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Mouse strain differences in susceptibility to cerebral ischemia are related to cerebral vascular anatomy
F C Barone1, D J Knudsen, A H Nelson
1Department of Cardiovascular Pharmacology, SmithKline Beecham Pharmaceuticals, King of Prussia, Pennsylvania.
Abstract:
The consequences of cerebral ischemia were studied in three different strains (BDF, CFW, and BALB/C) of mice. The different strains exhibited significant differences in susceptibility to 24-h focal ischemia. Following middle cerebral artery occlusion (MCAO), infarct volumes (mm3) were 5 +/- 3 in BDF, 15 +/- 5 in CFW, and 23 +/- 3 in BALB/C mice (p < 0.05). MCAO plus ipsilateral common carotid artery occlusion (CCAO) resulted in infarct volumes of 15 +/- 9 in BDF, 38 +/- 10 in CFW, and 72 +/- 12 in BALB/C mice (p < 0.05). In addition, MCAO plus CCAO produced death by 24 h in 42% of CFW and 67% of BALB/C mice, but not in any BDF mice (p < 0.05). CCAO alone produced multifocal hemispheric infarctions in 36% of BALB/C mice but not in the other two strains. Brains of all mouse strains subjected to sham surgery were free of any ischemic injury. Arterial blood pressures, blood gases, and blood cell profiles were relatively similar for the three mouse strains. However, carbon black studies of the cerebrovascular anatomy revealed an incomplete circle of Willis (i.e., a significant decrease in the frequency of patent posterior communicating arteries) for BALB/C compared with BDF mice (p < 0.05), with CFW mice being intermediary. Based on these anatomical data, BALB/C mice also were evaluated following transient global brain ischemia produced by bilateral CCAO. BALB/C mice exhibited a > 85% reduction in cortical microvascular perfusion and EEG power within 1 min of bilateral CCAO. Also, hippocampal neuronal CA1 damage and mortality over 7 days were related to the duration of global brain ischemia (p < 0.05). These data demonstrate a significant difference between mouse strains in their sensitivity to cerebral ischemia that appears to be related, at least in part, to the functional vascular anatomy at the level of the posterior communicating arteries. In particular, we point out the potential usefulness of BALB/C mice as a sensitive and reproducible model of focal and global ischemia.
Insights
Mouse strain significantly impacts cerebral ischemia outcomes. BALB/C mice show higher susceptibility to focal and global ischemia due to cerebrovascular anatomy, making them a valuable model for studying brain injury.
Area of Science:
- Neuroscience
- Cerebrovascular Research
- Animal Models
Background:
- Cerebral ischemia is a major cause of neurological damage.
- Understanding strain-specific susceptibility is crucial for developing effective treatments.
- Mouse models are essential for studying ischemia's pathophysiology.
Purpose of the Study:
- To investigate differences in susceptibility to cerebral ischemia among three mouse strains: BDF, CFW, and BALB/C.
- To explore the relationship between cerebrovascular anatomy and ischemic injury severity.
- To evaluate the suitability of BALB/C mice as a model for focal and global ischemia.
Main Methods:
- Induction of focal ischemia via middle cerebral artery occlusion (MCAO) and MCAO plus common carotid artery occlusion (CCAO).
- Assessment of infarct volumes, mortality rates, and neurological deficits.
- Cerebrovascular anatomy analysis using carbon black perfusion.
- Induction of global ischemia via bilateral CCAO in BALB/C mice.
- Monitoring of microvascular perfusion and electroencephalogram (EEG) power.
Main Results:
- BALB/C mice exhibited significantly larger infarct volumes and higher mortality rates following MCAO and CCAO compared to BDF and CFW mice.
- BALB/C mice demonstrated an incomplete circle of Willis, characterized by fewer patent posterior communicating arteries.
- CCAO alone induced multifocal hemispheric infarctions in BALB/C mice.
- BALB/C mice showed rapid and severe reductions in cortical perfusion and EEG power during global ischemia, with damage correlating to duration.
Conclusions:
- Mouse strain significantly influences susceptibility to cerebral ischemia.
- Cerebrovascular anatomy, particularly the posterior communicating arteries, plays a key role in determining ischemic injury severity.
- BALB/C mice represent a sensitive and reproducible model for studying both focal and global cerebral ischemia.