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![Overview of the endocannabinoid system (ECS), outlining key endocannabinoids, cannabinoid receptors, and related enzymes involved in endocannabinoid synthesis and degradation. DAG: Diacylglycerol; DAGL: Diacylglycerol lipase; 2-AG: 2-arachidonoylglycerol; NAPE: N-acylphosphatidylethanolamine; NAPE-PLD: N-acyl-phosphatidylethanolamine-specific phospholipase D; TRPV1: Transient receptor potential cation channel subfamily V member 1; CB1: Cannabinoid receptor 1; CB2: Cannabinoid receptor 2; GPR55: G protein-coupled receptor 55; MAGL: Monoacylglycerol lipase; FAAH: Fatty acid amide hydrolase; EMT: Endocannabinoid membrane transporter-"?" denotes controversy surrounding the presence of said transporter. Figure used with permission from the publisher in reference [47] (version used modified by reference [48]).](profile/J-Daniel-Lafreniere/publication/330449818/figure/fig1/AS:716078627962880@1547737857042/Overview-of-the-endocannabinoid-system-ECS-outlining-key-endocannabinoids-cannabinoid.png)
Overview of the endocannabinoid system (ECS), outlining key endocannabinoids, cannabinoid receptors, and related enzymes involved in endocannabinoid synthesis and degradation. DAG: Diacylglycerol; DAGL: Diacylglycerol lipase; 2-AG: 2-arachidonoylglycerol; NAPE: N-acylphosphatidylethanolamine; NAPE-PLD: N-acyl-phosphatidylethanolamine-specific phospholipase D; TRPV1: Transient receptor potential cation channel subfamily V member 1; CB1: Cannabinoid receptor 1; CB2: Cannabinoid receptor 2; GPR55: G protein-coupled receptor 55; MAGL: Monoacylglycerol lipase; FAAH: Fatty acid amide hydrolase; EMT: Endocannabinoid membrane transporter-"?" denotes controversy surrounding the presence of said transporter. Figure used with permission from the publisher in reference [47] (version used modified by reference [48]).
Source publication
Central nervous system (CNS) injury, such as stroke or trauma, is known to increase susceptibility to various infections that adversely affect patient outcomes (CNS injury-induced immunodepression—CIDS). The endocannabinoid system (ECS) has been shown to have immunoregulatory properties. Therefore, the ECS might represent a druggable target to over...
Context in source publication
Context 1
... 2-AG biosynthesis begins with phospholipase C-mediated hydrolysis of membrane phospholipids, yielding diacylglycerol (DAG) that is then converted to 2-AG by diacylglycerol lipase (DGL). The 2-AG is then inactivated by monoacylglycerol lipase (MAGL), while AEA is hydrolyzed by FAAH [45,47] (Figure 2). The ECS plays an important role in the regulation of the immune system in response to inflammation. ...
Citations
... It has also been observed in some studies that Gα i/o , likely via the Gβγ subunit, may stimulate cAMP synthesis and activate the Akt and ERK pathways, presumably by regulating various adenylyl cyclase isozymes [8,53,55,56]. The activation and increased expression of CB2 receptors have been shown in various neurodegenerative diseases, and these receptors have been intensively studied as possible pharmacological targets against neuroinflammation and neuroinflammation-related neurodegeneration [54,57,58]. The observed neuroprotective effects of CB2 receptor agonists and CB2 receptor activation are mainly related to the suppression of microglial activation, the modulation of cytokine release, and the production of reactive oxygen species (ROS) [10,38,54,[59][60][61]. ...
In the last few decades, endocannabinoids, plant-derived cannabinoids and synthetic cannabinoids have received growing interest as treatment options in neurodegenerative conditions. In various experimental settings, they have displayed antioxidative, anti-inflammatory, antiapoptotic, immunomodulatory, and neuroprotective effects. However, due to numerous targets and downstream effectors of their action, the cellular and molecular mechanisms underlying these effects are rather complex and still under discussion. Cannabinoids are able to neutralize free radicals and modulate the production of reactive oxygen species and the activity of antioxidative systems acting on CB1 and CB2 cannabinoid receptors. The activation of CB1 receptors stimulates signaling pathways involved in antioxidative defense and survival (such as the phosphoinositide 3-kinase (PI3K)/Akt, mitogen-activated protein kinase (MAPK), and Nrf2 pathways) and regulates glutamatergic signaling, the activation of N-methyl-D-aspartate (NMDA) receptors, calcium influx, and the induction of Ca2+-regulated signaling cascades, whereas the neuroprotective effects mediated by CB2 receptors are due to the suppression of microglial activation and the release of prooxidative and proinflammatory mediators. This review summarizes the main molecular mechanisms and new advances in understanding the antioxidative and neuroprotective effects of cannabinoids. Because of the plethora of possible pharmacological interventions related to oxidative stress and cannabinoid-mediated neuroprotection, future research should be directed towards a better understanding of the interplay between activated signal transduction pathways and molecular targets with the aim to improve treatment options and efficacy by targeting the endocannabinoid system.
... 4 The incidence of hemorrhagic stroke is lower than that of ischemic stroke, and the main treatment is surgical treatment of intracranial lesions and postoperative medication to control blood pressure and prevent vasospasm. 5 Because of the great harm of stroke, unsatisfactory treatment effect, and poor prognosis, the prevention and treatment of stroke is very urgent and important. ...
Stroke is one of the most important acute diseases that endanger human health and result in death, including acute cerebral hemorrhage and acute cerebral ischemia. Acute onset is its most prominent feature. Carbon monoxide (CO) is a colorless and odorless gas existing at room temperature. It is not only a common air pollutant, but also has been found to be closely related to stroke. A large amount of exogenous CO has an important impact on the incidence and prognosis of stroke, while endogenous CO as a gas signal also has an important impact on neuroprotection after stroke. Both low-dose CO inhalation and CO-releasing molecule-3 (a molecule that emits CO) treatment have shown the benefits of stroke, and perhaps the role of CO in stroke is one of the key areas for future research.
... A graphical representation of immune dysregulation following central nervous system (CNS) injury (modifi ording to Zhou et al., 2019[8]). ...
Patients suffering from stroke, traumatic brain injury, or other forms of central nervous system (CNS) injury have an increased risk of nosocomial infections due to CNS injury-induced immunosuppression (CIDS). Immediately after CNS-injury, the response in the brain is pro-inflammatory; however, subsequently, local and systemic immunity is suppressed due to the compensatory release of immunomodulatory neurotransmitters. CIDS makes patients susceptible to contracting infections, among which pneumonia is very common and often lethal. Ventilator-acquired pneumonia has a mortality of 20–50% and poses a significant risk to vulnerable patients such as stroke survivors. The mechanisms involved in CIDS are not well understood. In this review, we consolidate the evidence for cellular processes underlying the pathogenesis of CIDS, the emerging treatments, and speculate further on the immune elements at play.
... This activation inhibits neuro-in lammation and, thereby attenuates severity of CNS injury-induced immunodepression (CIDS). However, in later phases inhibition of CB2R can restore immune function, which may be a promising pharmacological strategy [118]. ...
Medical benefi ts of cannabis and related compounds is widely known. Discovery of
psychotropic plant cannabinoid Δ9-tetrahydrocannabinol have urged researchers to study more
about the cannabinoid system and related therapeutics in the fi eld of neurology and medicine.
Where activation of cannabinoid receptor type 1 (CB1R) yielded in unwanted and serious side
eff ects, discovery of cannabinoid receptor type 2 (CB2R) and its ligands gave a new hope. Till
now there is limited success in this fi eld because of complex expanded endocannabinoid system
comprising of receptors, ligands and enzymes. In this review we will update about the role of
endocannabinoidome relevant to neurological disorders.
... Central nervous system (CNS) injury is one of the primary causes of disability and mortality worldwide and includes conditions such as stroke, spinal cord injury, and traumatic brain injury. 1,2 Globally, stroke ranks the second leading cause of death, 3 the third leading cause of disability, 3,4 and up to 85% of stroke patients suffer from complicating medical events during the acute care. 5 Currently, acute stroke therapy is limited to reperfusion approaches and high-end medical support in dedicated stroke units. ...
Introduction: Acute central nervous system (CNS) injury, such as stroke, spinal cord injury, or traumatic brain injury can result in dysregulated immune response, and the condition is known as CNS injury-induced immunodeficiency syndrome (CIDS). The endocannabinoid system is an important homeostatic regulator in the CNS and immune system. Activation of cannabinoid 2 receptors (CB2R) on immune cells has been reported to dampen inflammation, suggesting a potential role of CB2R in the peripheral immune response following CNS injury. In this study, we have investigated the effect of CB2R modulation on the peripheral immune response during CIDS. Materials and Methods: Experimental CNS injury was induced in C57BL/6 mice through intracerebral injection of the vasopressor peptide, endothelin-1. A selective CB2R agonist (HU308) was used as an early treatment before the onset of CIDS and AM630, a selective CB2R antagonist, was administered as a later-phase therapy to combat the systemic immunodeficiency following the CNS injury. The peripheral immune response to endotoxin was studied 24 h after the CNS injury using intravital microscopy to examine leukocyte activation within the intestinal microcirculation in mice. Brain infarct size, and plasma levels of cytokines and soluble adhesion molecules were measured as additional parameters for the assessment of treatment outcomes. Results: Our results showed that early CB2R activation with HU308 reduced brain injury size and restored leukocyte response to endotoxin in the peripheral microcirculation. Late CB2R inhibition with AM630 also improved the peripheral leukocyte response to endotoxin and did not exacerbate the extent of brain injury. Discussion: CB2R activation has the potential to mitigate CNS injury as an early treatment by limiting neuroinflammation and preventing the development of CIDS. At the later stage with already-established CIDS, treatment may require dampening CB2R activation to improve the patient's outcome.
... Going forward, the legalisation of cannabis in Canada as of October, 2018, evidence of the unique Canadian legal context, may impact future results regarding cannabis use as either a contributing factor to injury, or as a potential neuroprotective buffer to injury as some surmise 28 . To inform future injury prevention efforts, ongoing monitoring of snowsport injuries remains important to evaluate past injury prevention strategies, to explore changing participation patterns (e.g., gender, age, snowboarding, terrain park use) and to examine the impact of other potential risk factors (e.g., legalised cannabis use). ...
Objectives
This research explores snowsport injury trends in western Canadian resorts over the decade 2008-2018.
Design
Ecological study.
Methods
Injury and participation data on alpine skiing and snowboarding was provided by the Canada West Ski Areas Association for 2008-2018. Inclusion criteria were met by 29 of 52 resorts, resulting in the analysis of 107,540 injury reports via SPSS 24, using descriptive statistics and chi-squared analysis.
Results
Over the decade: there was a gradual decline in the injury rate, averaging 2.24 injuries per 1000 skier days. Male snowboarders accounted for 1/3 of all injured participants, females were 42% of all. Day-ticket holders were the most injured of all customer-types, with most injuries occurring as the result of falls on marked, green/easiest terrain. For skiers, injuries to lower limbs, and especially knees, were most common. For snowboarders, upper limb injuries, especially wrists, were most common. 12.8% of the injured population required emergency transport. Advanced slopes/terrain had the highest proportion requiring emergency transport. Fewer skiers experienced head injuries than snowboarders. Snowboarders experienced a higher proportion of serious injuries.
Conclusions
Snowsport injuries are relatively rare when compared to other sports. Skiers were most prone to knee injuries and snowboarders to wrist injuries. Emergency transport was proportionally needed more from advanced slopes/terrain. Further research is needed into why and how participants make decisions around risk. Future injury prevention strategies should be evaluated in light of potential risk factors such as, social determinants of injury, fall mechanisms, changing participation patterns, age, snowsport discipline, and legal cannabis use.
... While dysregulation of the ECS is associated with detrimental outcomes in neurological injuries, targeted modulation of ECS remains an understudied approach to improve outcomes [6][7][8][9][10][11][12][13][14][15][16]. Of note, preclinical studies by our group and others found that selective activation of the non-psychoactive cannabinoid receptor 2 (CB2R) reduced neuropathology after a variety of neuropsychiatric and neurodegenerative diseases, including cerebral ischemia [11,17,18], traumatic brain injury (TBI) [15,19], neuropathic pain [20], stroke [11], neurodegenerative disease [21][22][23], depression [24], anxiety [25], schizophrenia-like behaviors [26], and drug addiction [27][28][29]. ...
... The association of the ECS in different physiological processes, such as synaptic plasticity and neuronal transmission, advances the probability of its role in neurological recovery [11][12][13][14][15][16]117]. Indeed, promising results have demonstrated that modulation of the ECS attenuates key features of neurological injury, including neurodegeneration, excitotoxicity, and immunomodulation [118]. ...
Cannabis-inspired medical products are garnering increasing attention from the scientific community, general public, and health policy makers. A plethora of scientific literature demonstrates intricate engagement of the endocannabinoid system with human immunology, psychology, developmental processes, neuronal plasticity, signal transduction, and metabolic regulation. Despite the therapeutic potential, the adverse psychoactive effects and historical stigma, cannabinoids have limited widespread clinical application. Therefore, it is plausible to weigh carefully the beneficial effects of cannabinoids against the potential adverse impacts for every individual. This is where the concept of “personalized medicine” as a promising approach for disease prediction and prevention may take into the account. The goal of this review is to provide an outline of the endocannabinoid system, including endocannabinoid metabolizing pathways, and will progress to a more in-depth discussion of the therapeutic interventions by endocannabinoids in various neurological disorders.
... The endocannabinoid system (ECS) is a prevalent neuromodulatory system composed of cannabinoid (CB) receptors (CBRs), their endogenous lipid-based ligands anandamide and 2-arachidonoylglycerol as well as their synthetic-cum-degradative enzymes. This complex structure plays important roles in the central nervous system participating in its response to different endogenous and environmental insults [7]. Two well-identified CB receptors, whose activation has demonstrated to develop a wide range of physiological and disease processes, include the CB type 1 receptor (CB1R) and the CB type 2 receptor (CB2R). ...
In the process of neonatal encephalopathy, oxidative stress and neuroinflammation have a prominent role after perinatal asphyxia. With the exception of therapeutic hypothermia, no therapeutic interventions are available in the clinical setting to target either the oxidative stress or inflammation, despite the high prevalence of neurological sequelae of this devastating condition. The endocannabinoid system (ECS), recently recognized as a widespread neuromodulatory system, plays an important role in the development of the central nervous system (CNS). This study aims to evaluate the potential effect of the cannabinoid (CB) agonist WIN 55,212-2 (WIN) on reactive oxygen species (ROS) and early inflammatory cytokine production after hypoxia–ischemia (HI) in fetal lambs. Hypoxic–ischemic animals were subjected to 60 min of HI by partial occlusion of the umbilical cord. A group of lambs received a single dose of 0.01 μg/kg WIN, whereas non-asphyctic animals served as controls. WIN reduced the widespread and notorious increase in inflammatory markers tumor necrosis factor (TNF)-α and interleukin (IL)-1β and IL-6 induced by HI, a modulatory effect not observed for oxidative stress. Our study suggests that treatment with a low dose of WIN can alter the profile of pro-inflammatory cytokines 3 h after HI.
... This immunomodulatory action is, however, both complex and situation-dependent. Nevertheless, there is promising pre-clinical evidence in various models, such as those of neuroinflammation, sepsis, arthritis, and vascular inflammation [3,4]. ...
As we learn more about the endocannabinoid system (ECS), our understanding and grasp of the system’s ubiquitous presence is expanding. In light of this, there is also a growing body of evidence for the therapeutic potential of ECS modulation in a range of clinical situations. Strategies include manipulation of the Cannabinoid 1 (CB1) receptor, mostly in terms of CNS processes, and activation of the Cannabinoid 2 (CB2) receptor as an anti‐inflammatory target.
Introduction: This work is aimed at understanding the endocannabinoid system and its derivatives, showing in a timeline where we find ourselves in relation to a controversial and marginalized subject. Methodology: The text presents a narrative review of the literature, supported by studies from the PubMed and SciELO platforms. Results and Discussion: In the face of chronic inflammatory processes, cannabidiol (CBD) and Δ9-tetrahydrocannabinol (THC) have been shown to be a therapeutic option in the control of nociception in some diseases, with the potential to relieve pain through activated CB1 and CB2 cannabinoid receptors, which in turn modulate responses to nociceptive stimuli, in particular, induce peripheral tissue repair. Conclusion: With more than 4,500 years of therapeutic use, today, the lack of standardization of drugs and the lack of evidence for future therapeutic solidification does not completely discredit its current role, understanding that more benefits than risks are presented.
