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Background: Cannabinoid receptors are involved in the neuro-pathogenic mechanisms of inflammatory conditions of the central nervous system and their expression can be modulated during diseases. Methods: In this manuscript we highlight the function of cannabinoid receptors, their signalling and expression at peripheral and central levels in order to understand their implication in neuro-inflammation and review the effects of cannabinoids in neuro-inflammatory disorders. Results: Brain inflammatory processes are characterized by infiltration of numerous types of cells: both peripheral and brain resident immune cells and other neuronal cells. The disruption of the blood brain barrier favours cell infiltration in the central nervous system with consequent neuronal damage, a common event in many neuro-inflammatory diseases. Cannabinoids affect brain adaptive and immune response, regulate inflammatory mediators and can exert a role in blood brain barrier damage prevention. Conclusion: Various patents describe the beneficial properties of cannabinoids in numerous neurodegenerative diseases with inflammatory components and overall effects support the therapeutic application of cannabinoids.
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... Cannabinoids, endogenous, synthetic, and natural types have been generally associated with anti-neuroinflammation by downregulating pro-inflammatory and/or upregulating anti-inflammatory cytokines typically through CB2Rs [93][94][95]. However, there is growing evidence demonstrating that natural and synthetic cannabinoids can indeed upregulate pro-inflammatory cytokines and thus possibly induce neuroinflammation and/or depression. ...
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Substance use/abuse is one of the main causes of depressive symptoms. Cannabis and synthetic cannabinoids in particular gained significant popularity in the past years. There is an increasing amount of clinical data associating such compounds with the inflammatory component of depression, indicated by the up-regulation of pro-inflammatory cytokines. Pro-inflammatory cytokines are also well-known to regulate the enzymes of the kynurenine pathway (KP), which is responsible for metabolizing tryptophan, a precursor in serotonin synthesis. Enhanced pro-inflammatory cytokine levels may over-activate the KP, leading to tryptophan depletion and reduced serotonin levels, which can subsequently precipitate depressive symptoms. Therefore, such mechanism might represent a possible link between the endocannabinoid system (ECS) and the KP in depression, via the inflammatory and dysregulated serotonergic component of the disorder. This review will summarize the data regarding those natural and synthetic cannabinoids that increase pro-inflammatory cytokines. Furthermore, the data on such cytokines associated with KP activation will be further reviewed accordingly. The interaction of the ECS and the KP has been postulated and demonstrated in some studies previously. This review will further contribute to this yet less explored connection and propose the KP to be the missing link between cannabinoid-induced inflammation and depressive symptoms.
... Both CB1 and CB2 receptors are known for their anti-inflammatory and antinociceptive properties. [5][6][7][8] Our ligand design followed a traditional SAR approach and was supported by molecular modeling studies of the reported X-ay structures of NAAA. 50 Several inhibitors were evaluated in stability assays and demonstrated very good plasma stability (t 1/2 > 120 min; human and rodents), but rather moderate microsomal stability (t 1/ 2~5 -15 min) in human and rodent liver microsomal preparations. ...
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N-acylethanolamine acid amidase (NAAA) inhibition represents an exciting novel approach to treat inflammation and pain. NAAA is a cysteine amidase which preferentially hydrolyzes the endogenous biolipids palmitoylethanolamide (PEA) and oleoylethanolamide (OEA). PEA is an endogenous agonist of the nuclear peroxisome proliferator-activated receptor-α (PPAR-α), which is a key regulator of inflammation and pain. Thus, blocking the degradation of PEA with NAAA inhibitors results in augmentation of the PEA/PPAR-α signaling pathway and regulation of inflammatory and pain processes. We have prepared a new series of NAAA inhibitors exploring the azetidine-nitrile (cyanamide) pharmacophore that led to the discovery of highly potent and selective compounds. Key analogs demonstrated single-digit nanomolar potency for hNAAA and showed >100-fold selectivity against serine hydrolases FAAH, MGL and ABHD6, and cysteine protease cathepsin K. Additionally, we have identified potent and selective dual NAAA-FAAH inhibitors to investigate a potential synergism between two distinct anti-inflammatory molecular pathways, the PEA/PPAR-α anti-inflammatory signaling pathway,1-4 and the cannabinoid receptors CB1 and CB2 pathways which are known for their antiinflammatory and antinociceptive properties.5-8 Our ligand design strategy followed a traditional structure-activity relationship (SAR) approach and was supported by molecular modeling studies of reported X-ray structures of hNAAA. Several inhibitors were evaluated in stability assays and demonstrated very good plasma stability (t1/2 > 2 h; human and rodents). The disclosed cyanamides represent promising new pharmacological tools to investigate the potential role of NAAA inhibitors and dual NAAA-FAAH inhibitors as therapeutic agents for the treatment of inflammation and pain.
... It has been suggested the abnormal brain connectivity seen in children with ASD could be due to lack of CB1 axon guidance (Schultz and Gould, 2016;Schultz, 2010;McFadden and Minshew, 2013). The cannabinoid receptors2 (CB2) are abundant in immune and microglial cells and primarily play a role in immune system regulation (Ranieri et al., 2016). Siniscalco et al. demonstrated that CB2, but not CB1, is upregulated in peripheral blood mononuclear cells of children affected by ASD compared to controls (Siniscalco et al., 2013). ...
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Background: The non-prescription medication paracetamol (acetaminophen, APAP) is currently recommended as a safe pain and fever treatment during pregnancy. However, recent studies suggest a possible association between APAP use in pregnancy and offspring neurodevelopment. Objectives: To conduct a review of publications reporting associations between prenatal APAP use and offspring neurodevelopmental outcomes. Methods: Relevant sources were identified through a key word search of multiple databases (Medline, CINAHL, OVID and TOXNET) in September 2016. All English language observational studies of pregnancy APAP and three classes of neurodevelopmental outcomes (autism spectrum disorder (ASD), attention deficit hyperactivity disorder (ADHD), and intelligence quotient (IQ)) were included. One reviewer (AZB) independently screened all titles and abstracts, extracted and analyzed the data. Results: 64 studies were retrieved and 55 were ineligible. Nine prospective cohort studies fulfilled all inclusion criteria. Data pooling was not appropriate due to heterogeneity in outcomes. All included studies suggested an association between prenatal APAP exposure and the neurodevelopmental outcomes; ADHD, ASD, or lower IQ. Longer duration of APAP use was associated with increased risk. Associations were strongest for hyperactivity and attention-related outcomes. Little modification of associations by indication for use was reported. Conclusions: Together, these nine studies suggest an increased risk of adverse neurodevelopmental outcomes following prenatal APAP exposure. Further studies are urgently needed with; precise indication of use and exposure assessment of use both in utero and in early life. Given the current findings, pregnant women should be cautioned against indiscriminate use of APAP. These results have substantial public health implications.
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Inflammation in the central nervous system (CNS) contributes to disease pathologies by disrupting the integrity of the blood–brain barrier (BBB). Tight junctions (TJ) are a key component of the BBB. Following hypoxic–ischaemic or mechanical injury to the brain, inflammatory mediators are released such as cytokines, chemokines, and growth factors. Simultaneously, matrix metalloproteinases (MMPs) are released which can degrade TJ proteins. Subsequently, the function and morphology of the BBB are disrupted, which allows immune cells an opportunity to enter into the brain parenchyma. This review summarises the information on the role of TJ protein families in the BBB and provides a comprehensive summary of the mechanisms whereby inflammation breaks down the BBB by increasing degradation of TJ proteins.
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The blood-brain barrier (BBB) limits entry of blood-derived products, pathogens, and cells into the brain that is essential for normal neuronal functioning and information processing. Post-mortem tissue analysis indicates BBB damage in Alzheimer's disease (AD). The timing of BBB breakdown remains, however, elusive. Using an advanced dynamic contrast-enhanced MRI protocol with high spatial and temporal resolutions to quantify regional BBB permeability in the living human brain, we show an age-dependent BBB breakdown in the hippocampus, a region critical for learning and memory that is affected early in AD. The BBB breakdown in the hippocampus and its CA1 and dentate gyrus subdivisions worsened with mild cognitive impairment that correlated with injury to BBB-associated pericytes, as shown by the cerebrospinal fluid analysis. Our data suggest that BBB breakdown is an early event in the aging human brain that begins in the hippocampus and may contribute to cognitive impairment. Copyright © 2015 Elsevier Inc. All rights reserved.