RT Journal Article SR Electronic T1 Hypoxia-Ischemia Induces DNA Synthesis without Cell Proliferation in Dying Neurons in Adult Rodent Brain JF The Journal of Neuroscience JO J. Neurosci. FD Society for Neuroscience SP 10763 OP 10772 DO 10.1523/JNEUROSCI.3883-04.2004 VO 24 IS 47 A1 Chia-Yi Kuan A1 Aryn J. Schloemer A1 Aigang Lu A1 Kevin A. Burns A1 Wei-Lan Weng A1 Michael T. Williams A1 Kenneth I. Strauss A1 Charles V. Vorhees A1 Richard A. Flavell A1 Roger J. Davis A1 Frank R. Sharp A1 Pasko Rakic YR 2004 UL http://www.jneurosci.org/content/24/47/10763.abstract AB Recent studies suggest that postmitotic neurons can reenter the cell cycle as a prelude to apoptosis after brain injury. However, most dying neurons do not pass the G1/S-phase checkpoint to resume DNA synthesis. The specific factors that trigger abortive DNA synthesis are not characterized. Here we show that the combination of hypoxia and ischemia induces adult rodent neurons to resume DNA synthesis as indicated by incorporation of bromodeoxyuridine (BrdU) and expression of G1/S-phase cell cycle transition markers. After hypoxia-ischemia, the majority of BrdU- and neuronal nuclei (NeuN)-immunoreactive cells are also terminal deoxynucleotidyl transferase-mediated biotinylated UTP nick end labeling (TUNEL)-stained, suggesting that they undergo apoptosis. BrdU+ neurons, labeled shortly after hypoxia-ischemia, persist for >5 d but eventually disappear by 28 d. Before disappearing, these BrdU+/NeuN+/TUNEL+ neurons express the proliferating cell marker Ki67, lose the G1-phase cyclin-dependent kinase (CDK) inhibitors p16INK4 and p27Kip1 and show induction of the late G1/S-phase CDK2 activity and phosphorylation of the retinoblastoma protein. This contrasts to kainic acid excitotoxicity and traumatic brain injury, which produce TUNEL-positive neurons without evidence of DNA synthesis or G1/S-phase cell cycle transition. These findings suggest that hypoxia-ischemia triggers neurons to reenter the cell cycle and resume apoptosis-associated DNA synthesis in brain. Our data also suggest that the demonstration of neurogenesis after brain injury requires not only BrdU uptake and mature neuronal markers but also evidence showing absence of apoptotic markers. Manipulating the aberrant apoptosis-associated DNA synthesis that occurs with hypoxia-ischemia and perhaps neurodegenerative diseases could promote neuronal survival and neurogenesis.