Effect of Early and Delayed Decompressive Craniectomy on Secondary Brain Damage after Controlled Cortical Impact in Mice

Abstract

The timing of decompressive craniectomy for the treatment of increased intracranial pressure (ICP) after traumatic brain injury (TBI) is a widely discussed clinical issue. Although we showed recently that early decompression is beneficial following experimental TBI, it remains unclear to what degree decompression craniectomy reduces secondary brain damage and if craniectomy is still beneficial when it is delayed by several hours as often inevitable during daily clinical practice. The aim of the current study was therefore to investigate the influence of craniectomy on secondary contusion expansion and brain edema formation and to determine the therapeutic window of craniectomy. Male C57/Bl6 mice were subjected to controlled cortical impact injury. Contusion volume, brain edema formation, and opening of the blood-brain barrier were investigated 2, 6, 12, and 24 h and 7 days after trauma. The effect of decompression craniectomy on secondary brain damage was studied in control mice (closed skull) and in animals craniotomized immediately or with a delay of 1, 3, or 8 h after trauma. Twenty-four hours after trauma, the time point of maximal lesion expansion (+60% vs. 15 min after trauma) and brain edema formation (+3.0% water content vs. sham), contusion volume in craniotomized mice did not show any secondary expansion; that is, contusion volume was similar to that observed in mice sacrificed immediately after trauma (18.3 +/- 5.3 vs. 22.2 +/- 1.4 mm(3)). Furthermore, brain edema formation was reduced by 52% in craniotomized animals. The beneficial effect of craniectomy was still present even when treatment was delayed by up to 3 h after trauma (p < 0.05). The current study clearly demonstrates that early craniectomy prevents secondary brain damage and significantly reduces brain edema formation after experimental TBI. Evaluation of early craniectomy as a therapeutic option after TBI in humans may therefore be indicated.

Causal Role of Apoptosis-Inducing Factor for Neuronal Cell Death Following Traumatic Brain Injury

“…9 The macroscopic manifestation of pericontusional cell death is a delayed increase of contusion volume over time, 10 a finding termed "secondary contusion expansion," and recently characterized experimentally in detail. 11 The ultimate steps leading to delayed cell death in pericontusional tissue are initiated by a combination of multiple mechanisms, such as over-activation of glutamate receptors, 12 free radical-mediated membrane damage, 13 nuclear translocation of transcription factors, tors, 15 and activation of apoptosis-like cell death signaling pathways. 8,16,17 Accumulating evidence suggests that the activation of caspases 18,19 by oligomerization of cell membrane-bound death receptors, 20,21 regulation of bcl-2 family proteins, 22 and the release of pro-apoptotic proteins from mitochondria 23,24 are the prominent signaling pathways that cause DNA fragmentation and pericontusional cell death.…”

“…11,14,40 Animals were anesthetized in a halothane chamber (4%). Anesthesia was maintained with a face mask using 1.2% halothane, 30% O 2 , and 69% N 2 O.…”

“…In contrast to pericontusional neurons, hippocampal neurons showed only cytoplasmic AIF staining at this time point ( Figure 4A, 2 hours). Six hours after brain injury, the time when progressive pericontusional cell death has been shown to occur, 11 both cortical and hippocampal neurons showed nuclear localization of AIF, indicating translocation of AIF from mitochondria to the nucleus ( Figures 3A and 4A, 6 hours). Nuclear translocation of AIF was mainly observed in cells showing advanced nuclear condensation and pyknosis, as demonstrated by double labeling of these cells with AIF and Hoechst 33342 ( Figure 5, AIFϩHoe, 6 hours).…”

“…In both brain regions, the maximal number of AIF-positive cells was observed at 12 hours after trauma, a time course that fits well with the kinetics of delayed neuronal cell death following controlled cortical impact in mice. 11 To investigate whether nuclear translocation of AIF plays a causal role in pericontusional cell death, we compared the contusion volumes of wild-type mice and Harlequin (Hq) mutant mice. Hq mice have a proviral insertion in the AIF gene resulting in deficient AIF expression; in other words, Hq mutant mice express only 20% of the AIF expressed by their wild-type littermates.…”

A microRNA-152 that targets the phosphatase and tensin homolog to inhibit low oxygen induced-apoptosis in human brain microvascular endothelial cells

“…While full recover is possible for some mild cases, sequelae of the central nervous system can also occur to different extents (Douglas-Escobar and Weiss, 2012;Chalak et al, 2014). During this process, hypoxia leads to a set of complicated pathological events including cell apoptosis (Zweckberger et al, 2006;Salmaso et al, 2014).…”