chemical structures and numbering system for CBD and Δ9- THC type cannabinoids. . The first CBD metabolites to be identified were isolated from rat liver Experiments in vitro with seven recombinant human CYP isoforms . by CBD of mouse hepatic microsomal metabolism as demonstrated for.