jwh-133 and Cerebral-Hemorrhage

The blood-brain barrier (BBB) disruption and the following development of brain edema, is the most life-threatening secondary injury after intracerebral hemorrhage (ICH). This study is to investigate a potential role and mechanism of JWH133, a selected cannabinoid receptor type2 (CB2R) agonist, on protecting blood-brain barrier integrity after ICH.. 192 adult male Sprague-Dawley (SD) rats were randomly divided into Sham; ICH + Vehicle; ICH + JWH 1.0 mg/kg, ICH + JWH 1.5 mg/kg and ICH + JWH 2.0 mg/kg; ICH + SR + JWH respectively. Animals were euthanized at 24 h following western blots and immunofluorescence staining, we also examined the effect of JWH133 on the brain water contents, neurobehavioral deficits and blood brain barrier (BBB) permeability, meanwhile reassessed the inflammatory cytokines concentrations around the hematoma by enzyme-linked immunosorbent assay (ELISA) in each group.. JWH133 (1.5 mg/kg) administration ameliorated brain edema, neurological deficits and blood-brain barrier damage, as well as microglia activation. The expression of pro-inflammatory mediators interleukin 1β (IL-1β), interleukin-6 (IL-6), tumor necrosis factor-α (TNF-α) and matrix metallopeptidase-2/9 (MMP2/9) were attenuated, but not monocyte chemoattractant protein-1 (MCP-1). Additionally, decreases in zonula occludens-1 (ZO-1) and claudin-5 expression were partially recovered by JWH133. Furthermore, JWH133 upregulated the expression level of MKP-1, which leads to the inhibition of MAPKs signaling pathway activation, especially for ERK and P38. However, these effects were reversed by pretreatment with a selective CB2R antagonist, SR144528.. CB2R agonist alleviated neuroinflammation and protected blood-brain barrier permeability in a rat ICH model. Further molecular mechanisms revealed which is probably mediated by enhancing the expression of MKP-1, then inhibited MAPKs signal transduction.

Topics: Animals; Biological Transport; Blood-Brain Barrier; Brain; Brain Edema; Camphanes; Cannabinoids; Cerebral Hemorrhage; Cytokines; Disease Models, Animal; Dual Specificity Phosphatase 1; Male; Permeability; Pyrazoles; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Signal Transduction

Blood‑brain barrier (BBB) disruption and consequent edema formation are the most common brain injuries following intracerebral hemorrhage (ICH). Endocannabinoid receptors can alter the permeability of various epithelial barriers and have potential neuroprotective effects. The present study aimed to explore whether the selective cannabinoid receptor 2 (CNR2) agonist, JWH133, can ameliorate BBB integrity and behavioral outcome by activating Ras‑related C3 botulinum toxin substrate 1 (Rac1) following ICH. Autologous arterial blood was injected into the basal ganglia of rats to induce ICH. Animals were randomly divided into the following groups: Sham‑operated, ICH+vehicle, ICH+JWH133, ICH+JWH13+vehicle, ICH+JWH133+AM630 (a selective CNR2 antagonist), ICH+AM630, ICH+JWH133 +NSC23766 (a Rac1 antagonist) and ICH+NSC23766. JWH133 and AM630 were independently intraperitoneally administrated at 1 h prior to ICH. NSC23766 was intracerebroventricularly (ICV) administered 30 min prior to ICH. A modified Garcia test, corner test, Evans blue extravasation and brain water content analysis were performed at 24 and 72 h following ICH. Western blotting and pull‑down assays were performed at 24 h following ICH. The results demonstrated that JWH133 treatment improved neurofunctional deficits, reduced perihematomal brain edema and alleviated BBB damage at 24 and 72 h following ICH. In addition, JWH133 treatment increased the protein expression levels of guanosine‑5'‑triphosphate‑Rac1 and of the adherens junction proteins occludin, zonula occludens‑1 and claudin‑5. However, these effects were reversed by AM630 and NSC23766 treatment. In conclusion, the present findings revealed that JWH133 treatment attenuated brain injury in a rat model of ICH via activation of the Rac1 signaling pathway, thus preserving BBB integrity.

Topics: Animals; Blood-Brain Barrier; Blotting, Western; Cannabinoids; Cerebral Hemorrhage; Indoles; Male; rac1 GTP-Binding Protein; Rats; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2

Fibrosis in ventricular system has a role in hydrocephalus following intraventricular hemorrhage (IVH). The cannabinoid receptor 2 (CB2) has been reported to participate in alleviating the fibrosis process of many diseases. However, its role in fibrosis after IVH was unclear so far, and we hypothesized that CB2 activation has potential to attenuate hydrocephalus after IVH via restricting fibrosis. So the present study was designed to investigate this hypothesis in a modified rat IVH model. Autologous non-anticoagulative blood injection model was induced to mimic ventricular extension of hemorrhage in adult Sprague-Dawley rats. Rats were randomized to receive JWH-133(CB2 agonist), SR144528 (CB2 antagonist) or saline. The lateral ventricular volumes, fibrosis in the subarachnoid space and ventricular wall, transforming growth factor-β 1(TGF-β1) in cerebrospinal fluid and brain tissue, and animal neurological scores were measured to evaluate the effects of CB2 in hydrocephalus following IVH. CB2 agonist JWH-133 significantly decreased the lateral ventricular volumes, improved the associated neurological deficits, down-regulated TGF-β1 expression, and alleviated fibrosis in the subarachnoid space and ventricular wall after IVH. All of these effects were reversed by SR144528. In conclusion, CB2 may have anti-fibrogenic effects after IVH. CB2 agonist suppressed fibrosis of ventricular system and alleviated hydrocephalus following IVH, which is partly mediated by inhibiting TGF-β1.

Topics: Animals; Brain; Camphanes; Cannabinoid Receptor Agonists; Cannabinoid Receptor Antagonists; Cannabinoids; Cerebral Hemorrhage; Disease Models, Animal; Fibrosis; Hydrocephalus; Male; Neuroprotective Agents; Pyrazoles; Random Allocation; Rats, Sprague-Dawley; Receptor, Cannabinoid, CB2; Transforming Growth Factor beta1