Abstract
We have previously reported free radical production after traumatic brain injury (TBI), which induces neural stem cell (NSC) degeneration and death. However, the effects of aging on NSC proliferation around the damaged area following TBI have not been investigated. Therefore, in this study, we used 10-week (young group) and 24-month-old (aged group) rat TBI models to investigate the effects of aging on NSC proliferation around damaged tissue using immunohistochemical and ex vivo techniques. Young and aged rats received TBI. At 1, 3 and 7 days after TBI, immunohistochemical and lipid peroxidation studies were performed. Immunohistochemistry revealed that the number of nestin-positive cells around the damaged area after TBI in the aged group decreased significantly when compared with those in the young group (P < 0.01). However, the number of 8-hydroxy-2′-deoxyguanosine-, 4-hydroxy-2-nonenal- and single-stranded DNA (ssDNA)-positive cells and the level of peroxidation around the damaged area after TBI significantly increased in the aged group, compared with those in the young group (P < 0.01). Furthermore, almost all ssDNA-positive cells in young and aged groups co-localized with NeuN and nestin staining. Ex vivo studies revealed that neurospheres, which differentiated into neurons and glia in culture, could only be isolated from injured brain tissue in young and aged groups at 3 days after TBI. These results indicate that, although there were fewer NSCs that have the potential to differentiate into neurons and glia, these NSCs escaped free radical-induced degeneration around the damaged area after TBI in the aged rat brain.








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Ates O, Cayli S, Altinoz E, Gurses I, Yucel N, Sener M, Kocak A, Yologlu S (2007) Neuroprotection by resveratrol against traumatic brain injury in rats. Mol Cell Biochem 294:137–144
Azbill RD, Mu X, Bruce-Keller AJ, Mattson MP, Springer JE (1997) Impaired mitochondrial function, oxidative stress and altered antioxidant enzyme activities following traumatic spinal cord injury. Brain Res 765:283–290
Belluardo N, Mudo G, Bonomo A, Di Liberto V, Frinchi M, Fuxe K (2008) Nicotine-induced fibroblast growth factor-2 restores the age-related decline of precursor cell proliferation in the subventricular zone of rat brain. Brain Res 1193:12–24
Campuzano O, Castillo-Ruiz MM, Acarin L, Castellano B, Gonzalez B (2009) Increased levels of proinflammatory cytokines in the aged rat brain attenuate injury-induced cytokine response after excitotoxic damage. J Neurosci Res 87:2484–2497
Chen S, Pickard JD, Harris NG (2003) Time course of cellular pathology after controlled cortical impact injury. Exp Neurol 182:87–102
Chirumamilla S, Sun D, Bullock MR, Colello RJ (2002) Traumatic brain injury induced cell proliferation in the adult mammalian central nervous system. J Neurotrauma 19:693–703
Das S, Mandal AK, Ghosh A, Panda S, Das N, Sarkar S (2008) Nanoparticulated quercetin in combating age related cerebral oxidative injury. Curr Aging Sci 1:169–174
Dinapoli VA, Benkovic SA, Li X, Kelly KA, Miller DB, Rosen CL, Huber JD, O’Callaghan JP (2010) Age exaggerates proinflammatory cytokine signaling and truncates signal transducers and activators of transcription 3 signaling following ischemic stroke in the rat. Neuroscience 170:633–644
Douen AG, Dong L, Vanance S, Munger R, Hogan MJ, Thompson CS, Hakim AM (2004) Regulation of nestin expression after cortical ablation in adult rat brain. Brain Res 1008:139–146
Gilmer LK, Ansari MA, Roberts KN, Scheff SW (2010) Age-related changes in mitochondrial respiration and oxidative damage in the cerebral cortex of the Fischer 344 rat. Mech Ageing Dev 131:133–143
Itoh T, Satou T, Hashimoto S, Ito H (2005) Isolation of neural stem cells from damaged rat cerebral cortex after TBI. NeuroReport 16:1687–1691
Itoh T, Satou T, Nishida S, Hashimoto S, Ito H (2006) Cultured rat astrocytes give rise to neural stem cells. Neurochem Res 31:1381–1387
Itoh T, Satou T, Hashimoto S, Ito H (2007) Immature and mature neurons coexist among glial scars after rat traumatic brain injury. Neurol Res 29:734–742
Itoh T, Satou T, Nishida S, Tsubaki M, Hashimoto S, Ito H (2009) The novel free radical scavenger, edaravone, increases neural stem cell number around the area of damage following rat traumatic brain injury. Neurotox Res 16:378–389
Itoh T, Satou T, Nishida S, Tsubaki M, Imano M, Hashimoto S, Ito H (2010) Edaravone protects against apoptotic neuronal cell death and improves cerebral function after traumatic brain injury in rats. Neurochem Res 35:348–355
Itoh T, Imano M, Nishida S, Tsubaki M, Hashimoto S, Ito A, Satou T (2011a) (-)-Epigallocatechin-3-gallate protects against neuronal cell death and improves cerebral function after traumatic brain injury in rats. Neuromolecular Med 13:300–309
Itoh T, Imano M, Nishida S, Tsubaki M, Hashimoto S, Ito A, Satou T (2011b) Exercise increases neural stem cell proliferation surrounding the area of damage following rat traumatic brain injury. J Neural Transm 118:193–202
Itoh T, Imano M, Nishida S, Tsubaki M, Hashimoto S, Ito A, Satou T (2011c) Exercise inhibits neuronal apoptosis and improves cerebral function following rat traumatic brain injury. J Neural Transm 118:1263–1272
Kawamata T, Katayama Y, Hovda DA, Yoshino A, Becker DP (1995) Lactate accumulation following concussive brain injury: the role of ionic fluxes induced by excitatory amino acids. Brain Res 674:196–204
Kontos HA (1985) George E. Brown memorial lecture. Oxygen radicals in cerebral vascular injury. Circ Res 57:508–516
Kuhn HG, Dickinson-Anson H, Gage FH (1996) Neurogenesis in the dentate gyrus of the adult rat: age-related decrease of neuronal progenitor proliferation. J Neurosci 16:2027–2033
Leker RR, Soldner F, Velasco I, Gavin DK, Androutsellis-Theotokis A, McKay RD (2007) Long-lasting regeneration after ischemia in the cerebral cortex. Stroke 38:153–161
Lynch AM, Lynch MA (2002) The age-related increase in IL-1 type I receptor in rat hippocampus is coupled with an increase in caspase-3 activation. Eur J Neurosci 15:1779–1788
Molteni R, Cattaneo A, Calabrese F, Macchi F, Olivier JD, Racagni G, Ellenbroek BA, Gennarelli M, Riva MA (2010) Reduced function of the serotonin transporter is associated with decreased expression of BDNF in rodents as well as in humans. Neurobiol Dis 37:747–755
Moon C, Ahn M, Kim S, Jin JK, Sim KB, Kim HM, Lee MY, Shin T (2004) Temporal patterns of the embryonic intermediate filaments nestin and vimentin expression in the cerebral cortex of adult rats after cryoinjury. Brain Res 1028:238–242
Ochoa JJ, Pamplona R, Ramirez-Tortosa MC, Granados-Principal S, Perez-Lopez P, Naudi A, Portero-Otin M, Lopez-Frias M, Battino M, Quiles JL (2011) Age-related changes in brain mitochondrial DNA deletion and oxidative stress are differentially modulated by dietary fat type and coenzyme Q. Free Radic Biol Med 50:1053–1064
Parent JM, Yu TW, Leibowitz RT, Geschwind DH, Sloviter RS, Lowenstein DH (1997) Dentate granule cell neurogenesis is increased by seizures and contributes to aberrant network reorganization in the adult rat hippocampus. J Neurosci 17:3727–3738
Picard-Riera N, Nait-Oumesmar B, Baron-Van EA (2004) Endogenous adult neural stem cells: limits and potential to repair the injured central nervous system. J Neurosci Res 76:223–231
Rice AC, Khaldi A, Harvey HB, Salman NJ, White F, Fillmore H, Bullock MR (2003) Proliferation and neuronal differentiation of mitotically active cells following traumatic brain injury. Exp Neurol 183:406–417
Rocha RA, Gimeno-Alcaniz JV, Martin-Ibanez R, Canals JM, Velez D, Devesa V (2011) Arsenic and fluoride induce neural progenitor cell apoptosis. Toxicol Lett 203:237–244
Seri B, Garcia-Verdugo JM, McEwen BS, Alvarez-Buylla A (2001) Astrocytes give rise to new neurons in the adult mammalian hippocampus. J Neurosci 21:7153–7160
Shi SS, Shao SH, Yuan BP, Pan F, Li ZL (2010) Acute stress and chronic stress change brain-derived neurotrophic factor (BDNF) and tyrosine kinase-coupled receptor (TrkB) expression in both young and aged rat hippocampus. Yonsei Med J 51:661–671
Sugawara T, Noshita N, Lewen A, Gasche Y, Ferrand-Drake M, Fujimura M, Morita-Fujimura Y, Chan PH (2002) Overexpression of copper/zinc superoxide dismutase in transgenic rats protects vulnerable neurons against ischemic damage by blocking the mitochondrial pathway of caspase activation. J Neurosci 22:209–217
Terry AV Jr, Kutiyanawalla A, Pillai A (2011) Age-dependent alterations in nerve growth factor (NGF)-related proteins, sortilin, and learning and memory in rats. Physiol Behav 102:149–157
Thored P, Arvidsson A, Cacci E, Ahlenius H, Kallur T, Darsalia V, Ekdahl CT, Kokaia Z, Lindvall O (2006) Persistent production of neurons from adult brain stem cells during recovery after stroke. Stem Cells 24:739–747
Wasserman JK, Schlichter LC (2008) White matter injury in young and aged rats after intracerebral hemorrhage. Exp Neurol 214:266–275
Xiong Y, Gu Q, Peterson PL, Muizelaar JP, Lee CP (1997) Mitochondrial dysfunction and calcium perturbation induced by traumatic brain injury. J Neurotrauma 14:23–34
Xu K, Puchowicz MA, Sun X, LaManna JC (2008) Mitochondrial dysfunction in aging rat brain following transient global ischemia. Adv Exp Med Biol 614:379–386
Yamamoto S, Yamamoto N, Kitamura T, Nakamura K, Nakafuku M (2001) Proliferation of parenchymal neural progenitors in response to injury in the adult rat spinal cord. Exp Neurol 172:115–127
Yeo JE, Kang SK (2007) Selenium effectively inhibits ROS-mediated apoptotic neural precursor cell death in vitro and in vivo in traumatic brain injury. Biochim Biophys Acta 1772:1199–1210
Yurek DM, Fletcher-Turner A (2001) Differential expression of GDNF, BDNF, and NT-3 in the aging nigrostriatal system following a neurotoxic lesion. Brain Res 891:228–235
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We thank Mari Yachi for technical assistance.
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Itoh, T., Imano, M., Nishida, S. et al. Appearance of neural stem cells around the damaged area following traumatic brain injury in aged rats. J Neural Transm 120, 361–374 (2013). https://doi.org/10.1007/s00702-012-0895-7
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DOI: https://doi.org/10.1007/s00702-012-0895-7