Multiple mechanisms involved in the large-spectrum therapeutic potential of cannabidiol in psychiatric disorders

Cannabidiol (CBD) is a major phytocannabinoid present in the Cannabis sativa plant. It lacks the psychotomimetic and other psychotropic effects that the main plant compound Δ⁹-tetrahydrocannabinol (THC) being able, on the contrary, to antagonize these effects. This property, together with its safety profile, was an initial stimulus for the investigation of CBD pharmacological properties. It is now clear that CBD has therapeutic potential over a wide range of non-psychiatric and psychiatric disorders such as anxiety, depression and psychosis. Although the pharmacological effects of CBD in different biological systems have been extensively investigated by in vitro studies, the mechanisms responsible for its therapeutic potential are still not clear. Here, we review recent in vivo studies indicating that these mechanisms are not unitary but rather depend on the behavioural response being measured. Acute anxiolytic and antidepressant-like effects seem to rely mainly on facilitation of 5-HT1A-mediated neurotransmission in key brain areas related to defensive responses, including the dorsal periaqueductal grey, bed nucleus of the stria terminalis and medial prefrontal cortex. Other effects, such as anti-compulsive, increased extinction and impaired reconsolidation of aversive memories, and facilitation of adult hippocampal neurogenesis could depend on potentiation of anandamide-mediated neurotransmission. Finally, activation of TRPV1 channels may help us to explain the antipsychotic effect and the bell-shaped dose-response curves commonly observed with CBD. Considering its safety profile and wide range of therapeutic potential, however, further studies are needed to investigate the involvement of other possible mechanisms (e.g. inhibition of adenosine uptake, inverse agonism at CB2 receptor, CB1 receptor antagonism, GPR55 antagonism, PPARγ receptors agonism, intracellular (Ca²⁺) increase, etc.), on CBD behavioural effects.     

Fluorinated Cannabidiol Derivatives: Enhancement of Activity in Mice Models Predictive of Anxiolytic,Antidepressant and Antipsychotic Effects

Cannabidiol (CBD) is a major Cannabis sativa constituent, which does not cause the typical marijuana psychoactivity. However, it has been shown to be active in a numerous pharmacological assays, including mice tests for anxiety, obsessive-compulsive disorder, depression and schizophrenia. In human trials the doses of CBD needed to achieve effects in anxiety and schizophrenia are high. We report now the synthesis of 3 fluorinated CBD derivatives, one of which, 4''-F-CBD (HUF-101) (1), is considerably more potent than CBD in behavioral assays in mice predictive of anxiolytic, antidepressant, antipsychotic and anti-compulsive activity. Similar to CBD, the anti-compulsive effects of HUF-101 depend on cannabinoid receptors.     

Antitumor mechanism of cannabidiol hidden behind cancer hallmarks

Cannabinoids have been utilized for recreational and therapeutic purposes for over 4,000 years. As the primary ingredient in exogenous cannabinoids, Cannabidiol (CBD) has drawn a lot of interest from researchers due to its negligible psychotropic side effects and potential tumor-suppressing properties. However, the obscure mechanisms that underlie them remain a mystery. Complex biological mechanisms are involved in the progression of cancer, and malignancies have a variety of acquired biological capabilities, including sustained proliferation, death evasion, neovascularization, tissue invasion and metastasis, immune escape, metabolic reprogramming, induction of tumor-associated inflammation, cancerous stemness and genomic instability. Nowadays, the role of CBD hidden in these hallmarks is gradually revealed. Nevertheless, flaws or inconsistencies in the recent studies addressing the anti-cancer effects of CBD still exist. The purpose of this review is to evaluate the potential mechanisms underlying the role of CBD in a range of tumor-acquired biological capabilities. We propose potential drugs that may have a synergistic effect with CBD and provide optional directions for future research.     

Effects of Δ9-tetrahydrocannabinol and cannabidiol on phospholipase and other enzymes regulating arachidonate metabolism

Δ9-Tetrahydrocannabinol (THC) and cannabidiol (CBD) caused a marked stimulation of phospholipase A₂ when incubated with intact human platelets that were prelabeled with [¹⁴C]arachidonate. CBD was about 1.5 x as potent as THC in the same concentration range (10→80 μM) Most of the released arachidonate was converted to lipoxygenase products. When [¹⁴C]arachidonate was incubated with lysed platelet extracts, THC inhibited both thromboxane synthetase and prostaglandin cyclooxygenase, so that the net effect was a redistribution of products toward the lipoxygenase pathway at the same time that a decrease in total cyclooxygenase product formation occurred. THC did not directly affect arachidonate lipoxygenase. Both THC and CBD also stimulated release from prelabeled neuroblastoma cells (NBA₂), which do not contain an active lipoxygenase pathway. In this case, accumulation of free arachidonate was detected by autoradiography. The multiple effects of THC and CBD on phospholipase A2 and arachidonate metabolism may mediate some of the pharmacological actions of these compounds, such as their anticonvulsant, anti-inflammatory, and hypotensive properties.     

Interactions between cannabidiol and delta9-THC during abstinence in morphine-dependent rats.

Male rats, each implanted with a pellet containing 75 mg morphine, were administered naloxone 72 hours later to precipitate abstinence. Two hours before naloxone, animals were pretreated acutely with either 10 mg/kg cannabidiol (CBD) or the vehicle. One hour later, an injection of the vehicle or a low dose of Δ⁹-THC that we have shown to exhibit slight efficacy in attenuating morphine abstinence signs was administered to each of the groups previously receiving the vehicle or CBD. Interactions between CBD and Δ⁹-THC were assessed during abstinence, precipitated one hour after the last series of injections. CBD had little effect on abstinence scores, but significantly increased the abstinence attenuating properties of Δ⁹-THC, Rotational behavior (turning), induced by Δ⁹-THC during abstinence, was also potentiated by CBD. These data extend previous reports of potentiation of pharmacological effects of THC by CBD to abstinence-attenuating properties and other effects of THC in morphine-dependent rats.     

Identification of functionally important amino acids in the cellulose-binding domain of Trichoderma reesei cellobiohydrolase I.

Cellobiohydrolase I (CBHI) of Trichoderma reesei has two functional domains, a catalytic core domain and a cellulose binding domain (CBD). The structure of the CBD reveals two distinct faces, one of which is flat and the other rough. Several other fungal cellulolytic enzymes have similar two-domain structures, in which the CBDs show a conserved primary structure. Here we have evaluated the contributions of conserved amino acids in CBHI CBD to its binding to cellulose. Binding isotherms were determined for a set of six synthetic analogues in which conserved amino acids were substituted. Two-dimensional NMR spectroscopy was used to assess the structural effects of the substitutions by comparing chemical shifts, coupling constants, and NOEs of the backbone protons between the wild-type CBD and the analogues. In general, the structural effects of the substitutions were minor, although in some cases decreased binding could clearly be ascribed to conformational perturbations. We found that at least two tyrosine residues and a glutamine residue on the flat face were essential for tight binding of the CBD to cellulose. A change on the rough face had only a small effect on the binding and it is unlikely that this face interacts with cellulose directly.     

Cannabidiol protects oligodendrocyte progenitor cells from inflammation-induced apoptosis by attenuating endoplasmic reticulum stress

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.     

Cannabidiol protects livers against nonalcoholic steatohepatitis induced by high-fat high cholesterol diet via regulating NF-κB and NLRP3 inflammasome pathway

Cannabidiol (CBD), an abundant nonpsychoactive constituent of marijuana, has been reported previously to protect against hepatic steatosis. In this study, we studied further the functions and mechanisms of CBD on liver inflammation induced by HFC diet. Mice feeding an HFC diet for 8 weeks were applied to test the protective effect of CBD on livers. RAW264.7 cells were incubated with LPS + ATP ± CBD to study the mechanisms of the effect of CBD against inflammasome activation. We found that CBD alleviated liver inflammation induced by HFC diet. CBD significantly inhibited the nuclear factor-κappa B (NF-κB) p65 nuclear translocation and the activation of nucleotide-binding domain like receptor protein 3 (NLRP3) inflammasome both in vivo and in vitro studies, which lead to the reduction of the expression of inflammation-related factors in our studies. In addition, Inhibitor of activation of NF-κB partly suppressed the NLRP3 inflammasome activation, while adding CBD further inhibited NF-κB activation and correspondingly suppressed the NLRP3 inflammasome activation in macrophages. In conclusion, the suppression of the activation of NLRP3 inflammasome through deactivation of NF-κB in macrophages by CBD might be one mechanism of its anti-inflammatory function in the liver.     

麻醉药物在肝细胞凋亡中的作用

围术期最常用,最重要的药物是全身麻醉药(包括吸入麻醉药和静脉麻醉药),麻醉药是适应手术的需要而出现的,经过长时间的发展,它的药理作用也越来越完善。在过去几年里很多研究报道的麻醉药的药理作用与介导的细胞凋亡之间的关系主要集中在神经系统。然而,麻醉实践中大部分麻醉药物都在肝脏代谢,已有证据表明麻醉药对肝细胞也有影响。麻醉药介导的细胞凋亡作用可能与caspase通路,Bcl-2家族,TRADD,FADD等多种因素有关。但不是所有麻醉药都对肝细胞有凋亡作用,部分还具有保护作用。因此本文就现有的麻醉药对肝细胞凋亡中的作用进行了综述。     

Cannabidiol Reverses Deficits in Hippocampal LTP in a Model of Alzheimer’s Disease

Here we demonstrate for the first time that cannabidiol (CBD) acts to protect synaptic plasticity in an in vitro model of Alzheimer’s disease (AD). The non-psycho active component of Cannabis sativa, CBD has previously been shown to protect against the neurotoxic effects of beta amyloid peptide (Aβ) in cell culture and cognitive behavioural models of neurodegeneration. Hippocampal long-term potentiation (LTP) is an activity dependent increase in synaptic efficacy often used to study cellular mechanisms related to memory. Here we show that acute application of soluble oligomeric beta amyloid peptide (Aβ_1–42) associated with AD, attenuates LTP in the CA₁ region of hippocampal slices from C57Bl/6 mice. Application of CBD alone did not alter LTP, however pre-treatment of slices with CBD rescued the Aβ_1–42 mediated deficit in LTP. We found that the neuroprotective effects of CBD were not reversed by WAY100635, ZM241385 or AM251, demonstrating a lack of involvement of 5HT_1A, adenosine (A_2A) or Cannabinoid type 1 (CB₁) receptors respectively. However in the presence of the PPARγ antagonist GW9662 the neuroprotective effect of CBD was prevented. Our data suggests that this major component of Cannabis sativa, which lacks psychoactivity may have therapeutic potential for the treatment of AD.

     

Mutation analysis of the cellulose-binding domain of the Clostridium cellulovorans cellulose-binding protein A.

Cellulose-binding protein A (CbpA) has been previously shown to mediate the interaction between crystalline cellulose substrates and the cellulase enzyme complex of Clostridium cellulovorans. CbpA contains a family III cellulose-binding domain (CBD) which, when expressed independently, binds specifically to crystalline cellulose. A series of N- and C-terminal deletions and a series of small internal deletions of the CBD were created to determine whether the entire region previously described as a CBD is required for the cellulose-binding function. The N- and C-terminal deletions reduced binding affinity by 10- to 100-fold. Small internal deletions of the CBD resulted in substantial reduction of CBD function. Some, but not all, point mutations throughout the sequence had significant disruptive effects on the binding ability of the CBD. Thus, mutations in any region of the CBD had effects on the binding of the fragment to cellulose. The results indicate that the entire 163-amino-acid region of the CBD is required for maximal binding to crystalline cellulose.     

企业与生物多样性:《生物多样性公约》新议题的产生与谈判进展

《生物多样性公约》(以下简称《公约》)是三大环境国际公约之一。随着《公约》谈判的不断推进, 企业与生物多样性(Business and Biodiversity)逐渐由《公约》中的一个概念发展成为《公约》谈判中的一个重要议题。1996年召开的《公约》缔约方大会第三次会议(COP-3)首次提出企业(私营部门)参与生物多样性的概念后, COP-5将企业参与列入《公约》议题, COP-6正式将企业参与纳入《公约》全球战略, COP-8首次将企业参与生物多样性单独纳入《公约》决定, 并提出下一步开展推动企业参与生物多样性的做法, COP-9拟定了《企业优先行动框架(2008-2010年)》, COP-10决定开展企业参与生物多样性对话论坛。迄今为止, 《公约》秘书处共组织了4次全球企业界与生物多样性伙伴关系(Global Partnership for Business and Biodiversity, GPBB)论坛, 就这一议题进行专题交流和探讨。企业与生物多样性也是当前我国生物多样性管理工作中的一个新课题, 中国对此十分重视, 并派代表团参加了GPBB-3和GPBB-4两次会议。鉴于目前中国经济发展状况与生物多样性保护面临的形势, 作者提出以下建议: (1)积极参与国际合作, 利用GPBB国际平台适时宣传我国生物多样性和生态文明建设成果; (2)加强技术研究, 制定我国企业参与生物多样性的相关标准、规范或指南; (3)深化平台建设, 搭建企业参与的中国生物多样性伙伴关系; (4)建立跨部门的企业参与生物多样性协调机制。     

The role of endothelial dysfunction and oxidative stress in cerebrovascular diseases

Cerebrovascular diseases (CBD) are one of the most dangerous complications of atherosclerosis. The clinical consequences of CBD deeply impact quality of life and the prognosis of patients. Atherosclerosis is the main cause of CBD development. Hypertension, dyslipidemia, diabetes, smoking, obesity, and other risk factors explain the higher CBD incidence in the general population, as they are able to anticipate the clinical expression of atherosclerosis. These risk factors are effectively able to promote endothelial dysfunction which is the premise for the early, clinical expression of atherosclerosis. The mechanisms by which risk factors can influence the occurrence of CBD are different and not fully understood. The inflammatory background of atherosclerosis can explain a great part of it. In particular, the oxidative stress may promote the development of vascular lesions by negatively influencing biochemical cellular processes of the endothelium, thus predisposing the vascular tree to morphological and functional damages. The aim of this narrative review is to evaluate the role of endothelial dysfunction and oxidative stress in CBD development.     

Behavior of different monocomponent endoglucanases on the accessibility and reactivity of dissolving-grade pulps for viscose process

Three different commercial monocomponent endoglucanases, with and without a cellulose-binding domain (CBD) and differences in their glycosidic hydrolysis mechanisms, were compared with respect to their ability to enhance the accessibility and reactivity of dissolving-grade pulps for viscose production. Hardwood (eucalyptus) and softwood (mixture of Norway spruce and Scots pine) commercial dried and never-dried bleached sulfite dissolving pulps were used for this purpose. The effects of the enzymatic treatments on pulps were studied by reactivity, according to Fock's method, and viscosity measurements, and recording of molecular weight distributions. Among the different assayed enzymes, endoglucanase with a CBD and an inverting hydrolysis mechanism was found to be the most effective in increasing the reactivity of both pulps. Simultaneously, the viscosity decreased, being more marked for softwood dissolving pulp. A narrower molecular weight distribution, with a great reduction in the amount of long-chain cellulose molecules was observed in both pulps, being more pronounced for softwood dissolving pulp. By contrast, endoglucanase without a CBD and a retaining hydrolysis mechanism showed a barley enhancement of the studied properties. The effects of the different endoglucanase treatments were more pronounced when never-dried dissolving pulps were used.     

Cannabidiol reduces Aβ-induced neuroinflammation and promotes hippocampal neurogenesis through PPARγ involvement

Peroxisome proliferator-activated receptor-γ (PPARγ) has been reported to be involved in the etiology of pathological features of Alzheimer's disease (AD). Cannabidiol (CBD), a Cannabis derivative devoid of psychomimetic effects, has attracted much attention because of its promising neuroprotective properties in rat AD models, even though the mechanism responsible for such actions remains unknown. This study was aimed at exploring whether CBD effects could be subordinate to its activity at PPARγ, which has been recently indicated as its putative binding site. CBD actions on β-amyloid-induced neurotoxicity in rat AD models, either in presence or absence of PPAR antagonists were investigated. Results showed that the blockade of PPARγ was able to significantly blunt CBD effects on reactive gliosis and subsequently on neuronal damage. Moreover, due to its interaction at PPARγ, CBD was observed to stimulate hippocampal neurogenesis. All these findings report the inescapable role of this receptor in mediating CBD actions, here reported.     

Desensitization of central cholinergic mechanisms and neuroadaptation to nicotine

This review focuses on neuroadaptation to nicotine. The first part of the paper delineates some possible general mechanisms subserving neuroadaptation to commonly abused drugs. The postulated role of the mesocorticolimbic neuroanatomical pathway and drug-receptor desensitization mechanisms in the establishment of tolerance to, dependence on, and withdrawal from psychoactive drugs are discussed. The second part of the review deals with the pharmacological effects of nicotine at both pre- and postsynaptic locations within the central nervous system, and the still-perplexing upregulation of brain nicotine-binding sites seen after chronic nicotine administration. A special emphasis has been put on desensitization of presynaptic cholinergic mechanisms, and postsynaptic neuronal nicotinic-receptor function and its modulation by endogenous substances. A comparison with the inactivation process occuring at peripheral nicotinic receptors is also included. Finally, a hypothesis on the possible connections between desensitization of central cholinergic mechanisms and neuroadaptation to nicotine is advanced. A brief comment on the necessity of fully understanding the effects of nicotine on the developing nervous system closes this work.     

Direct modulation of the outer mitochondrial membrane channel,voltage-dependent anion channel 1 (VDAC1) by cannabidiol: a novel mechanism for cannabinoid-induced cell death

Cannabidiol (CBD) is a non-psychoactive plant cannabinoid that inhibits cell proliferation and induces cell death of cancer cells and activated immune cells. It is not an agonist of the classical CB1/CB2 cannabinoid receptors and the mechanism by which it functions is unknown. Here, we studied the effects of CBD on various mitochondrial functions in BV-2 microglial cells. Our findings indicate that CBD treatment leads to a biphasic increase in intracellular calcium levels and to changes in mitochondrial function and morphology leading to cell death. Density gradient fractionation analysis by mass spectrometry and western blotting showed colocalization of CBD with protein markers of mitochondria. Single-channel recordings of the outer-mitochondrial membrane protein, the voltage-dependent anion channel 1 (VDAC1) functioning in cell energy, metabolic homeostasis and apoptosis revealed that CBD markedly decreases channel conductance. Finally, using microscale thermophoresis, we showed a direct interaction between purified fluorescently labeled VDAC1 and CBD. Thus, VDAC1 seems to serve as a novel mitochondrial target for CBD. The inhibition of VDAC1 by CBD may be responsible for the immunosuppressive and anticancer effects of CBD.