A cannabinoid receptor 2 agonist reduces blood–brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats

Lin, Li; Yun, Debo; Zhang, Yuan; Tao, Yihao; Tan, Qiang; Qiao, Fei; Luo, Baoming; Liu, Yi; Fan, Runjin; Xian, Jishu; Yu, Anyong

doi:10.1016/j.brainres.2018.06.006

Cited by 33 publications

(25 citation statements)

References 31 publications

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“…A relationship between CB2R and the BBB has been proposed in various diseases. The activation of CB2R potentially attenuates BBB damage in encephalitis, 27 a rat ICH model 28 and spinal cord ischemia-reperfusion injury. 29 We wanted to determine whether JWH015 protected the BSCB in a BCP model.…”

Section: Discussionmentioning

confidence: 99%

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Wang

et al. 2020

Reg Anesth Pain Med

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BackgroundDisruption of the blood–spinal cord barrier (BSCB) can facilitate inflammation that results in pain hypersensitivity. Proinflammatory cytokines produced by activated microglia and astrocytes damage the BSCB. This study aims to explore whether the BSCB is damaged in the bone cancer pain (BCP) model and to investigate a potential role and mechanism of JWH015 ((2-methyl-1-propyl-1H-indol-3-yl)−1-naphthalenylmethanone), a selective cannabinoid receptor 2 (CB2R) agonist, in preserving the BSCB integrity in the BCP model.MethodsWe used a male mouse model of BCP. Pain hypersensitivity was measured over time. Evans blue dye extravasation, transmission electron microscopy and Western blotting were performed to investigate the permeability and structural integrity of the BSCB. Immunofluorescence staining and western blotting were used to investigate the effect of JWH015 on the activation of glial cells and the levels of proinflammatory cytokines.ResultsA single intrathecal injection of JWH015 ameliorated pain hypersensitivity, the BSCB disruption and microglia and astrocyte activation. Decreases in the expression of ZO-1 and claudin-5 were partially restored by JWH015. The levels of the proinflammatory cytokines interleukin-1β and tumor necrosis factor-α and the enzyme MMP9 were reduced by JWH015. However, all effects were prevented by pretreatment with a CB2R-selective antagonist, AM630 ((6-iodo-2-methyl-1-(2-morpholinoethyl)−1H-indol-3-yl)(4-methoxyphenyl)methanone).ConclusionsJWH015 alleviates neuroinflammation and maintains the BSCB integrity and permeability in a mouse model of BCP, which is probably mediated by inhibiting glial cells activation. This study reveals the new analgesic mechanism of JWH015 on BCP and provides a perspective to explore novel drugs that target the BSCB to control BCP.

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Section: Discussionmentioning

confidence: 99%

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Wang

et al. 2020

Reg Anesth Pain Med

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“…In vivo animal studies showed that CB2R receptor is the main pharmacological target of natural or synthetic cannabinoids in protection against cognitive and motor impairment after TBI [ 1 , 44 , 45 , 46 , 47 , 48 , 49 , 51 , 54 , 55 , 57 , 58 , 59 , 60 ]. The inhibition of CB1R by SR141716 failed to show any beneficial effect on cognitive and motor impairment after TBI [ 50 ].…”

Section: Resultsmentioning

confidence: 99%

“…The main mechanisms through which cannabinoids improve cognitive and motor impairment after TBI are associated with decreasing the pro-inflammatory markers [ 1 , 44 , 46 , 47 , 48 , 52 , 53 , 57 , 58 ], decreasing oedema formation [ 44 , 45 , 47 , 54 , 55 , 58 , 60 ], decreasing BBB permeability [ 44 , 45 , 46 , 54 , 55 , 57 ], preventing neuronal cell loss [ 44 , 49 , 51 , 55 ] and increasing the levels of adherens jonction proteins [ 45 , 46 , 54 ].…”

Section: Resultsmentioning

confidence: 99%

“…The treatment with synthetic CB2R agonists immediately after injury showed promising results in recovery of the neurobehavioral deficits and sensorimotor impairment mainly due to the modulation of inflammatory markers [ 1 , 44 , 45 , 46 , 47 , 57 ], decrease of oedema formation [ 44 , 45 , 47 , 54 , 60 ], influence in the permeability of BBB [ 44 , 45 , 46 , 54 , 57 ], increase in adherence junction proteins [ 45 , 46 , 54 ] and prevention of neuronal loss [ 44 , 49 , 51 ].…”

Section: Discussionmentioning

confidence: 99%

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The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies

Calina

Buga

Mitroi

et al. 2020

JCM

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Neurological disorders such as neurodegenerative diseases or traumatic brain injury are associated with cognitive, motor and behavioural changes that influence the quality of life of the patients. Although different therapeutic strategies have been developed and tried until now to decrease the neurological decline, no treatment has been found to cure these pathologies. In the last decades, the implication of the endocannabinoid system in the neurological function has been extensively studied, and the cannabinoids have been tried as a new promising potential treatment. In this study, we aimed to overview the recent available literature regarding in vivo potential of natural and synthetic cannabinoids with underlying mechanisms of action for protecting against cognitive decline and motor impairments. The results of studies on animal models showed that cannabinoids in traumatic brain injury increase neurobehavioral function, working memory performance, and decrease the neurological deficit and ameliorate motor deficit through down-regulation of pro-inflammatory markers, oedema formation and blood–brain barrier permeability, preventing neuronal cell loss and up-regulating the levels of adherence junction proteins. In neurodegenerative diseases, the cannabinoids showed beneficial effects in decreasing the motor disability and disease progression by a complex mechanism targeting more signalling pathways further than classical receptors of the endocannabinoid system. In light of these results, the use of cannabinoids could be beneficial in traumatic brain injuries and multiple sclerosis treatment, especially in those patients who display resistance to conventional treatment.

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“…CB2R activation by the selective agonist AM1241 contributes to the regeneration of DA neurons through increased activation of the PI3K/AKT signaling pathway following MPTP-induced neurotoxicity in mice [25]. Activation of CB2R by JWH133 induced neuroinflammation by enhancing the expression of MAPK phosphatase-1 (MKP-1), followed by the inhibition of MAPK signaling and increased blood-brain barrier permeability in a rat model of intracerebral hemorrhage (ICH) [26]. The activation of CB2R is also associated with the activation of CREB, followed by increased expression of Bcl-2, an anti-apoptotic gene leading to decreased cleaved caspase-3 levels and augmented neurological deficits induced by subarachnoid hemorrhage (SAH) in male rats [27].…”

Section: Introductionmentioning

confidence: 99%

Potential Mechanisms Underlying the Deleterious Effects of Synthetic Cannabinoids Found in Spice/K2 Products

Basavarajappa

Subbanna

2019

Brain Sciences

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The chief psychoactive constituent of many bioactive phytocannabinoids (Δ9-tetrahydrocannabinol, Δ9-THC) found in hemp, cannabis or marijuana plants are scientifically denoted by the Latin term, Cannabis sativa, acts on cell surface receptors. These receptors are ubiquitously expressed. To date, two cannabinoid receptors have been cloned and characterized. Cannabinoid receptor type 1 (CB1R) is found to serve as the archetype for cannabinoid action in the brain. They have attracted wide interest as the mediator of all psychoactive properties of exogenous and endogenous cannabinoids and they are abundantly expressed on most inhibitory and excitatory neurons. Recent evidence established that cannabinoid receptor type 2 (CB2R) is also expressed in the neurons at both presynaptic and postsynaptic terminals and are involved in neuropsychiatric effects. Distinct types of cells in many regions in the brain express CB2Rs and the cellular origin of CB2Rs that induce specific behavioral effects are emerging. To mimic the bliss effects of marijuana, synthetic cannabinoids (SCBs) have been sprayed onto plant material, and this plant material has been consequently packaged and sold under brand name “Spice” or “K2”. These SCBs have been shown to maintain their affinity and functional activity for CB1R and CB2R and have been shown to cause severe harmful effects when compared to the effects of Δ9-THC. The present review discusses the potential brain mechanisms that are involved in the deleterious effects of SCBs.

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A cannabinoid receptor 2 agonist reduces blood–brain barrier damage via induction of MKP-1 after intracerebral hemorrhage in rats

Cited by 33 publications

References 31 publications

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

Spinal cannabinoid receptor 2 activation reduces hypersensitivity associated with bone cancer pain and improves the integrity of the blood–spinal cord barrier

The Treatment of Cognitive, Behavioural and Motor Impairments from Brain Injury and Neurodegenerative Diseases through Cannabinoid System Modulation—Evidence from In Vivo Studies

Potential Mechanisms Underlying the Deleterious Effects of Synthetic Cannabinoids Found in Spice/K2 Products

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