Cannabinoid receptor 2 attenuates microglial accumulation and brain injury following germinal matrix hemorrhage via ERK dephosphorylation in vivo and in vitro

Tang, Jun; Tao, Yihao; Tan, Liang; Yang, Liming; Niu, Yin; Chen, Qianwei; Yang, Yifeng; Feng, Hua; Chen, Zhi; Zhu, Gang

doi:10.1016/j.neuropharm.2015.04.028

Cited by 30 publications

(23 citation statements)

References 58 publications

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“…After a 24 h infusion, JWH133-administered animals showed attenuated edema and perihematomal tissue injury and improved motor and memory function (123). In addition, Iba1 + and reactive microglia populations were reduced (124). In a subsequent report, they characterized time-dependent changes in M1 markers in perihemotomas and found that upregulation of M1 marker (IFNγ, IL-1β, TNFα, CD68, CD86, and iNOS) expression started relatively early (6-24 h post-injury) and was attenuated by JWH133.…”

Section: Microglial Polarization By Ecb In Cerebral Hemorrhage and Stmentioning

confidence: 99%

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

2020

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Microglia, the resident immune cells of the central nervous system, mediate brain homeostasis by controlling neuronal proliferation/differentiation and synaptic activity. In response to external signals from neuropathological conditions, homeostatic (M0) microglia can adopt one of two activation states: the classical (M1) activation state, which secretes mediators of the proinflammatory response, and the alternative (M2) activation state, which presumably mediates the resolution of neuroinflammation and tissue repair/remodeling. Since chronic inflammatory activation of microglia is correlated with several neurodegenerative diseases, functional modulation of microglial phenotypes has been considered as a potential therapeutic strategy. The endocannabinoid (eCB) system, composed of cannabinoid receptors and ligands and their metabolic/biosynthetic enzymes, has been shown to activate anti-inflammatory signaling pathways that modulate immune cell functions. Growing evidence has demonstrated that endogenous, synthetic, and plant-derived eCB agonists possess therapeutic effects on several neuropathologies; however, the molecular mechanisms that mediate the anti-inflammatory effects have not yet been identified. Over the last decade, it has been revealed that the eCB system modulates microglial activation and population. In this review, we thoroughly examine recent studies on microglial phenotype modulation by eCB in neuroinflammatory and neurodegenerative disease conditions. We hypothesize that cannabinoid 2 receptor (CB2R) signaling shifts the balance of expression between neuroinflammatory (M1-type) genes, neuroprotective (M2-type) genes, and homeostatic (M0-type) genes toward the latter two gene expressions, by which microglia acquire therapeutic functionality.

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Section: Microglial Polarization By Ecb In Cerebral Hemorrhage and Stmentioning

confidence: 99%

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

2020

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“…85 Kainic acid-induced status epilepticus 86 and lipopolysaccharide (LPS)-induced inflammation 87 upregulate CB 1 R expression, either as a direct consequence of inflammation-induced sequelae or as a potential compensatory mechanism to limit prolonged hyperexcitability. Supporting a potential anti-inflammatory role of CB 1 R/CB2Rs, CB 2 R agonism decreases microglial activation, edema, excitotoxicity, oxidative stress, and cell death associated with stroke, 88 germinal matrix hemorrhage, 89 and traumatic brain injury. Furthermore, activation of CB 1 Rs 91 and CB 2 Rs 92 via synthetic agonists reduced inflammatory nociception in several animal models.…”

Section: Future Directionsmentioning

confidence: 97%

“…Δ 9 ‐THC acts primarily as a partial agonist at CB 1 Rs and CB 2 Rs on microglia, the primary CNS immune cells. Δ 9 ‐THC reduces LPS‐induced inflammation in vitro and in vivo by limiting release of the pro‐inflammatory cytokines IL‐1β, IL‐6, IL‐17, tumor necrosis factor α (TNFα), and interferon β (IFNβ), and elevating anti‐inflammatory cytokines such as IL‐10 . These effects may be age‐specific, however, as treating adolescent mice Δ 9 ‐THC exerts opposite effects when assayed later in life, increasing pro‐inflammatory and decreasing anti‐inflammatory cytokine release .…”

Section: Endocannabinoid System Cb1r/cb2rs and Inflammationmentioning

confidence: 99%

“…D 9 -THC reduces LPS-induced inflammation in vitro and in vivo by limiting release of the pro-inflammatory cytokines IL-1b, IL-6, IL-17, tumor necrosis factor a (TNFa), and interferon b (IFNb), and elevating antiinflammatory cytokines such as IL-10. [88][89][90][91][92][93][94] These effects may be age-specific, however, as treating adolescent mice D 9 -THC exerts opposite effects when assayed later in life, increasing pro-inflammatory and decreasing anti-inflammatory cytokine release. 95 In other studies, D 9 -THC limits oxidative stress in LPS-triggered inflammation, 98 reduces nitrite formation following intravitreal NMDA injection, 99 and decreases glutamate neurotoxicity and oxidative stress.…”

Section: Future Directionsmentioning

confidence: 99%

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Clinical studies and anti‐inflammatory mechanisms of treatments

French¹,

Koepp

Naegelin

et al. 2017

Epilepsia

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Summary In this exciting era, we are coming closer and closer to bringing an anti-inflammatory therapy to the clinic for the purpose of seizure prevention, modification, and/or suppression. At present, it is unclear what this approach might entail, and what form it will take. Irrespective of the therapy that ultimately reaches the clinic, there will be some commonalities with regard to clinical trials. A number of animal models have now been used to identify inflammation as a major underlying mechanism of both chronic seizures and the epileptogenic process. These models have demonstrated that specific anti-inflammatory treatments can be effective at both suppressing chronic seizures and interfering with the process of epileptogenesis. Some of these have already been evaluated in early phase clinical trials. It can be expected that there will soon be more clinical trials of both “conventional, broad spectrum” anti-inflammatory agents and novel new approaches to utilizing specific anti-inflammatory therapies with drugs or other therapeutic interventions. A summary of some of those approaches appears below, as well as a discussion of the issues facing clinical trials in this new domain.

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“…Western blot analysis was performed, as previously described. 16,31 The brains were perfused with saline before decapitation on Day 3 after injection. The perihematomal brain tissue (4-mm-thick brain tissue around the hema-toma) was sampled.…”

Section: Western Blot Analysismentioning

confidence: 99%

Urokinase, a promising candidate for fibrinolytic therapy for intracerebral hemorrhage

Tan

Chen

Niu

et al. 2017

JNS

Self Cite

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OBJECTIVE Intracerebral hemorrhage (ICH) is associated with a high rate of mortality and severe disability, while fibrinolysis for ICH evacuation is a possible treatment. However, reported adverse effects can counteract the benefits of fibrinolysis and limit the use of tissue-type plasminogen activator (tPA). Identifying appropriate fibrinolytics is still needed. Therefore, the authors here compared the use of urokinase-type plasminogen activator (uPA), an alternate thrombolytic, with that of tPA in a preclinical study. METHODS Intracerebral hemorrhage was induced in adult male Sprague-Dawley rats by injecting autologous blood into the caudate, followed by intraclot fibrinolysis without drainage. Rats were randomized to receive uPA, tPA, or saline within the clot. Hematoma and perihematomal edema, brain water content, Evans blue fluorescence and neurological scores, matrix metalloproteinases (MMPs), MMP mRNA, blood-brain barrier (BBB) tight junction proteins, and nuclear factor-κB (NF-κB) activation were measured to evaluate the effects of these 2 drugs in ICH. RESULTS In comparison with tPA, uPA better ameliorated brain edema and promoted an improved outcome after ICH. In addition, uPA therapy more effectively upregulated BBB tight junction protein expression, which was partly attributed to the different effects of uPA and tPA on the regulation of MMPs and its related mRNA expression following ICH. CONCLUSIONS This study provided evidence supporting the use of uPA for fibrinolytic therapy after ICH. Large animal experiments and clinical trials are required to further explore the efficacy and safety of uPA in ICH fibrinolysis.

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Cannabinoid receptor 2 attenuates microglial accumulation and brain injury following germinal matrix hemorrhage via ERK dephosphorylation in vivo and in vitro

Cited by 30 publications

References 58 publications

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

Endocannabinoid Modulation of Microglial Phenotypes in Neuropathology

Clinical studies and anti‐inflammatory mechanisms of treatments

Urokinase, a promising candidate for fibrinolytic therapy for intracerebral hemorrhage

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