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atas cbd

The export of samples is carried out in compliance with the national regulations of Indonesia for the export of biological material (see CBD Board). Over the past years, we developed agreements, standard operational procedures and Infosheets to implement the country’s regulation on research and export of biological material. It is a great success for EFForTS that procedures could be aligned and harmonized with the support of and in close cooperation with the governmental institutions in Indonesia: The State Ministry of Research and Technology and Higher Education (KEMENRISTEKDIKTI), the Ministry of Environment and Forestry (KLHK) and the National Focal Point of the CBD (Dr. Teguh Triono, see above, MoA between the University of Göttingen and the Consortium) – resulting in a transparent, open and trustful collaboration (see ABS measures within EFForTS ). Meanwhile, KEMENRISTEKDIKTI in Indonesia regards EFForTS as best practice example in increasing benefit sharing resulting from international research collaboration.

Access to research locations and export of collected samples or biological material are vital to the success of a research project such as EFForTS carrying out research concerning the CBD at international level. The implementation of the project followed the guidelines of the Deutsche Forschungsgemeinschaft (DFG; German Research Foundation) “Supplementary instructions of the DFG concerning projects with the scope of the CBD” .

Further, we initiated declaring due diligence in relation to Article 7(1) of Regulation (EU) No 511/2014 of the European Parliament and of the Council ‘On Compliance Measures for users from the Nagoya Protocol on Access to Genetic Resources and the Fair and Equitable Sharing of Benefits Arising from their Utilization in the Union’ by uploading the following National Permits of relevant EFForTS subprojects to the DECLARE Data submission portal hosted by the European Commission (bulk submission EC ID 27651, currently in revision by BfN): 1. Prior Informed Consent / PIC (Indonesian: PADIA, Persetujuan Atas Dasar Informasi Awal), signed by BKSDA Jambi (Balai Konservasi Sumber Daya Alam; Nature Conservation Agency at provincial level), 2. Collection Permits, signed by KKH Jakarta (Direktorat Konservasi Keanekaragaman Hayati; Directorate Biodiversity Conservation), and 3. Export Permits, signed by KSDAE Jakarta (Kementerian Lingkungan Hidup dan Kehutanan; The Ministry of Environment and Forestry of the Republik of Indonesia).

Atas cbd

Inflammation and oxidative stress are intimately involved in the genesis of many human diseases. Unraveling that relationship therapeutically has proven challenging, in part because inflammation and oxidative stress “feed off” each other. However, CBD would seem to be a promising starting point for further drug development given its anti-oxidant (although relatively modest) and anti-inflammatory actions on immune cells, such as macrophages and microglia. CBD also has the advantage of not having psychotropic side effects. Studies on models of human diseases support the idea that CBD attenuates inflammation far beyond its antioxidant properties, for example, by targeting inflammation-related intracellular signaling events. The details on how CBD targets inflammatory signaling remain to be defined. The therapeutic utility of CBD is a relatively new area of investigation that portends new discoveries on the interplay between inflammation and oxidative stress, a relationship that underlies tissue and organ damage in many human diseases.

CBD has been shown to modulate the function of the immune system. Overall these actions may be nuanced and concentration-dependent, but in general include suppression of both cell-mediated and humoral immunity and involve inhibition of proliferation, maturation, and migration of immune cells, antigen presentation, and humoral response [1,13]. Key aspects are discussed here. In most in vivo models of inflammation, CBD attenuates inflammatory cell migration/infiltration (e.g. neutrophils) [22]. During neuroinflammation, activated microglial cells migrate towards the site of injury where they release pro-inflammatory cytokines and cytotoxic agents, including ROS. Although important in removal of cellular debris and fighting infection, activated microglial cells often exacerbate local cell damage. CBD was shown to inhibit activated microglial cell migration by antagonizing the abnormal-cannabidiol (Abn-CBD)-sensitive receptor at concentrations < 1 µM [23]. Evidence that the Abn-CBD receptor is the orphan G protein-coupled receptor GPR18 was recently reported [24]. CBD was also shown to block endotoxin-induced oxidative stress resulting from retinal microglial cell activation in uveitis [25]. CBD blocked the immediate activation of NADPH oxidase as well as a second wave of ROS formation and the associated TNFα secretion and p38 MAPK activation. The direct antioxidant property of CBD is unlikely to be the entire explanation for these actions as they occurred at a concentration of 1 µM. Inhibition of adenosine uptake as discussed previously may have been involved. However, a complete understanding of the anti-inflammatory actions of CBD on microglial cells is not yet available. Recently, through an unidentified mechanism, CBD was reported to suppress LPS-induced pro-inflammatory signaling in cultured microglial cells, including NF-κB and STAT1 activation, while enhancing STAT3-related anti-inflammatory signaling [26].

Microglial hyperactivation is a common feature of a number of neurodegenerative diseases, including Parkinson’s, Alzheimer’s, Huntington’s, amyotrophic lateral sclerosis (ALS) and multiple sclerosis(MS) [61,62]. Activated microglia produce a number of pro- and anti-inflammatory cytokines, chemokines, glutamate, neurotrophic factors, prostanoids, and a variety of free radicals that together create a state of oxidative stress. Alzheimer’s disease, which is the most common form of dementia, is characterized by the deposition of “senile” plaques that are sites of microglia activation and inflammation. The resultant oxidative stress is a critical factor in the pathophysiology of Alzheimer’s [63]. The plaques are composed of insoluble aggregates of the beta-amyloid peptide (Aβ), which self-assembles as monomers, oligomers and finally fibrils. Recent evidence shows that the oligomeric form of beta-amyloid is the most neurotoxic species and is most effective as a chemotactic agent for microglia and stimulator of microglial oxidative stress [61,64]. Activated microglia are a major contributor of inflammatory factors in Alzheimer’s and secret a number of pro-inflammatory cytokines, which ironically further enhance Aβ production by neuronal cells [65]. In addition, an inflammatory state was shown to block the ability of microglia to phagocytize fibrillar Aβ [66]. Aging was also shown to negatively impact on the ability of microglia to internalize Aβ [67]. Microglia from aged mice were also shown to be less responsive to stimulation and to secrete greater amounts of IL-6 and TNFα compared to microglia of younger mice. Aged microglia also had lower levels of glutathione, suggesting an increased susceptibility to the harmful effects of oxidative stress. Finally, although controversial, evidence has been put forward suggesting that bone marrow-derived monocytic cells may somehow gain access to the diseased brain in Alzheimer’s and be better at phagocytosing amalyoid plaques than resident microglia [65,68].

Oxidative stress with reactive oxygen species generation is a key weapon in the arsenal of the immune system for fighting invading pathogens and to initiate tissue repair. If excessive or unresolved, however, immune-related oxidative stress can initiate further increasing levels of oxidative stress that cause organ damage and dysfunction. Targeting oxidative stress in these various diseases therapeutically has proven more problematic than first anticipated given the complexities and perversity of both the underlying disease and the immune response. However, growing evidence suggests that the endocannabinoid system, which includes the CB1 and CB2 G protein-coupled receptors and their endogenous lipid ligands, may be an area that is ripe for therapeutic exploitation. In this context, the related nonpsychotropic cannabinoid cannabidiol, which may interact with the endocannabinoid system, but has actions that are distinct, offers promise as a prototype for anti-inflammatory drug development. This review discusses recent studies suggesting that cannabidiol may have utility in treating a number of human diseases and disorders now known to involve activation of the immune system and associated oxidative stress, as a contributor to their etiology and progression. These include rheumatoid arthritis, types I and II diabetes, atherosclerosis, Alzheimer’s disease, hypertension, the metabolic syndrome, ischemia-reperfusion injury, depression, and neuropathic pain.

List of Abbreviations

Although CBD has not been considered for treating hypertension, a parallel between the role of microglia in diabetes and hypertension deserves mention. Activation of microglia within the paraventricular nucleus (PVN) was recently shown to contribute to neurogenic hypertension resulting from chronic angiotensin II infusion in the rat [46]. Microglia activation was associated with enhanced expression of pro-inflammatory cytokines, the acute administration of which into the left ventricle or PVN resulted in increased blood pressure. The hypertensive action of angiotensin II infusion could be blocked by overexpression of IL-10 in the PVN or intracerebroventricular infusion of minocycline, supporting the involvement of ROS.

CBD induces apoptosis of monocytes and certain normal and transformed lymphocytes, including thymocytes and splenocytes, through oxidative stress and increased ROS levels [27–31]. The basis for this action appears to be glutathione depletion due to adduct formation with the reactive metabolite of CBD, cannabidiol hydroxyquinone, thereby triggering cell death through caspase 8 activation and/or the intrinsic apoptotic pathway. Increased ROS from the upregulation of NADPH oxidases via an undefined mechanism may contribute to cell death as well [31]. A recent study assessed the impact of repeated administration of relatively low levels of CBD to adult male Wistar rats on peripheral blood lymphocyte subset distribution [32]. At 2.5 mg/kg/day for 14 days, CBD did not produce lymphopenia, but increased the total number of natural killer T (NKT) cells and percentage numbers of NKT and natural killer (NK) cells. A dose of 5 mg/kg/day did have a lymphopenic effect, but by reducing B, T, Tc and Th lymphocytes. Thus, CBD would appear to suppress specific immunity, while enhancing nonspecific antitumor and antiviral immune response. As discussed by the authors [32], the lymphopenic effect of CBD was observed at a concentration shown to be efficacious in a number of animal models of neurodegenerative and inflammatory diseases, including blocking the progression of collagen-induced arthritis in a murine model of rheumatoid arthritis, decreasing damage to pancreatic islets in the NOD mouse model of type 1 diabetes, lessening hyperalgesia in rat models of neuropathic and inflammatory pain, and preventing cerebral ischemia in gerbils.

Several interactions with relevance to the immune system and oxidative stress are discussed here. First, despite having low affinity for CB1 and CB2 receptors, CBD has been shown to antagonize the actions of cannabinoid CB1/CB2 receptor agonists in the low nanomolar range, consistent with non-competitive inhibition [13]. At 1–10 µM, CBD appears to function as an inverse agonist at both CB1 and CB2 receptors [13]. Second, CBD acts as an inhibitor (IC50 = 28 µM) of fatty acid amide hydrolase (FAAH), the major enzyme for endocannabinoid breakdown. Because FAAH activity correlates with gastrointestinal mobility, CBD may have utility in treating intestinal hypermotility associated with certain inflammatory diseases of the bowel [14].

Diabetes and Diabetic Complications

Inflammation and oxidative stress in atherosclerotic plaque formation. Endothelial dysfunction causes monocyte activation and their binding to endothelial cells, via the production of MCP-1, its binding to CCR2 receptors, and the upregulation of adhesion molecules on endothelial cells (1). Monocytes cross the endothelium and differentiate into macrophages (2). Due to ROS, LDL that traverses the endothelium is converted to mmLDL and oxLDL. Macrophages accumulate oxLDL through scavenger receptors and are turned into foam cells (3). Along with T cells, foam cells produce inflammatory mediators that stimulate migration of smooth muscle and endothelial cells into the intima (4). Figure taken with permission from Reference 88.

Based on rather scant evidence, some have proposed that CBD might have utility in treating neurodegenerative diseases [1,3,69–71]. CBD was shown to have a protective effect on cultured rat pheocromocytoma PC12 cells exposed to Aβ [72,73]. In a concentration-dependent manner, CBD increased cell survival, while decreasing ROS and nitrite production, lipid peroxidation, and iNOS protein expression. CBD was shown to have anti-inflammatory actions in vivo in a mouse model of Alzheimer’s neuroinflammation induced by injection of human Aβ into the hippocampus. CBD dose-dependently attenuated Aβ-induced glial fibrillary acidic protein (GFAP) mRNA, iNOS and IL-1β protein expression, and NO and IL-1β release [74]. In a recent study, CBD was found to protect against amphetamine-induced oxidative protein damage in a rat model of mania and to increase brain-derived neurotrophic factor (BDNF) expression levels in the reversal protocol [75]. Results of these preclinical studies are persuasive and support the need for double-blind placebo controlled trials to assess the therapeutic utility of CBD in patients with neurodegenerative diseases.

Atas cbd

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