Table 1.
Unique age-dependent features of cellular response to acute brain injury from immature animal studies.
| Mechanism | Unique response of developing brain | References |
|---|---|---|
| Energy metabolism |
• Improved potential for use of alternative fuels (ketones) | (Thomas et al., 2000; Prins et al., 2005) |
| • Shortened length of metabolic depression after TBI | ||
| Excitotoxicity | • Regional expression of NMDA, AMPA and kainate receptors is age- dependent |
(McDonald et al., 1988; McDonald et al., 1992; Monyer et al., 1994; Ben Ari et al., 1997; Pohl et al., 1999; Anderson et al., 1999; Sharma et al., 2000; Robertson et al., 2004) |
| • Heightened sensitivity of young brain to excitotoxicity after HI insult | ||
| • Potential for NMDA inhibition to promote delayed (apoptotic) cell death |
||
| • Potential for GABA receptor excitatory transmission at young ages | ||
| • Age-dependent differences in mitochondrial calcium uptake capacity | ||
| Mitochondrial permeability transition |
• Lack of effect of cyclosporin A (CsA) on mitochondrial Ca2+ uptake or HI injury |
(Puka-Sundvall et al., 2001; Robertson et al., 2004; Nakai et al., 2004; Setkowicz et al., 2004) |
| • CsA protection with intrauterine ischemia | ||
| • CsA worsened mortality (PND 6) and seizure length (PND 30) in immature rats |
||
| Oxidative stress | • Brain antioxidant enzymes have an age-dependent profile of activity and expression |
(Mavelli et al., 1982; Ditelberg et al., 1996; Fullerton et al., 1998; Khan and Black, 2003; Fan et al., 2003; Robertson et al., 2006; Bayir et al., 2006) |
| • Perinatal surges in antioxidant enzymes but lower levels of enzymes during other developmental times (versus adult) |
||
| • Worse outcome after HI insult in Cu,Zn-SOD overexpressing immature mice (PND 7) due to accumulation of H2O2 |
||
| • Limited upregulation of GPX after TBI in immature mouse (PND 21) compared to adult mouse |
||
| Cell death | • Immature brain has normal, basal programmed cell death mechanisms active in early development |
(Raff et al., 1993; Alonso et al., 1997; Shimohama et al., 1998; Bittigau et al., 1999; Krajewska et al., 2002; Johnston et al., 2002; Polster et al., 2003b; Vannucci and Hagberg, 2004; Zhu et al., 2005; Northington et al., 2005; Soane et al., 2008) |
| • Age-dependent expression of bcl-2 family proteins in tissue and mitochondria |
||
| • Susceptibility of immature brain to apoptotic cell death after hypoxic– ischemic insult |
||
| • Vulnerability of young brain to mitochondrial cytochrome c release upon exposure to pro-apoptotic stimuli |
||
| • Trauma-induced apoptosis is greater in young rats |
TBI – traumatic brain injury; HI – hypoxic–ischemic; PND – postnatal day; SOD – superoxide dismutase; GPX – glutathione peroxidase.