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.     

Cannabidiol Normalizes Caspase 3, Synaptophysin,and Mitochondrial Fission Protein DNM1L Expression Levels in Rats with Brain Iron Overload: Implications for Neuroprotection

We have recently shown that chronic treatment with cannabidiol (CBD) was able to recover memory deficits induced by brain iron loading in a dose-dependent manner in rats. Brain iron accumulation is implicated in the pathogenesis of neurodegenerative diseases, including Parkinson’s and Alzheimer’s, and has been related to cognitive deficits in animals and human subjects. Deficits in synaptic energy supply have been linked to neurodegenerative diseases, evidencing the key role played by mitochondria in maintaining viable neural cells and functional circuits. It has also been shown that brains of patients suffering from neurodegenerative diseases have increased expression of apoptosisrelated proteins and specific DNA fragmentation. Here, we have analyzed the expression level of brain proteins involved with mitochondrial fusion and fission mechanisms (DNM1L and OPA1), the main integral transmembrane protein of synaptic vesicles (synaptophysin), and caspase 3, an apoptosis-related protein, to gain a better understanding of the potential of CBD in restoring the damage caused by iron loading in rats. We found that CBD rescued iron-induced effects, bringing hippocampal DNM1L, caspase 3, and synaptophysin levels back to values comparable to the control group. Our results suggest that iron affects mitochondrial dynamics, possibly trigging synaptic loss and apoptotic cell death and indicate that CBD should be considered as a potential molecule with memory-rescuing and neuroprotective properties to be used in the treatment of cognitive deficits observed in neurodegenerative disorders.     

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.

     

Do new Access and Benefit Sharing procedures under the Convention on Biological Diversity threaten the future of biological control?

Under the Convention on Biological Diversity (CBD) countries have sovereign rights over their genetic resources. Agreements governing the access to these resources and the sharing of the benefits arising from their use need to be established between involved parties [i.e. Access and Benefit Sharing (ABS)]. This also applies to species collected for potential use in biological control. Recent applications of CBD principles have already made it difficult or impossible to collect and export natural enemies for biological control research in several countries. If such an approach is widely applied it would impede this very successful and environmentally safe pest management method based on the use of biological diversity. The CBD is required to agree a comprehensive Access and Benefit Sharing process in 2010, in preparation for which the IOBC (International Organization for Biological Control of Noxious Animals and Plants) Global Commission on Biological Control and Access and Benefit Sharing has prepared this position paper. Here, we first describe the practice of biological control in relation to the principles of ABS, illustrated extensively by case studies and successes obtained with biological control. Next, we emphasise the very limited monetary benefits generated in biological control when compared to other fields of ABS such as the collection of germplasm for development of human drugs, chemical pesticides or crop cultivars. Subsequently, we inform the biological control community of good ABS practice and challenges, and we hope to make clear to the community involved in ABS under the CBD the special situation with regard to biological control. Finally, based on the non-commercial academic research model, we make recommendations which would facilitate the practice of collection and exchange of biological control agents, propose a workable framework to assist policy makers and biological control practitioners, and urge biological control leaders in each country to get involved in the discussions with their national ABS contact point to take their needs into consideration.     

Cannabinoid-induced cell death in endometrial cancer cells: involvement of TRPV1 receptors in apoptosis

Among a variety of phytocannabinoids, Δ⁹-tetrahydrocannabinol (THC) and cannabidiol (CBD) are the most promising therapeutic compounds. Besides the well-known palliative effects in cancer patients, cannabinoids have been shown to inhibit in vitro growth of tumor cells. Likewise, the major endocannabinoids (eCBs), anandamide (AEA) and 2-arachidonoylglycerol (2-AG), induce tumor cell death. The purpose of the present study was to characterize cannabinoid elements and evaluate the effect of cannabinoids in endometrial cancer cell viability. The presence of cannabinoid receptors, transient receptor potential vanilloid 1 (TRPV1), and endocannabinoid-metabolizing enzymes were determined by qRT-PCR and Western blot. We also examined the effects and the underlying mechanisms induced by eCBs and phytocannabinoids in endometrial cancer cell viability. Besides TRPV1, both EC cell lines express all the constituents of the endocannabinoid system. We observed that at concentrations higher than 5 μM, eCBs and CBD induced a significant reduction in cell viability in both Ishikawa and Hec50co cells, whereas THC did not cause any effect. In Ishikawa cells, contrary to Hec50co, treatment with AEA and CBD resulted in an increase in the levels of activated caspase ?3/?7, in cleaved PARP, and in reactive oxygen species generation, confirming that the reduction in cell viability observed in the MTT assay was caused by the activation of the apoptotic pathway. Finally, these effects were dependent on TRPV1 activation and intracellular calcium levels. These data indicate that cannabinoids modulate endometrial cancer cell death. Selective targeting of TPRV1 by AEA, CBD, or other stable analogues may be an attractive research area for the treatment of estrogen-dependent endometrial carcinoma. Our data further support the evaluation of CBD and CBD-rich extracts for the potential treatment of endometrial cancer, particularly, that has become non-responsive to common therapies.     

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--recent advances

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.     

Exchange of Natural Enemies for Biological Control: Is it a Rocky Road?—The Road in the Euro-Mediterranean Region and the South American Common Market

The access and benefit sharing (ABS) regulations from the Convention on Biological Diversity (CBD) for the use of natural resources became an important issue because the biodiversity of developing countries was heavily accessed and unilaterally exploited by pharmaceutical and seed companies. However, natural enemies used for biological control are living and unmodified genetic resources which cannot be patented and have been treated as resources such as drugs, seeds, or other commercial products. Consequently, the ABS requirements have limited not only the use of natural enemies but also the positive effects that scientifically supported biological control strategies have on the society, the environment, and the economy, reducing problems of pesticide residues, water and soil contamination, and non-target effects. During the last several years, the biological control scientific community has faced new and extremely complicated legislation dictated by a high and diverse number of governmental agencies at different levels, making the access to natural resources for biocontrol purposes a rocky road. Society at large should be aware of how the strict ABS regulations affect the use of natural enemies as biological resources to secure food production, food safety, and global environmental protection. We discuss in here the current difficulties derived from CBD for the exchange of natural enemies taking as example the Euro-Mediterranean region, Argentina, and Brazil to demonstrate how long and diverse are the steps to be followed to obtain the required permits for access and exportation/importation of natural enemies. We then argue that the public visibility of biocontrol strategies should be increased and their benefits highlighted in order to persuade legislators for the development of a less bureaucratic, more expedient, and more centralized regulatory frame, greatly favoring the practice and benefits of biological control. We finally propose a general framework in which ABS issues should be dealt in ways to attend the CBD, but also to make the use of natural resources for the biological control of pests to secure food production and security a possible alternative.     

Cannabidiol inhibits the skeletal muscle Nav1.4 by blocking its pore and by altering membrane elasticity

Cannabidiol (CBD) is the primary nonpsychotropic phytocannabinoid found in Cannabis sativa, which has been proposed to be therapeutic against many conditions, including muscle spasms. Among its putative targets are voltage-gated sodium channels (Navs), which have been implicated in many conditions. We investigated the effects of CBD on Nav1.4, the skeletal muscle Nav subtype. We explored direct effects, involving physical block of the Nav pore, as well as indirect effects, involving modulation of membrane elasticity that contributes to Nav inhibition. MD simulations revealed CBD’s localization inside the membrane and effects on bilayer properties. Nuclear magnetic resonance (NMR) confirmed these results, showing CBD localizing below membrane headgroups. To determine the functional implications of these findings, we used a gramicidin-based fluorescence assay to show that CBD alters membrane elasticity or thickness, which could alter Nav function through bilayer-mediated regulation. Site-directed mutagenesis in the vicinity of the Nav1.4 pore revealed that removing the local anesthetic binding site with F1586A reduces the block of I_Na by CBD. Altering the fenestrations in the bilayer-spanning domain with Nav1.4-WWWW blocked CBD access from the membrane into the Nav1.4 pore (as judged by MD). The stabilization of inactivation, however, persisted in WWWW, which we ascribe to CBD-induced changes in membrane elasticity. To investigate the potential therapeutic value of CBD against Nav1.4 channelopathies, we used a pathogenic Nav1.4 variant, P1158S, which causes myotonia and periodic paralysis. CBD reduces excitability in both wild-type and the P1158S variant. Our in vitro and in silico results suggest that CBD may have therapeutic value against Nav1.4 hyperexcitability.     

Protective effects of melatonin on male fertility preservation and reproductive system

Melatonin is a ubiquitous indoleamine hormone synthesized primarily by the pineal gland. Diverse biological actions of melatonin involve quite complex mechanisms via its membrane receptors. More recently, studies have focused on the role of melatonin in male fertility preservation and male reproductive system. The protective effects of melatonin on immature testicular tissue freshness and activity maintenance and the preservation of sperm and spermatogonial stem cells (SSCs) have attracted considerable attention in recent years. Furthermore, since melatonin has strong antioxidant and anti-apoptotic properties, researchers have examined its potential role in male reproductive system. In this article, recent progress regarding melatonin's effects on male fertility preservation and its potential role is reviewed.     

Lead contamination affects the primary productivity traits,biosynthesis of macromolecules and distribution of metal in durum wheat (Triticumdurum L.)

Lead (Pb) pollution emerged as an international issue particularly during second and third industrial revolution and is of serious global concern. Cereal crops have shown different capabilities, innate variability and mechanisms to cope with heavy metals present in their environment. Keeping in view the perspectives of food security and safety with increasing demand for Triticum durum L. it becomes imperative to appraise sustainability potential of the crop for Pb contaminated soils. The current study was conducted to test the hypothesis that T. durum germplasm holds genetic variability to evolve under Pb contamination through modulations of morpho-biochemical parameters of selective advantage. The performance of nine T. durum L. cultivars (CBD25, CBD46, CBD58, CBD59, CBD63, CBD66, CBD68, CBD69 and CBD82) was evaluated following exposure to varying Pb levels (control, 10, 20 and 40 mg kg⁻¹) in soil. Growth, biosynthesis of macromolecules and metal distribution in plant parts were assessed using valid procedures and protocols. The cultivars exhibited a differential degree of tolerance to Pb and among the tested germplasm, CBD59 performed better followed by CBD63 and CBD66 for their primary productivity traits, biosynthesis of pigments and other macromolecules (amino acids, proteins and sugar) along with resilience for Pb uptake and its consequent bioaccumulation in grains. The traits used in the study served as strong predictors to provide superior/selective ability to survive under contaminated environment. The study signified that metal tolerance/sensitivity in the cultivars is independent of magnitude of metal stress, growth responses and Pb accumulation in plant parts hence varied in space and time. The existence of genetic variability, which is a pre-requisite for selection can definitely be of great advantage for future breeding projects to develop high yielding varieties/ cultivars of durum wheat with Pb free grains to assure food security and safety.     

Cannabidiol activates PINK1-Parkin-dependent mitophagy and mitochondrial-derived vesicles

The PINK1/Parkin pathway plays an important role in maintaining a healthy pool of mitochondria. Activation of this pathway can lead to apoptosis, mitophagy, or mitochondrial-derived vesicle formation, depending on the nature of mitochondrial damage. The signaling by which PINK/Parkin activation leads to these different mitochondrial outcomes remains understudied. Here we present evidence that cannabidiol (CBD) activates the PINK1-Parkin pathway in a unique manner. CBD stimulates PINK1-dependent Parkin mitochondrial recruitment similarly to other well-studied Parkin activators but with a distinctive shift in the temporal dynamics and mitochondrial fates. The mitochondrial permeability transition pore inhibitor cyclosporine A exclusively diminished the CBD-induced PINK1/Parkin activation and its associated mitochondrial effects. Unexpectedly, CBD treatment also induced elevated production of mitochondrial-derived vesicles (MDV), a potential quality control mechanism that may help repair partial damaged mitochondria. Our results suggest that CBD may engage the PINK1-Parkin pathway to produce MDV and repair mitochondrial lesions via mitochondrial permeability transition pore opening. This work uncovered a novel link between CBD and PINK1/Parkin-dependent MDV production in mitochondrial health regulation.     

Biological effects of radiofrequency fields: does modulation matter?

This commentary considers modulation as a factor of potential biological importance in assessment of risk of radiofrequency (RF) energy emitted by communications systems and other technologies. Modulation introduces a spread of frequencies into a carrier waveform, but in nearly all cases this spread is small compared to the frequency of the carrier. Consequently, any nonthermal (field-dependent) biological effects related to modulation must result from interaction mechanisms that are fast enough to produce a response at radiofrequencies. Despite considerable speculation, no such mechanisms have been established. While a variety of modulation-dependent biological effects of RF energy have been reported, few such effects have been independently confirmed. Some widely discussed effects, for example a reported modulation-dependent effect of RF fields on the efflux of calcium from brain tissue, remain controversial with no established biological significance. The lack of understanding of the mechanisms underlying such effects prevents any assessment of their significance for communications signals with complex modulation characteristics. Future research should be directed at confirmation and mechanistic understanding of reported biological effects related to modulation. While modulation should be considered in the design of risk studies involving communications-type signals, it should not compromise other aspects of good study design, such as maintaining adequate statistical power and identifying dose-response relationships.     

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.     

Cannabidiol inhibits lung cancer cell invasion and metastasis via intercellular adhesion molecule-1

Cannabinoids inhibit cancer cell invasion via increasing tissue inhibitor of matrix metalloproteinases-1 (TIMP-1). This study investigates the role of intercellular adhesion molecule-1 (ICAM-1) within this action. In the lung cancer cell lines A549, H358, and H460, cannabidiol (CBD; 0.001-3 μM) elicited concentration-dependent ICAM-1 up-regulation compared to vehicle via cannabinoid receptors, transient receptor potential vanilloid 1, and p42/44 mitogen-activated protein kinase. Up-regulation of ICAM-1 mRNA by CBD in A549 was 4-fold at 3 μM, with significant effects already evident at 0.01 μM. ICAM-1 induction became significant after 2 h, whereas significant TIMP-1 mRNA increases were observed only after 48 h. Inhibition of ICAM-1 by antibody or siRNA approaches reversed the anti-invasive and TIMP-1-upregulating action of CBD and the likewise ICAM-1-inducing cannabinoids Δ(9)-tetrahydrocannabinol and R(+)-methanandamide when compared to isotype or nonsilencing siRNA controls. ICAM-1-dependent anti-invasive cannabinoid effects were confirmed in primary tumor cells from a lung cancer patient. In athymic nude mice, CBD elicited a 2.6- and 3.0-fold increase of ICAM-1 and TIMP-1 protein in A549 xenografts, as compared to vehicle-treated animals, and an antimetastatic effect that was fully reversed by a neutralizing antibody against ICAM-1 [% metastatic lung nodules vs. isotype control (100%): 47.7% for CBD + isotype antibody and 106.6% for CBD + ICAM-1 antibody]. Overall, our data indicate that cannabinoids induce ICAM-1, thereby conferring TIMP-1 induction and subsequent decreased cancer cell invasiveness.     

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.     

Systemic Injections of Cannabidiol Enhance Acetylcholine Levels from Basal Forebrain in Rats

Cannabis sativa is a plant that contains more than 500 components, of which the most studied are Δ⁹-tetrahydrocannabinol (Δ⁹-THC) and cannabidiol (CBD). Several studies have indicated that CBD displays neurobiological effects, including wake promotion. Moreover, experimental evidence has shown that injections of CBD enhance wake-related compounds, such as monoamines (dopamine, serotonin, epinephrine, and norepinephrine). However, no clear evidence is available regarding the effects of CBD on additional wake-related neurochemicals such as acetylcholine (ACh). Here, we demonstrate that systemic injections of CBD (0, 5, 10 or 30 mg/kg, i.p.) at the beginning of the lights-on period, increase the extracellular levels of ACh collected from the basal forebrain and measured by microdialysis and HPLC means. Moreover, the time course effects on the contents of ACh were present 5 h post-injection of CBD. Altogether, these data demonstrate that CBD increases ACh levels in a brain region related to wake control. This study is the first to show the effects of ACh levels in CBD-treated rats and suggests that the basal forebrain might be a site of action of CBD for wakefulness modulation.     

生态系统途径——生态系统管理的一种新理念

介绍了生态系统途径的概念和内涵．生态系统途径最早由西方生态学家提出。随后得到一系列国际学术组织和国家的认同和支持,其中《生物多样性公约》、世界自然保护联盟和世界野生动物基金发挥了重要作用,．生态系统途径的实质是对土地、水和生物资源进行综合管理,旨在生态系统保护、生物资源可持续利用和共享生物资源三者之间达到平衡．作为生态系统管理的一种方法论,它以生物为核心。将人类及文化的多样性视为生态系统的一个组成部分,2000年《生物多样性公约》缔约国会议上制定的生态系统管理的12条基本原则和5项行动指南,丰富了生态系统途径的内涵,明确了实施的办法,我国在生态系统管理方面有着丰富的学术储备和经验总结。但也存在一定问题。

     

Methallothioneins and their role in the metabolism and toxicity of metals.

Recent investigations have provided considerable new information regarding the biological role of metallothioneins. The synthesis of this protein is induced in cells by certain metals. It can tightly bind with zinc, copper, cadmium, mercury or silver reducing the availability of diffusible forms of these metals within cells and therefore decreasing their toxic potential. The metallothioneins may also have an important role in regulating the normal absorption and homeostasis of zinc and copper. It is paradoxical, however, in that a protein synthesized within the cell to reduce toxicity, may, in itself, be toxic when excreted or leaked out from the cell to the extracellular space. Further studies are required to elucidate the mechanisms involved in these effects.