Research reportEffect of hypotension severity on hippocampal CA1 neurons in a rat global ischemia model
Introduction
The global ischemia model has been used to analyze selective vulnerability in the hippocampal CA1 subregion. Neuronal death in the CA1 subregion has been shown to occur 2–3 days after ischemia [1], [9], [16]. The 2-vessel occlusion model, first described by Smith et al. [15], is one of the most frequently used global ischemia paradigms in rodents [17], [18], [19]. Although researchers often fail to induce bilateral CA1 neuronal death using Smith’s or a modified 2-vessel occlusion model [5], [13], improvement in the technical aspects of the ‘‘success rate’’ has not been fully discussed. On the other hand, the effect of hypotension severity on neuronal death has not been thoroughly studied. We induced 10 min of global ischemia using a 2-vessel occlusion and hypotension model with various severities of hypotension. Subsequent neuronal damage in the hippocampal CA1 pyramidal cell layer was immunohistochemically studied. The neuronal proliferation was examined by administration of a thymidine analog, bromodeoxyuridine (BrdU). Neuronal apoptosis after global ischemia was also characterized by terminal deoxynucleotidyl transferase-mediated uridine 5′-triphosphate-biotin nick end labeling (TUNEL) staining.
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Surgery
Transient global ischemia was induced by bilateral common carotid artery occlusion and bleeding to lower the mean arterial blood pressure (MABP) to 26-30 mmHg (severe hypotension group), 31-35 mmHg (moderate hypotension group) and 36-40 mmHg (mild hypotension group) using the method originally described by Smith et al. [15] with some modifications [1]. Male Sprague-Dawley rats (225–275 g, Charles River Laboratories, Wilmington, MA) were anesthetized with 5% isoflurane and maintained during
Results
The physiological data before and 10 min after ischemia were not significantly different among the three groups (Table 1). As shown in Table 2, severe hypotension caused more than 50% mortality, however, moderate and mild hypotension caused substantially lower mortality. A majority of the postoperative deaths occurred within 3 days of ischemia. The percentage of the damaged area in the mild hypotension group was significantly lower than in the moderate and severe groups (Fig. 1A). In the mild
Discussion
Several studies have described the fact that unilateral CA1 neuronal cell death often occurs using the model of bilateral carotid occlusion combined with systemic hypotension [5], [13]. Smith et al. [15] originally designed this model to lower the MABP to 50 mmHg, and this severity of hypotension was used as a standard MABP during ischemia [17], [18], [19]. However, it has been reported that the MABP of 50 mmHg did not induce consistent bilateral hippocampal injury [5]. In their model, the
Acknowledgements
This study was supported by National Institutes of Health grants NS14543, NS25372, NS36147, NS37530, NS38653 and NO1 NS82386. P.H.C. is a recipient of the Jacob Javits Neuroscience Investigator Award. We thank Bernard Calagui, Liza Reola and Jane O. Kim for technical assistance.
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