Endocannabinoid Receptors in the CNS: Potential Drug Targets for the Prevention and Treatment of Neurologic and Psychiatric Disorders

Estrada, José Antonio; Contreras, Irazú

doi:10.2174/1570159x18666200217140255

Cited by 23 publications

(17 citation statements)

References 207 publications

(137 reference statements)

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“…The retrograde endocannabinoid signalling system is a lipid-based neuromodulatory system with important roles in the CNS including in physiological and neurodegenerative processes [94,95]. It has been associated to pathogenesis of PD as well as AD and ischemia [95][96][97] and suggested as a therapeutic target for treatment of a range of neurodegenerative disorders including AD, PD, HD, multiple sclerosis (MS), and ALS [98][99][100]. Putative roles for its regulation via post-translational deimination have not been previously identified and therefore bring a novel angle of modulation of endocannabinoid signalling pathways in neurodegeneration, including in early disease stages.…”

Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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The identification of biomarkers for early diagnosis of Parkinson's disease (PD) is of pivotal importance for improving approaches for clinical intervention. The use of translatable animal models of pre-motor PD therefore offers optimal opportunities for novel biomarker discovery in vivo. Peptidylarginine deiminases (PADs) are a family of calcium-activated enzymes that contribute to protein misfolding through post-translational deimination of arginine to citrulline. Furthermore, PADs are an active regulator of extracellular vesicle (EV) release. Both protein deimination and extracellular vesicles (EVs) are gaining increased attention in relation to neurodegenerative diseases, including in PD, while roles in pre-motor PD have yet to be investigated. The current study aimed at identifying protein candidates of deimination in plasma and plasma-EVs in a rat model of pre-motor PD, to assess putative contributions of such post-translational changes in the early stages of disease. EV-cargo was further assessed for deiminated proteins as well as three key micro-RNAs known to contribute to inflammation and hypoxia (miR21, miR155, and miR210) and also associated with PD. Overall, there was a significant increase in circulating plasma EVs in the PD model compared with sham animals and inflammatory and hypoxia related microRNAs were significantly increased in plasma-EVs of the pre-motor PD model. A significantly higher number of protein candidates were deiminated in the pre-motor PD model plasma and plasma-EVs, compared with those in the sham animals. KEGG (Kyoto encyclopedia of genes and genomes) pathways identified for deiminated proteins in the pre-motor PD model were linked to "Alzheimer's disease", "PD", "Huntington's disease", "prion diseases", as well as for "oxidative phosphorylation", "thermogenesis", "metabolic pathways", "Staphylococcus aureus infection", gap junction, "platelet activation", "apelin signalling", "retrograde endocannabinoid signalling", "systemic lupus erythematosus", and "non-alcoholic fatty liver disease". Furthermore, PD brains showed significantly increased staining for total deiminated proteins in the brain vasculature in cortex and hippocampus, as well as increased immunodetection of deiminated histone H3 in dentate gyrus and cortex. Our findings identify EVs and post-translational protein deimination as novel biomarkers in early pre-motor stages of PD. Figure 2. EV characterisation from rat plasma. (A) Representative Nanosight graphs showing nanoparticle tracking analysis (NTA) analysis of plasma EV profiles from sham-treated rats (Sham; n = 3). (B) Representative Nanosight graphs showing NTA analysis of plasma EV profiles from the premotor PD rat models (PD; n = 3). (C) Western blotting (WB) confirms that rat plasma-EVs are positive for the EV-specific markers CD63 and flotillin-1 (Flot-1); the molecular weight standard is indicated in kilo Daltons (kDa). (D,E) Transmission electron microscopy (TEM) images showing EVs isolated from sham (D) and pre-motor PD model (PD; (E)) rat plasma, revea...

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Section: Discussionmentioning

confidence: 99%

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Sancandi¹,

Uysal-Onganer

Kraev

et al. 2020

IJMS

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“…The ECS is further involved in the modulation of the hypothalamic pituitary axis (HPA) and brain derived neurotrophic factor (BDNF) (6,33). The ECS also modulates inflammation: CB1 activation decreases inflammation through astrocytes, and CB2 through microglia (34). Importantly, these systems are also involved in the pathophysiology of depression (35)(36)(37).…”

Section: Potential Mechanisms Underlying the Relationship Between Cannabis And Depressionmentioning

confidence: 99%

“…Since apathy and anhedonia are also seen in depression, one can theorize that the effects of CU may overlap with the symptoms of depression, leading to their exacerbation or potentially confounding the diagnosis of MDD. Although anhedonia can be seen as the result of cannabis-induced inflammation (34), a recent review concludes that the ultimate effect of cannabis is anti-inflammatory (89). Decreased dopamine activity, as seen with chronic CU (44), has also been proposed to be a cause of anhedonia in depression.…”

Section: Influence Of Cannabis On the Course And Clinical Presentation Of Depressionmentioning

confidence: 99%

Down and High: Reflections Regarding Depression and Cannabis

et al. 2021

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In light of the recent changes in the legal status of cannabis in Canada, the understanding of the potential impact of the use of cannabis by individuals suffering from depression is increasingly considered as being important. It is fundamental that we look into the existing literature to examine the influence of cannabis on psychiatric conditions, including mood disorders. In this article, we will explore the relationship that exists between depression and cannabis. We will examine the impact of cannabis on the onset and course of depression, and its treatment. We have undertaken a wide-ranging review of the literature in order to address these questions. The evidence from longitudinal studies suggest that there is a bidirectional relationship between cannabis use and depression, such that cannabis use increases the risk for depression and vice-versa. This risk is possibly higher in heavy users having initiated their consumption in early adolescence. Clinical evidence also suggests that cannabis use is associated with a worse prognosis in individuals with major depressive disorder. The link with suicide remains controversial. Moreover, there is insufficient data to determine the impact of cannabis use on cognition in individuals with major depression disorder. Preliminary evidence suggesting that the endogenous cannabinoid system is involved in the pathophysiology of depression. This will need to be confirmed in future positron emission tomography studies. Randomized controlled trials are needed to investigate the potential efficacy of motivational interviewing and/or cognitive behavioral therapy for the treatment of cannabis use disorder in individuals with major depressive major disorder. Finally, although there is preclinical evidence suggesting that cannabidiol has antidepressant properties, randomized controlled trials will need to properly investigate this possibility in humans.

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“…The ECS modulation of the immune system can promote neurogenesis or neurodegeneration ( Molina-Holgado and Molina-Holgado, 2010 ; Tanasescu et al, 2013 ). Cannabinoid drugs have been used as therapeutic tools in a great number of neuroinflammatory and ageing animal models that involve cognitive dysregulation ( Bisogno and di Marzo, 2008 ; Bilkei-Gorzo, 2012 ; Chiurchiù et al, 2018 ; Estrada and Contreras, 2020 ). As reported below, several studies have analysed the neuroprotective actions of cannabinoid drugs in pathologies that combine neuroinflammatory responses and cognitive impairments, but present different aetiologies, such as Parkinson’s disease (PD), Alzheimer’s disease (AD) or traumatic brain injury (TBI) ( Schurman and Lichtman, 2017 ; Rodrigues et al, 2019 ; Uddin et al, 2020 ).…”

Section: Cannabinoids and Neuroinflammationmentioning

confidence: 99%

Cannabinoid Drugs-Related Neuroprotection as a Potential Therapeutic Tool Against Chemotherapy-Induced Cognitive Impairment

2021

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In recent years, and particularly associated with the increase of cancer patients’ life expectancy, the occurrence of cancer treatment sequelae, including cognitive impairments, has received considerable attention. Chemotherapy-induced cognitive impairments (CICI) can be observed not only during pharmacological treatment of the disease but also long after cessation of this therapy. The lack of effective tools for its diagnosis together with the limited treatments currently available for alleviation of the side-effects induced by chemotherapeutic agents, demonstrates the need of a better understanding of the mechanisms underlying the pathology. This review focuses on the comprehensive appraisal of two main processes associated with the development of CICI: neuroinflammation and oxidative stress, and proposes the endogenous cannabinoid system (ECS) as a new therapeutic target against CICI. The neuroprotective role of the ECS, well described in other cognitive-related neuropathologies, seems to be able to reduce the activation of pro-inflammatory cytokines involved in the neuroinflammatory supraspinal processes underlying CICI. This review also provides evidence supporting the role of cannabinoid-based drugs in the modulation of oxidative stress processes that underpin cognitive impairments, and warrant the investigation of endocannabinoid components, still unknown, that may mediate the molecular mechanism behind this neuroprotective activity. Finally, this review points forward the urgent need of research focused on the understanding of CICI and the investigation of new therapeutic targets.

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Endocannabinoid Receptors in the CNS: Potential Drug Targets for the Prevention and Treatment of Neurologic and Psychiatric Disorders

Cited by 23 publications

References 207 publications

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Protein Deimination Signatures in Plasma and Plasma-EVs and Protein Deimination in the Brain Vasculature in a Rat Model of Pre-Motor Parkinson’s Disease

Down and High: Reflections Regarding Depression and Cannabis

Cannabinoid Drugs-Related Neuroprotection as a Potential Therapeutic Tool Against Chemotherapy-Induced Cognitive Impairment

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