Possible Receptor Mechanisms Underlying Cannabidiol Effects on Addictive-like Behaviors in Experimental Animals

Substance use disorder (SUD) is a serious public health problem worldwide for which available treatments show limited effectiveness. Since the legalization of cannabis and the approval of cannabidiol (CBD) by the US Food and Drug Administration, therapeutic potential of CBD for the treatment of SUDs and other diseases has been widely explored. In this mini-review article, we first review the history and evidence supporting CBD as a potential pharmacotherapeutic. We then focus on recent progress in preclinical research regarding the pharmacological efficacy of CBD and the underlying receptor mechanisms on addictive-like behavior. Growing evidence indicates that CBD has therapeutic potential in reducing drug reward, as assessed in intravenous drug self-administration, conditioned place preference and intracranial brain-stimulation reward paradigms. In addition, CBD is effective in reducing relapse in experimental animals. Both in vivo and in vitro receptor mechanism studies indicate that CBD may act as a negative allosteric modulator of type 1 cannabinoid (CB1) receptor and an agonist of type 2 cannabinoid (CB2), transient receptor potential vanilloid 1 (TRPV1), and serotonin 5-HT_1A receptors. Through these multiple-receptor mechanisms, CBD is believed to modulate brain dopamine in response to drugs of abuse, leading to attenuation of drug-taking and drug-seeking behavior. While these findings suggest that CBD is a promising therapeutic candidate, further investigation is required to verify its safety, pharmacological efficacy and the underlying receptor mechanisms in both experimental animals and humans.     

The (Poly)Pharmacology of Cannabidiol in Neurological and Neuropsychiatric Disorders: Molecular Mechanisms and Targets

Cannabidiol (CBD), the major nonpsychoactive Cannabis constituent, has been proposed for the treatment of a wide panel of neurological and neuropsychiatric disorders, including anxiety, schizophrenia, epilepsy and drug addiction due to the ability of its versatile scaffold to interact with diverse molecular targets that are not restricted to the endocannabinoid system. Albeit the molecular mechanisms responsible for the therapeutic effects of CBD have yet to be fully elucidated, many efforts have been devoted in the last decades to shed light on its complex pharmacological profile. In particular, an ever-increasing number of molecular targets linked to those disorders have been identified for this phytocannabinoid, along with the modulatory effects of CBD on their cascade signaling. In this view, here we will try to provide a comprehensive and up-to-date overview of the molecular basis underlying the therapeutic effects of CBD involved in the treatment of neurological and neuropsychiatric disorders.     

Cannabidiol and the Canonical WNT/β-Catenin Pathway in Glaucoma

Glaucoma is a progressive neurodegenerative disease which constitutes the main frequent cause of irreversible blindness. Recent findings have shown that oxidative stress, inflammation and glutamatergic pathway play key roles in the causes of glaucoma. Recent studies have shown a down regulation of the WNT/β-catenin pathway in glaucoma, associated with overactivation of the GSK-3β signaling. WNT/β-catenin pathway is mainly associated with oxidative stress, inflammation and glutamatergic pathway. Cannabidiol (CBD) is a non-psychotomimetic phytocannabinoid derived from Cannabis sativa plant which possesses many therapeutic properties across a range of neuropsychiatric disorders. Since few years, CBD presents an increased interest as a possible drug in anxiolytic disorders. CBD administration is associated with increase of the WNT/β-catenin pathway and decrease of the GSK-3β activity. CBD has a lower affinity for CB1 but can act through other signaling in glaucoma, including the WNT/β-catenin pathway. CBD downregulates GSK3-β activity, an inhibitor of WNT/β-catenin pathway. Moreover, CBD was reported to suppress pro-inflammatory signaling and neuroinflammation, oxidative stress and glutamatergic pathway. Thus, this review focuses on the potential effects of cannabidiol, as a potential therapeutic strategy, on glaucoma and some of the presumed mechanisms by which this phytocannabinoid provides its possible benefit properties through the WNT/β-catenin pathway.     

The Contribution of Small Vessel Disease to Neurodegeneration: Focus on Alzheimer’s Disease,Parkinson’s Disease and Multiple Sclerosis

Brain small vessel disease (SVD) refers to a variety of structural and functional changes affecting small arteries and micro vessels, and manifesting as white matter changes, microbleeds and lacunar infarcts. Growing evidence indicates that SVD might play a significant role in the neurobiology of central nervous system (CNS) neurodegenerative disorders, namely Alzheimer’s disease (AD) and Parkinson’s disease (PD), and neuroinflammatory diseases, such as multiple sclerosis (MS). These disorders share different pathophysiological pathways and molecular mechanisms (i.e., protein misfolding, derangement of cellular clearance systems, mitochondrial impairment and immune system activation) having neurodegeneration as biological outcome. In these diseases, the actual contribution of SVD to the clinical picture, and its impact on response to pharmacological treatments, is not known yet. Due to the high frequency of SVD in adult-aged patients, it is important to address this issue. In this review, we report preclinical and clinical data on the impact of SVD in AD, PD and MS, with the main aim of clarifying the predictability of SVD on clinical manifestations and treatment response.     

Tryptophanyl-tRNA Synthetase as a Potential Therapeutic Target

Tryptophanyl-tRNA synthetase (WRS) is an essential enzyme that catalyzes the ligation of tryptophan (Trp) to its cognate tRNA^trp during translation via aminoacylation. Interestingly, WRS also plays physiopathological roles in diseases including sepsis, cancer, and autoimmune and brain diseases and has potential as a pharmacological target and therapeutic. However, WRS is still generally regarded simply as an enzyme that produces Trp in polypeptides; therefore, studies of the pharmacological effects, therapeutic targets, and mechanisms of action of WRS are still at an emerging stage. This review summarizes the involvement of WRS in human diseases. We hope that this will encourage further investigation into WRS as a potential target for drug development in various pathological states including infection, tumorigenesis, and autoimmune and brain diseases.     

Synergistic Interactions of Cannabidiol with Chemotherapeutic Drugs in MCF7 Cells: Mode of Interaction and Proteomics Analysis of Mechanisms

Cannabidiol (CBD), a nonpsychoactive phytocannabinoid, has recently emerged as a potential cytotoxic agent in addition to its ameliorative activity in chemotherapy-associated side effects. In this work, the potential interactions of CBD with docetaxel (DOC), doxorubicin (DOX), paclitaxel (PTX), vinorelbine (VIN), and 7-ethyl-10-hydroxycamptothecin (SN−38) were explored in MCF7 breast adenocarcinoma cells using different synergy quantification models. The apoptotic profiles of MCF7 cells after the treatments were assessed via flow cytometry. The molecular mechanisms of CBD and the most promising combinations were investigated via label-free quantification proteomics. A strong synergy was observed across all synergy models at different molar ratios of CBD in combination with SN−38 and VIN. Intriguingly, synergy was observed for CBD with all chemotherapeutic drugs at a molar ratio of 636:1 in almost all synergy models. However, discording synergy trends warranted the validation of the selected combinations against different models. Enhanced apoptosis was observed for all synergistic CBD combinations compared to monotherapies or negative controls. A shotgun proteomics study highlighted 121 dysregulated proteins in CBD-treated MCF7 cells compared to the negative controls. We reported the inhibition of topoisomerase II β and α, cullin 1, V-type proton ATPase, and CDK-6 in CBD-treated MCF7 cells for the first time as additional cytotoxic mechanisms of CBD, alongside sabotaged energy production and reduced mitochondrial translation. We observed 91 significantly dysregulated proteins in MCF7 cells treated with the synergistic combination of CBD with SN−38 (CSN−38), compared to the monotherapies. Regulation of telomerase, cell cycle, topoisomerase I, EGFR1, protein metabolism, TP53 regulation of DNA repair, death receptor signalling, and RHO GTPase signalling pathways contributed to the proteome-wide synergistic molecular mechanisms of CSN−38. In conclusion, we identified significant synergistic interactions between CBD and the five important chemotherapeutic drugs and the key molecular pathways of CBD and its synergistic combination with SN−38 in MCF7 cells. Further in vivo and clinical studies are warranted to evaluate the implementation of CBD-based synergistic adjuvant therapies for breast cancer.     

The Metabolic Efficacy of a Cannabidiolic Acid (CBDA) Derivative in Treating Diet- and Genetic-Induced Obesity

Obesity is a global medical problem; its common form is known as diet-induced obesity (DIO); however, there are several rare genetic disorders, such as Prader–Willi syndrome (PWS), that are also associated with obesity (genetic-induced obesity, GIO). The currently available therapeutics for treating DIO and GIO are very limited, and they result in only a partial improvement. Cannabidiolic acid (CBDA), a constituent of Cannabis sativa, gradually decarboxylates to cannabidiol (CBD). Whereas the anti-obesity properties of CBD have been reasonably identified, our knowledge of the pharmacology of CBDA is more limited due to its instability. To stabilize CBDA, a new derivative, CBDA-O-methyl ester (HU-580, EPM301), was synthesized. The therapeutic potential of EPM301 in appetite reduction, weight loss, and metabolic improvements in DIO and GIO was tested in vivo. EPM301 (40 mg/kg/d, i.p.) successfully resulted in weight loss, increased ambulation, as well as improved glycemic and lipid profiles in DIO mice. Additionally, EPM301 ameliorated DIO-induced hepatic dysfunction and steatosis. Importantly, EPM301 (20 and 40 mg/kg/d, i.p.) effectively reduced body weight and hyperphagia in a high-fat diet-fed Magel2^null mouse model for PWS. In addition, when given to standard-diet-fed Magel2^null mice as a preventive treatment, EPM301 completely inhibited weight gain and adiposity. Lastly, EPM301 increased the oxidation of different nutrients in each strain. All together, EPM301 ameliorated obesity and its metabolic abnormalities in both DIO and GIO. These results support the idea to further promote this synthetic CBDA derivative toward clinical evaluation in humans.     

A Review of the Application and Pharmacological Properties of <Emphasis Type="Italic">α</Emphasis>-Bisabolol and <Emphasis Type="Italic">α</Emphasis>-Bisabolol-Rich Oils

α-Bisabolol is a naturally occurring sesquiterpene alcohol which was first isolated from Matricaria chamomilla (Asteraceae) in the twentieth century and has since been identified in other aromatic plants such as Eremanthus erythropappus, Smyrniopsis aucheri and Vanillosmopsis species. Recently, α-bisabolol was identified as a major constituent of Salvia runcinata essential oil, a plant indigenous to South Africa. The use of α-bisabolol or bisabolol-rich oil as an anti-inflammatory agent is ubiquitous. This compound also exhibits several other pharmacological properties such as analgesic, antibiotic and anticancer activities. Mutagenicity and genotoxicity of bisabolol have also been investigated. Due to the low toxicity associated with bisabolol the Food and Drug Administration (FDA) has granted this constituent with Generally Regarded as Safe (GRAS) status which has promoted its use as an active ingredient in several commercial products. This review aims to summarise the role of α-bisabolol in pharmacological and/or physiological processes and to discuss some of the possible mechanisms of action of this commercially important molecule.     

Opportunities,Challenges and Pitfalls of Using Cannabidiol as an Adjuvant Drug in COVID-19 †

Severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection may lead to coronavirus disease 2019 (COVID-19) which, in turn, may be associated with multiple organ dysfunction. In this review, we present advantages and disadvantages of cannabidiol (CBD), a non-intoxicating phytocannabinoid from the cannabis plant, as a potential agent for the treatment of COVID-19. CBD has been shown to downregulate proteins responsible for viral entry and to inhibit SARS-CoV-2 replication. Preclinical studies have demonstrated its effectiveness against diseases of the respiratory system as well as its cardioprotective, nephroprotective, hepatoprotective, neuroprotective and anti-convulsant properties, that is, effects that may be beneficial for COVID-19. Only the latter two properties have been demonstrated in clinical studies, which also revealed anxiolytic and antinociceptive effects of CBD (given alone or together with Δ⁹-tetrahydrocannabinol), which may be important for an adjuvant treatment to improve the quality of life in patients with COVID-19 and to limit post-traumatic stress symptoms. However, one should be aware of side effects of CBD (which are rarely serious), drug interactions (also extending to drugs acting against COVID-19) and the proper route of its administration (vaping may be dangerous). Clearly, further clinical studies are necessary to prove the suitability of CBD for the treatment of COVID-19.     

Fabrication and investigation of the optoelectrical properties of MoS2/CdS heterojunction solar cells

Molybdenum disulfide (MoS₂)/cadmium sulfide (CdS) heterojunction solar cells were successfully synthesized via chemical bath deposition (CBD) and chemical vapor deposition (CVD). The as-grown CdS film on a fluorine tin oxide (FTO) substrate deposited by CBD is continuous and compact. The MoS₂ film deposited by CVD is homogeneous and continuous, with a uniform color and a thickness of approximately 10 nm. The optical absorption range of the MoS₂/CdS heterojunction covers the visible and near-infrared spectral regions of 350 to 800 nm, which is beneficial for the improvement of solar cell efficiency. Moreover, the MoS₂/CdS solar cell exhibits good current-voltage (I-V) characteristics and pronounced photovoltaic behavior, with an open-circuit voltage of 0.66 V and a short-circuit current density of 0.227 × 10^-6 A/cm², comparable to the results obtained from other MoS₂-based solar cells. This research is critical to investigate more efficient and stable solar cells based on graphene-like materials in the future.     

Functional Properties of the Catalytic Domain of Mouse Acidic Mammalian Chitinase Expressed in Escherichia coli

Mouse acidic mammalian chitinase (AMCase) plays important physiological roles in defense and nutrition. AMCase is composed of an N-terminal catalytic domain (CatD) and a C-terminal chitin-binding domain (CBD). We expressed CatD of mouse AMCase as a recombinant fusion protein with Protein A and V5-His in Escherichia coli (Protein A-CatD-V5-His), evaluated its functional properties and compared them to the full-length AMCase (Protein A-AMCase-V5-His). Under our experimental conditions, the chitinolytic activity of both proteins against 4-nitrophenyl N,N''-diacetyl-β-d-chitobioside was equivalent with regard to their specific enzymatic activities, optimal pH and temperature as well as to the pH and temperature stability. CatD bound to chitin beads and cleaved the N-acetylglucosamine hexamer, colloidal and crystalline chitin as well as the shrimp shell, and released primarily N,N''-diacetylchitobiose fragments at pH 2.0. These results indicate that the primary structure of CatD is sufficient to form a proper tertiary structure required for chitinolytic activity, recognize chitin substrates and degrade them in the absence of a CBD. Our recombinant proteins can be used for further studies evaluating pathophysiological roles of AMCase in different diseases.     

Using Proteomics to Understand How Leishmania Parasites Survive inside the Host and Establish Infection

Leishmania is a protozoan parasite that causes a wide range of different clinical manifestations in mammalian hosts. It is a major public health risk on different continents and represents one of the most important neglected diseases. Due to the high toxicity of the drugs currently used, and in the light of increasing drug resistance, there is a critical need to develop new drugs and vaccines to control Leishmania infection. Over the past few years, proteomics has become an important tool to understand the underlying biology of Leishmania parasites and host interaction. The large-scale study of proteins, both in parasites and within the host in response to infection, can accelerate the discovery of new therapeutic targets. By studying the proteomes of host cells and tissues infected with Leishmania, as well as changes in protein profiles among promastigotes and amastigotes, scientists hope to better understand the biology involved in the parasite survival and the host-parasite interaction. This review demonstrates the feasibility of proteomics as an approach to identify new proteins involved in Leishmania differentiation and intracellular survival.     

The Anti-Inflammatory Properties of Licorice (Glycyrrhiza glabra)-Derived Compounds in Intestinal Disorders

Intestinal diseases, such as inflammatory bowel diseases (IBDs) and colorectal cancer (CRC), are a significant source of morbidity and mortality worldwide. Epidemiological data have shown that IBD patients are at an increased risk for the development of CRC. IBD-associated cancer develops against a background of chronic inflammation and oxidative stress, and their products contribute to cancer development and progression. Therefore, the discovery of novel drugs for the treatment of intestinal diseases is urgently needed. Licorice (Glycyrrhiza glabra) has been largely used for thousands of years in traditional Chinese medicine. Licorice and its derived compounds possess antiallergic, antibacterial, antiviral, anti-inflammatory, and antitumor effects. These pharmacological properties aid in the treatment of inflammatory diseases. In this review, we discuss the pharmacological potential of bioactive compounds derived from Licorice and addresses their anti-inflammatory and antioxidant properties. We also discuss how the mechanisms of action in these compounds can influence their effectiveness and lead to therapeutic effects on intestinal disorders.     

The Phenoxyalkyltriazine Antagonists for 5-HT6 Receptor with Promising Procognitive and Pharmacokinetic Properties In Vivo in Search for a Novel Therapeutic Approach to Dementia Diseases

Among the serotonin receptors, one of the most recently discovered 5-HT₆ subtype is an important protein target and its ligands may play a key role in the innovative treatment of cognitive disorders. However, none of its selective ligands have reached the pharmaceutical market yet. Recently, a new chemical class of potent 5-HT₆ receptor agents, the 1,3,5-triazine-piperazine derivatives, has been synthesized. Three members, the ortho and meta dichloro- (1,2) and the unsubstituted phenyl (3) derivatives, proved to be of special interest due to their high affinities (1,2) and selectivity (3) toward 5-HT₆ receptor. Thus, a broader pharmacological profile for 1–3, including comprehensive screening of the receptor selectivity and drug-like parameters in vitro as well as both, pharmacokinetic and pharmacodynamic properties in vivo, have been investigated within this study. A comprehensive analysis of the obtained results indicated significant procognitive-like activity together with beneficial drug-likeness in vitro and pharmacokinetics in vivo profiles for both, (RS)-4-[1-(2,3-dichlorophenoxy)propyl]-6-(4-methylpiperazin-1-yl)-1,3,5-triazin-2-amine (2) and (RS)-4-(4-methylpiperazin-1-yl)-6-(1-phenoxypropyl)-1,3,5-triazin-2-amine (3), but insensibly predominant for compound 2. Nevertheless, both compounds (2 and 3) seem to be good Central Nervous System drug candidates in search for novel therapeutic approach to dementia diseases, based on the 5-HT₆ receptor target.     

Yeasts as Complementary Model Systems for the Study of the Pathological Repercussions of Enhanced Synphilin-1 Glycation and Oxidation

Synphilin-1 has previously been identified as an interaction partner of α-Synuclein (αSyn), a primary constituent of neurodegenerative disease-linked Lewy bodies. In this study, the repercussions of a disrupted glyoxalase system and aldose reductase function on Synphilin-1 inclusion formation characteristics and cell growth were investigated. To this end, either fluorescent dsRed-tagged or non-tagged human SNCAIP, which encodes the Synphilin-1 protein, was expressed in Saccharomyces cerevisiae and Schizosaccharomyces pombe yeast strains devoid of enzymes Glo1, Glo2, and Gre3. Presented data shows that lack of Glo2 and Gre3 activity in S. cerevisiae increases the formation of large Synphilin-1 inclusions. This correlates with enhanced oxidative stress levels and an inhibitory effect on exponential growth, which is most likely caused by deregulation of autophagic degradation capacity, due to excessive Synphilin-1 aggresome build-up. These findings illustrate the detrimental impact of increased oxidation and glycation on Synphilin-1 inclusion formation. Similarly, polar-localised inclusions were observed in wild-type S. pombe cells and strains deleted for either glo1⁺ or glo2⁺. Contrary to S. cerevisiae, however, no growth defects were observed upon expression of SNCAIP. Altogether, our findings show the relevance of yeasts, especially S. cerevisiae, as complementary models to unravel mechanisms contributing to Synphilin-1 pathology in the context of neurodegenerative diseases.     

TXNDC5, a Newly Discovered Disulfide Isomerase with a Key Role in Cell Physiology and Pathology

Thioredoxin domain-containing 5 (TXNDC5) is a member of the protein disulfide isomerase family, acting as a chaperone of endoplasmic reticulum under not fully characterized conditions As a result, TXNDC5 interacts with many cell proteins, contributing to their proper folding and correct formation of disulfide bonds through its thioredoxin domains. Moreover, it can also work as an electron transfer reaction, recovering the functional isoform of other protein disulfide isomerases, replacing reduced glutathione in its role. Finally, it also acts as a cellular adapter, interacting with the N-terminal domain of adiponectin receptor. As can be inferred from all these functions, TXNDC5 plays an important role in cell physiology; therefore, dysregulation of its expression is associated with oxidative stress, cell ageing and a large range of pathologies such as arthritis, cancer, diabetes, neurodegenerative diseases, vitiligo and virus infections. Its implication in all these important diseases has made TXNDC5 a susceptible biomarker or even a potential pharmacological target.     

Cannabidiol and Other Cannabinoids in Demyelinating Diseases

A growing body of preclinical evidence indicates that certain cannabinoids, including cannabidiol (CBD) and synthetic derivatives, may play a role in the myelinating processes and are promising small molecules to be developed as drug candidates for management of demyelinating diseases such as multiple sclerosis (MS), stroke and traumatic brain injury (TBI), which are three of the most prevalent demyelinating disorders. Thanks to the properties described for CBD and its interesting profile in humans, both the phytocannabinoid and derivatives could be considered as potential candidates for clinical use. In this review we will summarize current advances in the use of CBD and other cannabinoids as future potential treatments. While new research is accelerating the process for the generation of novel drug candidates and identification of druggable targets, the collaboration of key players such as basic researchers, clinicians and pharmaceutical companies is required to bring novel therapies to the patients.