PMID- 31860812 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20230619 IS - 1933-0693 (Electronic) IS - 0022-3085 (Linking) VI - 134 IP - 1 DP - 2019 Dec 20 TI - Disruption of P2X4 purinoceptor and suppression of the inflammation associated with cerebral aneurysm formation. PG - 102-114 LID - 10.3171/2019.9.JNS19270 [doi] AB - OBJECTIVE: There are no effective therapeutic drugs for cerebral aneurysms, partly because the pathogenesis remains unresolved. Chronic inflammation of the cerebral arterial wall plays an important role in aneurysm formation, but it is not clear what triggers the inflammation. The authors have observed that vascular endothelial P2X4 purinoceptor is involved in flow-sensitive mechanisms that regulate vascular remodeling. They have thus hypothesized that shear stress-associated hemodynamic stress on the endothelium causes the inflammatory process in the cerebral aneurysm development. METHODS: To test their hypothesis, the authors examined the role of P2X4 in cerebral aneurysm development by using P2X4-/- mice and rats that were treated with a P2X4 inhibitor, paroxetine, and subjected to aneurysm-inducing surgery. Cerebral aneurysms were induced by unilateral carotid artery ligation and renovascular hypertension. RESULTS: The frequency of aneurysm induction evaluated by light microscopy was significantly lower in the P2X4-/- mice (p = 0.0488) and in the paroxetine-treated male (p = 0.0253) and female (p = 0.0204) rats compared to control mice and rats, respectively. In addition, application of paroxetine from 2 weeks after surgery led to a significant reduction in aneurysm size in the rats euthanized 3 weeks after aneurysm-inducing surgery (p = 0.0145), indicating that paroxetine suppressed enlargement of formed aneurysms. The mRNA and protein expression levels of known inflammatory contributors to aneurysm formation (monocyte chemoattractant protein-1 [MCP-1], interleukin-1beta [IL-1beta], tumor necrosis factor-alpha [TNFalpha], inducible nitric oxide synthase [iNOS], and cyclooxygenase-2 [COX-2]) were all significantly elevated in the rats that underwent the aneurysm-inducing surgery compared to the nonsurgical group, and the values in the surgical group were all significantly decreased by paroxetine administration according to quantitative polymerase chain reaction techniques and Western blotting. Although immunolabeling densities for COX-2, iNOS, and MCP-1 were not readily observed in the nonsurgical mouse groups, such densities were clearly seen in the arterial wall of P2X4+/+ mice after aneurysm-inducing surgery. In contrast, in the P2X4-/- mice after the surgery, immunolabeling of COX-2 and iNOS was not observed in the arterial wall, whereas that of MCP-1 was readily observed in the adventitia, but not the intima. CONCLUSIONS: These data suggest that P2X4 is required for the inflammation that contributes to both cerebral aneurysm formation and growth. Enhanced shear stress-associated hemodynamic stress on the vascular endothelium may trigger cerebral aneurysm development. Paroxetine may have potential for the clinical treatment of cerebral aneurysms, given that this agent exhibits efficacy as a clinical antidepressant. FAU - Fukuda, Miyuki AU - Fukuda M AD - 1Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto. AD - 2Department of Neurosurgery, Graduate School of Medicine, Kyoto University, Kyoto. FAU - Fukuda, Shunichi AU - Fukuda S AD - 1Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto. FAU - Ando, Joji AU - Ando J AD - 3Laboratory of Biomedical Engineering, School of Medicine, Dokkyo Medical University, Mibu City, Tochigi. FAU - Yamamoto, Kimiko AU - Yamamoto K AD - 4Department of Biomedical Engineering, Graduate School of Medicine, University of Tokyo, Bunkyo-ku, Tokyo. FAU - Yonemoto, Naohiro AU - Yonemoto N AD - Departments of5Biostatistics and. FAU - Suzuki, Takashi AU - Suzuki T AD - 1Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto. AD - 6Psychiatry, Graduate School of Medicine, Kyoto University, Kyoto; and. FAU - Niwa, Youko AU - Niwa Y AD - 1Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto. FAU - Inoue, Takayuki AU - Inoue T AD - 7Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute. FAU - Satoh-Asahara, Noriko AU - Satoh-Asahara N AD - 7Department of Endocrinology, Metabolism, and Hypertension Research, Clinical Research Institute. FAU - Hasegawa, Koji AU - Hasegawa K AD - 8Division of Translational Research, and. FAU - Shimatsu, Akira AU - Shimatsu A AD - 9Clinical Research Institute, National Hospital Organization Kyoto Medical Center, Kyoto, Japan. FAU - Tsukahara, Tetsuya AU - Tsukahara T AD - 1Department of Neurosurgery, National Hospital Organization Kyoto Medical Center, Kyoto. LA - eng PT - Journal Article DEP - 20191220 PL - United States TA - J Neurosurg JT - Journal of neurosurgery JID - 0253357 SB - IM OTO - NOTNLM OT - animal model OT - cerebral aneurysm formation OT - inflammation OT - therapeutic drug OT - vascular disorders OT - vascular flow-sensitive mechanism OT - wall shear stress EDAT- 2019/12/21 06:00 MHDA- 2019/12/21 06:01 CRDT- 2019/12/21 06:00 PHST- 2019/01/31 00:00 [received] PHST- 2019/09/24 00:00 [accepted] PHST- 2019/12/21 06:01 [medline] PHST- 2019/12/21 06:00 [pubmed] PHST- 2019/12/21 06:00 [entrez] AID - 2019.9.JNS19270 [pii] AID - 10.3171/2019.9.JNS19270 [doi] PST - epublish SO - J Neurosurg. 2019 Dec 20;134(1):102-114. doi: 10.3171/2019.9.JNS19270.