A novel global ischemia-reperfusion rat model with asymmetric brain damage simulating post-cardiac arrest brain injury

Abstract

BACKGROUND: Post-cardiac arrest brain injury (PCABI) is a major cause of disability and death in patients with post-cardiac arrest syndrome (PCAS). However, there have been no suitable animal models with characteristic behaviors and cerebral damage adequately mimicking clinical PCABI. NEW METHOD: We established a chimeric model by increasing transient middle cerebral artery occlusion-mediated ipsilateral hemisphere damage in the 4-vessel occlusion (4VO) model, thereby inducing global forebrain asymmetric hemisphere ischemia. Severity of brain damage was then evaluated by behavioral and histological approaches. Neuroprotection was assessed by performing targeted temperature management (TTM) for two hours. RESULTS: Comatose behaviors were observed in both groups. Compared to the 4VO group, the chimeric group exhibited a higher neurological deficit score (NDS) (70.5 +/- 17.6 vs. 139.5 +/- 16.8, p = 0.0002), decreased brain cell viability (88.6 +/- 18.0% vs. 5.7 +/- 2.7%, p < 0.0001), and increased inflammation in the cortex (10.3 +/- 1.6% vs. 16.9 +/- 1.1%, p = 0.0061). After TTM neuroprotection, the chimeric-TTM group showed improvement in NDS (139.5 +/- 16.8 vs. 0.0 +/- 0.0, p < 0.0001), cortex and hippocampus cell viability (5.7 +/- 2.7% vs. 72.8 +/- 10.0%, p < 0.0001; and 2.5 +/- 1.5% vs. 75.5 +/- 10.3%, p < 0.0001, respectively) and inflammation (16.9 +/- 1.1% vs. 11.0 +/- 2.3%, p = 0.190; and 30.9 +/- 1.7% vs. 16.6 +/- 1.2%, p < 0.0001, respectively) compared to the chimeric group. COMPARISON WITH EXISTING METHOD: Unlike the extensive brain damage found in clinical PCAS settings, the existing 4VO models showed only global forebrain damage involving CA1 lesions on both hippocampi. Our model induced global forebrain and additional asymmetric hemisphere ischemic damages, which resulted in simulating PCABI-specific clinical manifestations than conventional models. CONCLUSIONS: Our model adequately simulates clinical PCABI and reflects appropriate neuroprotective effects of TTM.