Author:
Shikata Eiji,Miyamoto Takeshi,Yamaguchi Tadashi,Yamaguchi Izumi,Kagusa Hiroshi,Gotoh Daiki,Shimada Kenji,Tada Yoshiteru,Yagi Kenji,Kitazato Keiko T.,Kanematsu Yasuhisa,Takagi Yasushi
Abstract
Abstract
Background and purpose
An aneurysmal subarachnoid hemorrhage is a devastating event. To establish an effective therapeutic strategy, its pathogenesis must be clarified, particularly the pathophysiology of brain harboring intracranial aneurysms (IAs). To elucidate the pathology in brain harboring IAs, we examined the significance of the receptor for advanced glycation end-products (RAGE)/mineralocorticoid receptor (MR) pathway and Na+/K+-ATPase (ATP1α3).
Methods
Ten-week-old female rats were subjected to oophorectomy as well as hypertension and hemodynamic changes to induce IAs, and were fed a high-salt diet. Brain damage in these rats was assessed by inflammatory changes in comparison to sham-operated rats fed a standard diet.
Results
Six weeks after IA induction (n = 30), irregular morphological changes, i.e., an enlarged vessel diameter and vascular wall, were observed in all of the left posterior cerebral arteries (Lt PCAs) prone to rupture. Approximately 20% of rats had ruptured IAs within 6 weeks. In brain harboring unruptured IAs at the PCA, the mRNA levels of RAGE and MR were higher, and that of ATP1α3 was lower than those in the sham-operated rats (p < 0.05, each). Immunohistochemically, elevated expression of RAGE and MR, and decreased expression of ATP1α3 were observed in the brain parenchyma adjacent to the Lt PCA, resulting in increased Iba-1 and S100B expression that reflected the inflammatory changes. There was no difference between the unruptured and ruptured aneurysm rat groups. Treatment with the MR antagonist esaxerenone abrogated these changes, and led to cerebral and vascular normalization and prolonged subarachnoid hemorrhage-free survival (p < 0.05).
Conclusions
Regulation of the imbalance between the RAGE/MR pathway and ATP1α3 may help attenuate the damage in brain harboring IAs, and further studies are warranted to clarify the significance of the down-regulation of the MR/RAGE pathway and the up-regulation of ATP1α3 for attenuating the pathological changes in brain harboring IAs.
Publisher
Springer Science and Business Media LLC
Subject
Cellular and Molecular Neuroscience,Neurology,Immunology,General Neuroscience
Reference31 articles.
1. Macdonald RL, Schweizer TA. Spontaneous subarachnoid haemorrhage. Lancet. 2017;389(10069):655–66.
2. Miyamoto T, Kung DK, Kitazato KT, Yagi K, Shimada K, Tada Y, et al. Site-specific elevation of interleukin-1beta and matrix metalloproteinase-9 in the Willis circle by hemodynamic changes is associated with rupture in a novel rat cerebral aneurysm model. J Cereb Blood Flow Metab. 2017;37(8):2795–805.
3. Yamaguchi T, Miyamoto T, Kitazato KT, Shikata E, Yamaguchi I, Korai M, et al. Time-dependent and site-dependent morphological changes in rupture-prone arteries: ovariectomized rat intracranial aneurysm model. J Neurosurg. 2019:1–9.
4. Matsushita N, Kitazato KT, Tada Y, Sumiyoshi M, Shimada K, Yagi K, et al. Increase in body Na+/water ratio is associated with cerebral aneurysm formation in oophorectomized rats. Hypertension. 2012;60(5):1309–15.
5. Tada Y, Kitazato KT, Tamura T, Yagi K, Shimada K, Kinouchi T, et al. Role of mineralocorticoid receptor on experimental cerebral aneurysms in rats. Hypertension. 2009;54(3):552–7.