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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.

SUBMITTER: Kitamura A

PROVIDER: S-EPMC5012514 | biostudies-literature | 2016 Sep

REPOSITORIES: biostudies-literature

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Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory.

Kitamura Akihiro A Saito Satoshi S Maki Takakuni T Oishi Naoya N Ayaki Takashi T Hattori Yorito Y Yamamoto Yumi Y Urushitani Makoto M Kalaria Raj N RN Fukuyama Hidenao H Horsburgh Karen K Takahashi Ryosuke R Ihara Masafumi M

Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism 20151013 9

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) ...[more]

PMID: 26661170

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Project description:BACKGROUND: This study was performed within the scope of two multi-center European Commission-funded projects (HEPMEAP and PAMCHAR) concerning source-composition-toxicity relationship for particulate matter (PM) sampled in Europe. The present study aimed to optimize the design for PM in vivo toxicity screening studies in terms of dose and time between a single exposure and the determination of the biological responses in a rat model mimicking human disease resulting in susceptibility to ambient PM. Dust in thoracic PM size-range (aerodynamic diameter <10 mum) was sampled nearby a road tunnel (RTD) using a high volume cascade impactor. Spontaneously hypertensive rats were exposed to urban dust collected in Ottawa, Canada (EHC-93 10 mg/kg of body weight; reference PM) or different RTD doses (0.3, 1, 3, 10 mg/kg of body weight) by intratracheal instillation. Necropsy was performed at 4, 24, or 48 hr after exposure. RESULTS: The neutrophil numbers in bronchoalveolar lavage fluid increased tremendously after exposure to the highest RTD doses or EHC-93. Furthermore, PM exposure slightly affected blood coagulation since there was a small but significant increase in the plasma fibrinogen levels (factor 1.2). Pulmonary inflammation and oxidative stress as well as changes in blood coagulation factors and circulating blood cell populations were observed within the range of 3 to 10 mg PM/kg of body weight without significant pulmonary injury. CONCLUSION: The optimal dose for determining the toxicity ranking of ambient derived PM samples in spontaneously hypertensive rats is suggested to be between 3 and 10 mg PM/kg of body weight under the conditions used in the present study. At a lower dose only some inflammatory effects were detected, which will probably be too few to be able to discriminate between PM samples while a completely different response pattern was observed with the highest dose. In addition to the dose, a 24-hr interval from exposure to sacrifice seemed appropriate to assess the relative toxic potency of PM since the majority of the health effects were observed one day after PM exposure compared to the other times examined. The aforementioned considerations provide a good basis for conducting PM toxicity screening studies in spontaneously hypertensive rats.

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Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory.

Publications

Gradual cerebral hypoperfusion in spontaneously hypertensive rats induces slowly evolving white matter abnormalities and impairs working memory.

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