The mammalian body has a highly developed immune system which guards against continuous invading protein attacks and aims at preventing, attenuating or repairing the inflicted damage. It is ...conceivable that through evolution analogous biological protective systems have been evolved against non-protein attacks. There is emerging evidence that lipid endocannabinoid signaling through cannabinoid 2 (CB
2) receptors may represent an example/part of such a protective system/armamentarium. Inflammation/tissue injury triggers rapid elevations in local endocannabinoid levels, which in turn regulate signaling responses in immune and other cells modulating their critical functions. Changes in endocannabinoid levels and/or CB
2 receptor expressions have been reported in almost all diseases affecting humans, ranging from cardiovascular, gastrointestinal, liver, kidney, neurodegenerative, psychiatric, bone, skin, autoimmune, lung disorders to pain and cancer, and modulating CB
2 receptor activity holds tremendous therapeutic potential in these pathologies. While CB
2 receptor activation in general mediates immunosuppressive effects, which limit inflammation and associated tissue injury in large number of pathological conditions, in some disease states activation of the CB
2 receptor may enhance or even trigger tissue damage, which will also be discussed alongside the protective actions of the CB
2 receptor stimulation with endocannabinoids or synthetic agonists, and the possible biological mechanisms involved in these effects.
Microglial activation is an invariant feature of Alzheimer's disease (AD). It is noteworthy that cannabinoids are neuroprotective by preventing β-amyloid (Aβ)-induced microglial activation both in ...vitro and in vivo. On the other hand, the phytocannabinoid cannabidiol (CBD) has shown anti-inflammatory properties in different paradigms. In the present study, we compared the effects of CBD with those of other cannabinoids on microglial cell functions in vitro and on learning behavior and cytokine expression after Aβ intraventricular administration to mice. CBD, (R)-(+)-2,3-dihydro-5-methyl-3-(4-morpholinylmethyl) pyrrolo-1,2,3-d,e-1,4-benzoxazin-6-yl-1-naphthalenyl-methanone WIN 55,212-2 (WIN), a mixed CB(1)/CB(2) agonist, and 1,1-dimethylbutyl-1-deoxy-Δ(9)-tetrahydrocannabinol JWH-133 (JWH), a CB(2)-selective agonist, concentration-dependently decreased ATP-induced (400 μM) increase in intracellular calcium (Ca(2+)(i)) in cultured N13 microglial cells and in rat primary microglia. In contrast, 4-4-(1,1-dimethylheptyl)-2,6-dimethoxyphenyl-6,6-dimethyl-bicyclo3.1.1hept-2-ene-2-methanol HU-308 (HU), another CB(2) agonist, was without effect. Cannabinoid and adenosine A(2A) receptors may be involved in the CBD action. CBD- and WIN-promoted primary microglia migration was blocked by CB(1) and/or CB(2) antagonists. JWH and HU-induced migration was blocked by a CB(2) antagonist only. All of the cannabinoids decreased lipopolysaccharide-induced nitrite generation, which was insensitive to cannabinoid antagonism. Finally, both CBD and WIN, after subchronic administration for 3 weeks, were able to prevent learning of a spatial navigation task and cytokine gene expression in β-amyloid-injected mice. In summary, CBD is able to modulate microglial cell function in vitro and induce beneficial effects in an in vivo model of AD. Given that CBD lacks psychoactivity, it may represent a novel therapeutic approach for this neurological disease.
•CBDA methyl ester (HU-580) is known to be more stable than CBDA.•Oral administration in different genetic depression models: male WKY and FSL rats.•1 mg/kg HU-580 reduced immobility and increased ...swimming in both strains.•This is the first report of antidepressant efficacy of HU-580.•Support provided for a novel treatment for depression and associated disorders.
Cannabidiolic acid methyl ester (HU-580) was recently shown to reduce stress-induced anxiety-like behavior in rats. The aim of this study was to examine the antidepressant effect of HU-580 in two different rat models of depression.
Using the forced swim test (FST), we evaluated the effect of HU-580 in 43 Wistar–Kyoto (WKY) and 23 Flinders Sensitive Line (FSL) adult male rats.
1 mg/kg HU-580 reduced immobility and increased swimming in WKY rats, compared to vehicle-treated controls (p < 0.05). This dose exerted similar effects in FSL rats (p < 0.05).
This is the first report of antidepressant efficacy of HU-580. These findings expand the very limited existent results, suggesting that HU-580 is a potent anxiolytic agent. Taken together with its chemical stability, HU-580 emerges as a candidate for a future antidepressant medication.
BACKGROUND AND PURPOSE To evaluate the hypothesis that activation of somatodendritic 5‐HT1A autoreceptors in the dorsal raphe nucleus (DRN) produces the anti‐emetic/anti‐nausea effects of cannabidiol ...(CBD), a primary non‐psychoactive cannabinoid found in cannabis.
EXPERIMENTAL APPROACH The potential of systemic and intra‐DRN administration of 5‐HT1A receptor antagonists, WAY100135 or WAY100635, to prevent the anti‐emetic effect of CBD in shrews (Suncus murinus) and the anti‐nausea‐like effects of CBD (conditioned gaping) in rats were evaluated. Also, the ability of intra‐DRN administration of CBD to produce anti‐nausea‐like effects (and reversal by systemic WAY100635) was assessed. In vitro studies evaluated the potential of CBD to directly target 5‐HT1A receptors and to modify the ability of the 5‐HT1A agonist, 8‐OH‐DPAT, to stimulate 35SGTPγS binding in rat brainstem membranes.
KEY RESULTS CBD suppressed nicotine‐, lithium chloride (LiCl)‐ and cisplatin (20 mg·kg−1, but not 40 mg·kg−1)‐induced vomiting in the S. murinus and LiCl‐induced conditioned gaping in rats. Anti‐emetic and anti‐nausea‐like effects of CBD were suppressed by WAY100135 and the latter by WAY100635. When administered to the DRN: (i) WAY100635 reversed anti‐nausea‐like effects of systemic CBD, and (ii) CBD suppressed nausea‐like effects, an effect that was reversed by systemic WAY100635. CBD also displayed significant potency (in a bell‐shaped dose–response curve) at enhancing the ability of 8‐OH‐DPAT to stimulate 35SGTPγS binding to rat brainstem membranes in vitro. Systemically administered CBD and 8‐OH‐DPAT synergistically suppressed LiCl‐induced conditioned gaping.
CONCLUSIONS AND IMPLICATIONS These results suggest that CBD produced its anti‐emetic/anti‐nausea effects by indirect activation of the somatodendritic 5‐HT1A autoreceptors in the DRN.
LINKED ARTICLES This article is part of a themed section on Cannabinoids in Biology and Medicine. To view the other articles in this section visit http://dx.doi.org/10.1111/bph.2012.165.issue‐8. To view Part I of Cannabinoids in Biology and Medicine visit http://dx.doi.org/10.1111/bph.2011.163.issue‐7
Two types of cannabinoid receptor have been discovered so far, CB(1) (2.1: CBD:1:CB1:), cloned in 1990, and CB(2) (2.1:CBD:2:CB2:), cloned in 1993. Distinction between these receptors is based on ...differences in their predicted amino acid sequence, signaling mechanisms, tissue distribution, and sensitivity to certain potent agonists and antagonists that show marked selectivity for one or the other receptor type. Cannabinoid receptors CB(1) and CB(2) exhibit 48% amino acid sequence identity. Both receptor types are coupled through G proteins to adenylyl cyclase and mitogen-activated protein kinase. CB(1) receptors are also coupled through G proteins to several types of calcium and potassium channels. These receptors exist primarily on central and peripheral neurons, one of their functions being to inhibit neurotransmitter release. Indeed, endogenous CB(1) agonists probably serve as retrograde synaptic messengers. CB(2) receptors are present mainly on immune cells. Such cells also express CB(1) receptors, albeit to a lesser extent, with both receptor types exerting a broad spectrum of immune effects that includes modulation of cytokine release. Of several endogenous agonists for cannabinoid receptors identified thus far, the most notable are arachidonoylethanolamide, 2-arachidonoylglycerol, and 2-arachidonylglyceryl ether. It is unclear whether these eicosanoid molecules are the only, or primary, endogenous agonists. Hence, we consider it premature to rename cannabinoid receptors after an endogenous agonist as is recommended by the International Union of Pharmacology Committee on Receptor Nomenclature and Drug Classification. Although pharmacological evidence for the existence of additional types of cannabinoid receptor is emerging, other kinds of supporting evidence are still lacking.
Cannabidiol (CBD) is the most abundant cannabinoid in Cannabis sativa that has no psychoactive properties. CBD has been approved to treat inflammation, pain and spasticity associated with multiple ...sclerosis (MS), of which demyelination and oligodendrocyte loss are hallmarks. Thus, we investigated the protective effects of CBD against the damage to oligodendrocyte progenitor cells (OPCs) mediated by the immune system. Doses of 1 μM CBD protect OPCs from oxidative stress by decreasing the production of reactive oxygen species. CBD also protects OPCs from apoptosis induced by LPS/IFNγ through the decrease of caspase 3 induction via mechanisms that do not involve CB1, CB2, TRPV1 or PPARγ receptors. Tunicamycin-induced OPC death was attenuated by CBD, suggesting a role of endoplasmic reticulum (ER) stress in the mode of action of CBD. This protection against ER stress-induced apoptosis was associated with reduced phosphorylation of eiF2α, one of the initiators of the ER stress pathway. Indeed, CBD diminished the phosphorylation of PKR and eiF2α induced by LPS/IFNγ. The pro-survival effects of CBD in OPCs were accompanied by decreases in the expression of ER apoptotic effectors (CHOP, Bax and caspase 12), and increased expression of the anti-apoptotic Bcl-2. These findings suggest that attenuation of the ER stress pathway is involved in the 'oligoprotective' effects of CBD during inflammation.
Background and purpose: We aimed to demonstrate the involvement of 5‐HT1A receptors in the therapeutic effect of cannabidiol, a non‐psychoactive constituent of Cannabis sativa, in a model of hepatic ...encephalopathy induced by bile‐duct ligation (BDL) in mice.
Experimental approach: Cannabidiol (5 mg·kg−1; i.p.) was administered over 4 weeks to BDL mice. Cognition and locomotion were evaluated using the eight‐arm maze and the open field tests respectively. Hippocampi were analysed by RT‐PCR for expression of the genes for tumour necrosis factor‐α receptor 1, brain‐derived neurotrophic factor (BDNF) and 5‐HT1A receptor. N‐(2‐(4‐(2‐methoxy‐phenyl)‐1‐piperazin‐1‐yl)ethyl)‐N‐(2‐pyridyl) cyclohexanecarboxamide (WAY‐100635), a 5‐HT1A receptor antagonist (0.5 mg·kg−1), was co‐administered with cannabidiol. Liver function was evaluated by measuring plasma liver enzymes and bilirubin.
Key results: Cannabidiol improved cognition and locomotion, which were impaired by BDL, and restored hippocampal expression of the tumour necrosis factor‐α receptor 1 and the BDNF genes, which increased and decreased, respectively, following BDL. It did not affect reduced 5‐HT1A expression in BDL mice. All the effects of cannabidiol, except for that on BDNF expression, were blocked by WAY‐100635, indicating 5‐HT1A receptor involvement in cannabidiol's effects. Cannabidiol did not affect the impaired liver function in BDL.
Conclusions and implications: The behavioural outcomes of BDL result from both 5‐HT1A receptor down‐regulation and neuroinflammation. Cannabidiol reverses these effects through a combination of anti‐inflammatory activity and activation of this receptor, leading to improvement of the neurological deficits without affecting 5‐HT1A receptor expression or liver function. BDNF up‐regulation by cannabidiol does not seem to account for the cognitive improvement.
Major depressive disorder (MDD) stands as a significant cause of disability globally. Cannabidiolic Acid-Methyl Ester (CBDA-ME) (EPM-301, HU-580), a derivative of Cannabidiol, demonstrates immediate ...antidepressant-like effects, yet it has undergone only minimal evaluation in psychopharmacology. Our goal was to investigate the behavioral and potential molecular mechanisms associated with the chronic oral administration of this compound in the Wistar Kyoto (WKY) genetic model of treatment-resistant depression. Male WKY rats were subjected to behavioral assessments before and after receiving chronic (14-day) oral doses of CBDA-ME (0.5 mg/kg), 15 mg/kg of imipramine or vehicle. At the end of the study, plasma corticosterone levels and mRNA expression of various genes in the medial Prefrontal Cortex and Hippocampus were measured. Behavioral outcomes from CBDA-ME treatment indicated an antidepressant-like effect similar to imipramine, as oral ingestion reduced immobility and increased swimming duration in the Forced Swim Test. Neither treatment influenced locomotion in the Open Field Test nor preference in the Saccharin Preference Test. The behavioral impact in WKY rats coincided with reduced corticosterone serum levels, upregulated mRNA expression of Cannabinoid receptor 1, Fatty Acid Amide Hydrolase, and Corticotropin-Releasing Hormone Receptor 1, alongside downregulation of the Serotonin Transporter in the hippocampus. Additionally, there was an upregulation of CB1 mRNA expression and downregulation of Brain-Derived Neurotrophic Factor in the mPFC. These findings contribute to our limited understanding of the antidepressant effects of CBDA-ME and shed light on its potential psychopharmacological mechanisms. This discovery opens up possibilities for utilizing cannabinoids in the treatment of major depressive disorder and related conditions.
•Cannabinoids have demonstrated potential in the treatment of MDD.•In this study chronic oral ingestion of CBDA- ME was explored in male WKY.•Anti-Depressive-like effect was found in addition to reduced CORT serum levels.•Possible molecular changes were found in the rat's hippocampus and mPFC.•This study exhibits novel discoveriess for utilizing cannabinoids for MDD.
In response to traumatic brain injury, there is local and transient accumulation of 2-AG at the site of injury, peaking at 4 h and sustained up to at least 24 h. Neuroprotection exerted by exogenous ...2-AG suggests that the formation of 2-AG may serve as a molecular regulator of pathophysiological events, attenuating the brain damage. Inhibition of this protective effect by SR-141716A, a CB(1) cannabinoid receptor antagonist, and the lack of effect of 2-AG in CB(1) knockout mice suggest that 2-AG and the CB(1) receptor may be important in the pathophysiology of traumatic brain injury. 2-AG exerts its neuroprotective effect after traumatic brain injury, at least in part, by inhibition of NF-kappaB transactivation. 2-AG also inhibits, at an early stage (2-4 h), the expression of the main proinflammatory cytokines, TNF-alpha, IL-6, and IL-1beta, and is accompanied by reduction of BBB permeability. Moreover, the CB(1), CB(2), and TRVP1 receptors are expressed on microvascular endothelial cells, and their activation by 2-AG counteracts endothelin (ET-1)-induced cerebral microvascular responses (namely, Ca(2+) mobilization and cytoskeleton rearrangement). This suggests that the functional interaction between 2-AG and ET-1 may provide a potential alternative pathway for abrogating ET-1-inducible vasoconstriction after brain injury and play a role in the neuroprotective effects exerted by 2-AG, as a potent vasodilator.
PDF
