Cannabinoid receptor 2 agonist attenuates blood‑brain barrier damage in a rat model of intracerebral hemorrhage by activating the Rac1 pathway

Wang,Zhe; Li,Yongfu; Cai,Shuangyong; Li,Rui; Cao,Guanbo

doi:10.3892/ijmm.2018.3834

Cannabinoid receptor 2 agonist attenuates blood‑brain barrier damage in a rat model of intracerebral hemorrhage by activating the Rac1 pathway

Authors:
- Zhe Wang
- Yongfu Li
- Shuangyong Cai
- Rui Li
- Guanbo Cao
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Affiliations: Department of Neurosurgery, Jiulongpo District People's Hospital, Chongqing 401329, P.R. China
Published online on: August 22, 2018 https://doi.org/10.3892/ijmm.2018.3834
Pages: 2914-2922

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Abstract

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.

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1	Broderick JP, Adams HP Jr, Barsan W, Feinberg W, Feldmann E, Grotta J, Kase C, Krieger D, Mayberg M, Tilley B, et al: Guidelines for the management of spontaneous intracerebral hemorrhage: A statement for healthcare professionals from a special writing group of the stroke council, American Heart Association. Stroke. 30:905–915. 1999. View Article : Google Scholar : PubMed/NCBI
2	Qureshi AI, Mendelow AD and Hanley DF: Intracerebral haemorrhage. Lancet. 373:1632–1644. 2009. View Article : Google Scholar : PubMed/NCBI
3	Sweeney MD, Sagare AP and Zlokovic BV: Blood-brain barrier breakdown in Alzheimer disease and other neurodegenerative disorders. Nat Rev Neurol. 14:133–150. 2018. View Article : Google Scholar : PubMed/NCBI
4	Guan JX, Sun SG, Cao XB, Chen ZB and Tong ET: Effect of thrombin on blood brain barrier permeability and its mechanism. Chin Med J (Engl). 117:1677–1681. 2004.
5	Ballabh P, Braun A and Nedergaard M: The blood-brain barrier: An overview: Structure, regulation, and clinical implications. Neurobiol Dis. 16:1–13. 2004. View Article : Google Scholar : PubMed/NCBI
6	Bazzoni G and Dejana E: Endothelial cell-to-cell junctions: Molecular organization and role in vascular homeostasis. Physiol Rev. 84:869–901. 2004. View Article : Google Scholar : PubMed/NCBI
7	Luh C, Kuhlmann CR, Ackermann B, Timaru-Kast R, Luhmann HJ, Behl C, Werner C, Engelhard K and Thal SC: Inhibition of myosin light chain kinase reduces brain edema formation after traumatic brain injury. J Neurochem. 112:1015–1025. 2010. View Article : Google Scholar
8	Kahles T, Luedike P, Endres M, Galla HJ, Steinmetz H, Busse R, Neumann-Haefelin T and Brandes RP: NADPH oxidase plays a central role in blood-brain barrier damage in experimental stroke. Stroke. 38:3000–3006. 2007. View Article : Google Scholar : PubMed/NCBI
9	Xu JY and Chen C: Endocannabinoids in synaptic plasticity and neuroprotection. Neuroscientist. 21:152–168. 2015. View Article : Google Scholar
10	Devane WA, Dysarz FR III, Johnson MR, Melvin LS and Howlett AC: Determination and characterization of a cannabinoid receptor in rat brain. Mol Pharmacol. 34:605–613. 1988.PubMed/NCBI
11	Matsuda LA, Lolait SJ, Brownstein MJ, Young AC and Bonner TI: Structure of a cannabinoid receptor and functional expression of the cloned cDNA. Nature. 346:561–564. 1990. View Article : Google Scholar : PubMed/NCBI
12	Haugh O, Penman J, Irving AJ and Campbell VA: The emerging role of the cannabinoid receptor family in peripheral and neuro-immune interactions. Curr Drug Targets. 17:1834–1840. 2016. View Article : Google Scholar : PubMed/NCBI
13	Chi OZ, Barsoum S, Grayson J, Hunter C, Liu X and Weiss HR: Effects of cannabinoid receptor agonist WIN 55,212-2 on blood-brain barrier disruption in focal cerebral ischemia in rats. Pharmacology. 89:333–338. 2012. View Article : Google Scholar : PubMed/NCBI
14	Fujii M, Sherchan P, Krafft PR, Rolland WB, Soejima Y and Zhang JH: Cannabinoid type 2 receptor stimulation attenuates brain edema by reducing cerebral leukocyte infiltration following subarachnoid hemorrhage in rats. J Neurol Sci. 342:101–106. 2014. View Article : Google Scholar : PubMed/NCBI
15	Tao Y, Tang J, Chen Q, Guo J, Li L, Yang L, Feng H, Zhu G and Chen Z: Cannabinoid CB2 receptor stimulation attenuates brain edema and neurological deficits in a germinal matrix hemorrhage rat model. Brain Res. 1602:127–135. 2015. View Article : Google Scholar : PubMed/NCBI
16	Amenta PS, Jallo JI, Tuma RF and Elliott MB: A cannabinoid type 2 receptor agonist attenuates blood-brain barrier damage and neurodegeneration in a murine model of traumatic brain injury. J Neurosci Res. 90:2293–2305. 2012. View Article : Google Scholar : PubMed/NCBI
17	Etienne-Manneville S and Hall A: Rho GTPases in cell biology. Nature. 420:629–635. 2002. View Article : Google Scholar : PubMed/NCBI
18	Gerhard R, John H, Aktories K and Just I: Thiol-modifying phenylarsine oxide inhibits guanine nucleotide binding of Rho but not of Rac GTPases. Mol Pharmacol. 63:1349–1355. 2003. View Article : Google Scholar : PubMed/NCBI
19	Huang B, Krafft PR, Ma Q, Rolland WB, Caner B, Lekic T, Manaenko A, Le M, Tang J and Zhang JH: Fibroblast growth factors preserve blood-brain barrier integrity through RhoA inhibition after intracerebral hemorrhage in mice. Neurobiol Dis. 46:204–214. 2012. View Article : Google Scholar : PubMed/NCBI
20	Persidsky Y, Heilman D, Haorah J, Zelivyanskaya M, Persidsky R, Weber GA, Shimokawa H, Kaibuchi K and Ikezu T: Rho-mediated regulation of tight junctions during monocyte migration across the blood-brain barrier in HIV-1 encephalitis (HIVE). Blood. 107:4770–4780. 2006. View Article : Google Scholar : PubMed/NCBI
21	Tang J, Chen Q, Guo J, Yang L, Tao Y, Li L, Miao H, Feng H, Chen Z and Zhu G: Minocycline attenuates neonatal germin al-matrix-hemorrhage-induced neuroinflammation and brain edema by activating cannabinoid receptor 2. Mol Neurobiol. 53:1935–1948. 2016. View Article : Google Scholar
22	Yang F, Wang Z, Zhang JH, Tang J, Liu X, Tan L, Huang QY and Feng H: Receptor for advanced glycation end-product antagonist reduces blood-brain barrier damage after intracerebral hemorrhage. Stroke. 46:1328–1336. 2015. View Article : Google Scholar : PubMed/NCBI
23	Garcia JH, Wagner S, Liu KF and Hu XJ: Neurological deficit and extent of neuronal necrosis attributable to middle cerebral artery occlusion in rats. Statistical validation. Stroke. 26:627–635. 1995. View Article : Google Scholar : PubMed/NCBI
24	Li X, Blizzard KK, Zeng Z, DeVries AC, Hurn PD and McCullough LD: Chronic behavioral testing after focal ischemia in the mouse: Functional recovery and the effects of gender. Exp Neurol. 187:94–104. 2004. View Article : Google Scholar : PubMed/NCBI
25	Manaenko A, Chen H, Kammer J, Zhang JH and Tang J: Comparison Evans Blue injection routes: Intravenous versus intraperitoneal, for measurement of blood-brain barrier in a mice hemorrhage model. J Neurosci Methods. 195:206–210. 2011. View Article : Google Scholar
26	Ma Q, Huang B, Khatibi N, Rolland WN II, Suzuki H, Zhang JH and Tang J: PDGFR-alpha inhibition preserves blood-brain barrier after intracerebral hemorrhage. Ann Neurol. 70:920–931. 2011. View Article : Google Scholar : PubMed/NCBI
27	Cheng CC, Lai YC, Lai YS, Hsu YH, Chao WT, Sia KC, Tseng YH and Liu YH: Transient knockdown-mediated deficiency in plectin alters hepatocellular motility in association with activated FAK and Rac1-GTPase. Cancer Cell Int. 15:292015. View Article : Google Scholar : PubMed/NCBI
28	Wang L, Fan W, Cai P, Fan M, Zhu X, Dai Y, Sun C, Cheng Y, Zheng P and Zhao BQ: Recombinant ADAMTS13 reduces tissue plasminogen activator-induced hemorrhage after stroke in mice. Ann Neurol. 73:189–198. 2013. View Article : Google Scholar : PubMed/NCBI
29	Vose LR, Vinukonda G, Jo S, Miry O, Diamond D, Korumilli R, Arshad A, Zia MT, Hu F, Kayton RJ, et al: Treatment with thyroxine restores myelination and clinical recovery after intra-ventricular hemorrhage. J Neurosci. 33:17232–17246. 2013. View Article : Google Scholar : PubMed/NCBI
30	Zhou Y, Wang Y, Wang J, Anne Stetler R and Yang QW: Inflammation in intracerebral hemorrhage: From mechanisms to clinical translation. Prog Neurobiol. 115:25–44. 2014. View Article : Google Scholar
31	Yang MC, Zhang HZ, Wang Z, You FL and Wang YF: The molecular mechanism and effect of cannabinoid-2 receptor agonist on the blood-spinal cord barrier permeability induced by ischemia-reperfusion injury. Brain Res. 1636:81–92. 2016. View Article : Google Scholar : PubMed/NCBI
32	Aijaz S, Balda MS and Matter K: Tight junctions: Molecular architecture and function. Int Rev Cytol. 248:261–298. 2006. View Article : Google Scholar : PubMed/NCBI
33	Kurihara R, Tohyama Y, Matsusaka S, Naruse H, Kinoshita E, Tsujioka T, Katsumata Y and Yamamura H: Effects of peripheral cannabinoid receptor ligands on motility and polarization in neutrophil-like HL60 cells and human neutrophils. J Biol Chem. 281:12908–12918. 2006. View Article : Google Scholar : PubMed/NCBI
34	Rom S, Zuluaga-Ramirez V, Dykstra H, Reichenbach NL, Pacher P and Persidsky Y: Selective activation of cannabinoid receptor 2 in leukocytes suppresses their engagement of the brain endothelium and protects the blood-brain barrier. Am J Pathol. 183:1548–1558. 2013. View Article : Google Scholar : PubMed/NCBI
35	Correa F, Mestre L, Docagne F and Guaza C: Activation of cannabinoid CB2 receptor negatively regulates IL-12p40 production in murine macrophages: Role of IL-10 and ERK1/2 kinase signaling. Br J Pharmacol. 145:441–448. 2005. View Article : Google Scholar : PubMed/NCBI
36	Montecucco F, Lenglet S, Braunersreuther V, Burger F, Pelli G, Bertolotto M, Mach F and Steffens S: CB cannabinoid receptor activation is cardioprotective in a mouse model of ischemia/reperfusion. J Mol Cell Cardiol. 46:612–620. 2009. View Article : Google Scholar : PubMed/NCBI
37	Sophocleous A, Marino S, Logan JG, Mollat P, Ralston SH and Idris AI: Bone cell-autonomous contribution of type 2 cannabinoid receptor to breast cancer-induced osteolysis. J Biol Chem. 290:22049–22060. 2015. View Article : Google Scholar : PubMed/NCBI
38	Gomez O, Sanchez-Rodriguez MA, Ortega-Gutierrez S, Vazquez-Villa H, Guaza C, Molina-Holgado F and Molina-Holgado E: A basal tone of 2-arachidonoylglycerol contributes to early oligodendrocyte progenitor proliferation by activating phosphatidylinositol 3-Kinase (PI3K)/AKT and the mammalian target of rapamycin (MTOR) pathways. J Neuroimmune Pharmacol. 10:309–317. 2015. View Article : Google Scholar : PubMed/NCBI