[Show abstract][Hide abstract] ABSTRACT: The molecular mechanisms of neuronal cell death following circulatory arrest are still not fully understood. In the current study we investigated the role of apoptosis-inducing factor (AIF), a major caspase-independent mitochondrial cell death protein, for neuronal cell death following global cerebral ischemia (GCI). C57/Bl6 or low AIF expressing Harlequin mutant mice (AIF(low)) and their wild-type littermates were subjected to 10 min of GCI. DNA damage, nuclear pathology, and localization of AIF were investigated 6, 24, and 72 h after GCI by TUNEL and DAPI staining, and immunohistochemistry, respectively. Cell death of hippocampal CA1 neurons following GCI was associated with nuclear translocation of AIF, nuclear pyknosis, and DNA fragmentation, i.e. ∼80% of all TUNEL-positive neurons had nuclear AIF staining. In AIF(low) mice neuronal cell loss was reduced by 60% (p<0.02). The current experiments suggest that AIF-mediated signaling represents a novel mechanism of neuronal cell death following GCI.
[Show abstract][Hide abstract] ABSTRACT: Existing murine models of global cerebral ischemia are technically challenging thereby hampering the use of genetically engineered mice to study cardiac arrest-induced brain damage. We therefore investigated, if disconnecting the cerebral circulation from vertebral collateral blood flow by proximal occlusion of the basilar artery together with temporary bilateral common carotid artery occlusion (BCCAo) may be a more feasible approach. C57/Bl6 mice were anesthetized and the basilar artery was occluded through a ventral approach. Ten days later BCCAo was performed for 8-14min. Increasing durations of ischemia resulted in enhanced neuronal cell death in cortex, striatum, and hippocampus (22-63%) and increased neurological dysfunction and mortality (0-36%). Following 10min of BCCAo, the duration of global ischemia with the most favorable mortality/neuronal cell death ratio, hippocampal damage started 6h after the insult while cortical and striatal damage was delayed by at least 24h. No further loss of neuronal cells was observed later than 3 days. The proposed two-step approach resulted in complete cerebral ischemia and caused neuronal damage with high reproducibility and small variability. In combination with transgenic and knock-out mice this technically feasible model may help to extend our knowledge on the pathophysiology of cardiac arrest-induced brain damage.
[Show abstract][Hide abstract] ABSTRACT: Global cerebral edema is an independent risk factor for early death and poor outcome after subarachnoid hemorrhage (SAH). In the present study, the time course of brain edema formation, neurological deficits, and neuronal cell loss were investigated in the rat filament SAH model.
Brain water content and neurological deficits were determined in rats randomized to sham (1-, 24-, or 48-hour survival), SAH by endovascular perforation (1-, 24-, or 48-hour survival), or no surgery (control). The neuronal cell count (CA1-3) was quantified in a separate set of SAH (6-, 24-, 48-, or 72-hour survival) and shamoperated animals.
Brain water content increased significantly 24 (80.2 +/- 0.4% [SAH] vs 79.2 +/- 0.1% [sham]) and 48 hours (79.8 +/- 0.2% [SAH] vs 79.3 +/- 0.1% [sham]) after SAH. The neuroscore was significantly worse after SAH (33 +/- 15 [24 hours after SAH] vs 0 +/- 0 points [sham]) and correlated with the extent of brain edema formation (r = 0.96, p < 0.001). No hippocampal damage was present up to 72 hours after SAH.
Brain water content and neurological dysfunction reached a maximum at 24 hours after SAH. This time point, therefore, seems to be optimal to test the effects of therapeutic interventions on brain edema formation. Neuronal cell loss was not present in CA1-3 up to 72 hours of SAH. Therefore, morphological damage needs to be evaluated at later time points.
Journal of Neurosurgery 05/2009; 111(5):988-94. DOI:10.3171/2009.3.JNS08412 · 3.74 Impact Factor