title: Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory.
abstract: Rats subjected to bilateral common carotid arteries (CCAs) occlusion or 2-vessel occlusion (2VO) have been used as animal models of subcortical ischemic vascular dementia (SIVD). However, these models possess an inherent limitation in that cerebral blood flow (CBF) drops sharply and substantially after ligation of CCAs without vascular risk factors and causative small vessel changes. We previously reported a novel rat model of 2-vessel gradual occlusion (2VGO) in which ameroid constrictors (ACs) were placed bilaterally in the CCAs of Wistar-Kyoto rats. To simulate SIVD pathology more closely, we applied ACs in spontaneously hypertensive rats (SHRs), which naturally develop small vessel pathology, and compared their phenotypes with SHR-2VO and sham-operated rats. The mortality rate of the SHR-2VGO was 0% while that of the SHR-2VO was 56.5%. The CBF of the SHR-2VO dropped to 50% of the baseline level at 3 h, whereas the SHR-2VGO showed a gradual CBF reduction reaching only 68% of the baseline level at seven days. The SHR-2VGO showed slowly evolving white matter abnormalities and subsequent spatial working memory impairments of a similar magnitude to the remaining SHR-2VO at 28 days. We suggest the SHR-2VGO robustly replicates selective aspects of the pathophysiology of SIVD with low mortality rate.
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan manto@kuhp.kyoto-u.ac.jp.
authors.forename: Akihiro
authors.initials: A
authors.lastname: Kitamura
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Saito
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Takakuni
authors.initials: T
authors.lastname: Maki
authors.affiliation: Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Naoya
authors.initials: N
authors.lastname: Oishi
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Takashi
authors.initials: T
authors.lastname: Ayaki
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Yorito
authors.initials: Y
authors.lastname: Hattori
authors.affiliation: Department of Regenerative Medicine and Tissue Engineering, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Yumi
authors.initials: Y
authors.lastname: Yamamoto
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Makoto
authors.initials: M
authors.lastname: Urushitani
authors.affiliation: Institute of Neuroscience, Campus for Ageing and Vitality, Newcastle University, UK.
authors.forename: Raj N
authors.initials: RN
authors.lastname: Kalaria
authors.affiliation: Human Brain Research Center, Graduate School of Medicine, Kyoto University, Kyoto, Japan.
authors.forename: Hidenao
authors.initials: H
authors.lastname: Fukuyama
authors.affiliation: Centre for Neuroregeneration, University of Edinburgh, Edinburgh, UK.
authors.forename: Karen
authors.initials: K
authors.lastname: Horsburgh
authors.affiliation: Department of Neurology, Graduate School of Medicine, Kyoto University, Sakyo-ku, Kyoto, Japan.
authors.forename: Ryosuke
authors.initials: R
authors.lastname: Takahashi
authors.affiliation: Department of Stroke and Cerebrovascular Diseases, National Cerebral and Cardiovascular Center, Suita, Japan.
authors.forename: Masafumi
authors.initials: M
authors.lastname: Ihara
mesh_terms: D000818:Animals; D017536:Carotid Artery, Common / Q000503:physiopathology*; D002560:Cerebrovascular Circulation; D015140:Dementia, Vascular / Q000401:mortality / Q000503:physiopathology*; D008570:Memory, Short-Term; D009026:Mortality; D011918:Rats, Inbred SHR; D011921:Rats, Inbred WKY; D066127:White Matter / Q000503:physiopathology
keywords: Vascular dementia; ameroid constrictor; chronic cerebral hypoperfusion; spontaneously hypertensive rat; white matter change