Rat 4Vessel Occlusion

Unlike gerbils, rats exhibit robust communication between carotid and vertebral arterial supplies to the brain. Therefore, one surgical approach to selective forebrain ischemia in the rat involves permanent cauterization of both vertebral arteries at the level of the first cervical

Figure 2 Insult thresholds for hippocampal CA1 neuronal injury in rodent models of global ischemia. The proportion of surviving neurons is plotted against insult duration. Data for rat (x) and gerbil (+) are derived from recent studies that monitored ischemic depolarization to define insult severity for individual hippocampi (60,80), and they demonstrate the comparability of results for the two species. Mice typically exhibit longer insult thresholds, the C57Bl/6 strain (open symbols) showing greater vulnerability than the SV129 strain (closed symbols). Compatible results have been obtained for insults produced by cardiac arrest (triangles) (99), 2-vessel occlusion (VO) (squares) (114), and 3-VO (circles) (116). One early 3-VO study in mice indicated a threshold consistent with rat and gerbil studies (half-open circles) (115), perhaps reflecting more aggressive control of head temperature. Except for the cardiac arrest study, for which data were available on mean depolarization time, mouse results are plotted as group averages, using insult duration defined by occlusion times.

Figure 2 Insult thresholds for hippocampal CA1 neuronal injury in rodent models of global ischemia. The proportion of surviving neurons is plotted against insult duration. Data for rat (x) and gerbil (+) are derived from recent studies that monitored ischemic depolarization to define insult severity for individual hippocampi (60,80), and they demonstrate the comparability of results for the two species. Mice typically exhibit longer insult thresholds, the C57Bl/6 strain (open symbols) showing greater vulnerability than the SV129 strain (closed symbols). Compatible results have been obtained for insults produced by cardiac arrest (triangles) (99), 2-vessel occlusion (VO) (squares) (114), and 3-VO (circles) (116). One early 3-VO study in mice indicated a threshold consistent with rat and gerbil studies (half-open circles) (115), perhaps reflecting more aggressive control of head temperature. Except for the cardiac arrest study, for which data were available on mean depolarization time, mouse results are plotted as group averages, using insult duration defined by occlusion times.

vertebra, followed later by bilateral carotid artery occlusion (63). This 4-vessel occlusion (VO) is typically performed as a 2-stage procedure, allowing a day for recovery following the initial surgery for vertebral cauterization and preparatory isolation of the carotid arteries. Occluding devices are left in place around the carotid arteries to permit their rapid retrieval and occlusion. An early modification of the method led to additional routing of a suture line around the neck musculature, but behind the trachea and major vessels, to be tightened at the time of occlusion to further limit collateral perfusion (64) . The standard model involved carotid occlusion in unanesthetized animals under brief restraint, permitting early behavioral evaluation. Criteria for successful occlusion included prompt loss of righting reflex, bilateral pupil dilation, and unresponsiveness to tail pinch. The original 4-VO methodology with described modifications can result in reproducible ischemia, with a success rate of up to 90% of operated animals from the Wistar colony employed (65).

Generally comparable results were noted in a modified method in which carotid occlusions were performed under initial halothane anesthesia (66). However, technical challenges can be associated with vertebral artery cauterization and inconsistencies have been reported (67,68). Alternative approaches have been suggested to improve visual confirmation of vessel disruption (69,70). A 3-VO model has also been developed in which the basilar artery is occluded in place of the vertebral arteries (71 ) . Inter- and intrastrain heterogeneity impact model reproducibility (63,68,72,73), presumably reflecting variations in collateral perfusion, but supplemental neck ligatures have not been systematically applied across laboratories. Some studies in anesthetized animals have alternatively included systemic hypotension (67,74,75 ), or at least avoidance of pressure increases after carotid artery occlusion (76), to improve insult uniformity. A completely surgical extension of this approach involves a 7-vessel procedure (77) with permanent basilar artery cauterization, temporary clamping of bilateral external carotid, and pterygopalatine arteries to attenuate collateral perfusion, and, finally, carotid artery occlusions.

Long occlusions were initially required to produce a given extent of brain injury after 4-VO (5 ), undoubtedly reflecting unrecognized protective effects of incidental head cooling (74). Recent applications have used anesthetized animals with epidural temperature control and electrophysiologic monitoring of ischemic depolarization to verify successful occlusion (78-80), considered in detail below. This implementation of the model exhibits a threshold for CA1 neuronal injury identical to that observed in the gerbil (Fig. 2).

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