Glutathione peroxidase overexpression does not rescue impaired neurogenesis in the injured immature brain

Brain and Spinal Injury Center and Department of Neurological Surgery, University of California, San Francisco, California, USA.
Journal of Neuroscience Research (Impact Factor: 2.59). 06/2009; 87(8):1848-57. DOI: 10.1002/jnr.21996
Source: PubMed


Traumatic brain injury (TBI) is a leading cause of disability among young children and is associated with long-term cognitive deficits. These clinical findings have prompted an investigation of the hippocampus in an experimental model of trauma to the developing brain at postnatal day (p21). Previous studies using this model have revealed a progressive loss of neurons in the hippocampus as brain-injured animals mature to young adulthood. Here we determined whether this hippocampal vulnerability is likewise reflected in altered neurogenesis and whether the antioxidant glutathione peroxidase (GPx) modulates neurogenesis during maturation of the injured immature brain. Male transgenic mice that overexpress GPx and wild-type littermates were subjected to controlled cortical impact or sham surgery on p21. At 2 weeks postinjury, the numbers of proliferating cells and immature neurons within the subgranular zone were measured by using Ki-67 and doublecortin, respectively. Bromodeoxyuridine (BrdU) was used to label dividing cells beginning 2 weeks postinjury. Survival (BrdU(+)) and neuronal differentiation (BrdU(+)/NeuN(+)) were then measured 4 weeks later via confocal microscopy. Two-way ANOVA revealed no significant interaction between genotype and injury. Subsequent analysis of the individual effects of injury and genotype, however, showed a significant reduction in subgranular zone proliferation (Ki-67) at 2 weeks postinjury (P = 0.0003) and precursor cell survival (BrdU(+)) at 6 weeks postinjury (P = 0.016) and a trend toward reduced neuronal differentiation (BrdU(+)/NeuN(+)) at 6 weeks postinjury (P = 0.087). Overall, these data demonstrate that traumatic injury to the injured immature brain impairs neurogenesis during maturation and suggest that GPx cannot rescue this reduced neurogenesis.

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    • "Using a rat cryoinjury model to mimic human brain contusions, a more robust increase in SVZ proliferation and neuroblast production was seen after injury at pnd 6 and 10 compared to pnd 21, suggesting that the age at which the injury occurs considerably affects the regenerative capacity (Covey et al., 2010). Similarly, neurogenesis is impaired in mice after TBI at pnd 21, which show reduced proliferation of SGZ cells and limited precursor cell survival at 6 weeks after injury (Potts et al., 2009). Comparing the impact of HI injury in the mouse brain at pnd 9 and 21, this insult disrupts the growth of the granule cell layer (GCL) in the hippocampus in pnd 9 brains, whereas in pnd 21 brains, where the GCL had reached its full size, the volume was unaffected by HI (Qiu et al., 2007). "
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    • "Previous reports have demonstrated an increase in cell proliferation using BrdU-labeling, or other markers of immature neurons after brain injury (Dash et al., 2001; Braun et al., 2002; Sun et al., 2007; Urrea et al., 2007). However, in the hippocampus this increase does not last, as other studies have demonstrated that doublecortin-positive cells are decreased from 14 days to 6 weeks post-injury (Rola et al., 2006; Gao et al., 2008; Potts et al., 2009). To our knowledge, this is the first report of a loss of doublecortin-positive cells at 3 months after brain injury and induction of seizures. "
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    • "However, we failed to observe protection of CM-treated Dcx + cells by glutathione. This is in agreement with a recent study demonstrating that overexpression of the antioxidant enzyme glutathione peroxidase did not attenuate the decrease in neurogenesis associated with traumatic brain injury (Potts et al., 2009). "
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