is sufficient for neuroprotection, it is not necessary for HDAC inhibitor neuroprotection, because these agents can completely protect neurons cultured from p21 waf1/cip1 -null mice. Together these findings demonstrate (1) that pulse inhibition of HDACs in cortical neurons can induce neuroprotection without apparent toxicity; (2) that p21 waf1/cip1 is sufficient but not necessary to mimic the protective effects of HDAC inhibition; and (3) that oxidative stress in this model induces neuronal cell death via cell cycle-independent pathways that can be inhibited by a cytosolic, noncanonical action of p21 waf1/cip1 .

The penumbral concept is defined as different areas within the ischemic region evolve into irreversible brain injury over time and that this evolution is most critically linked to the severity of the decline in cerebral blood flow (CBF). The ischemic penumbra was initially defined as a region of reduced CBF with absent spontaneous or induced electrical potentials that still maintained ionic homeostasis and transmembrane electrical potentials. The reduction of CBF levels to between 10 and 15 mL/100 g/min and approximately 25 mL/100 g/min are likely to identify penumbral tissue, and the ischemic core of irreversible ischemic tissue has a CBF value below the lower threshold. The role of identifying this critically deprived brain tissue from CBF in triaging patients for endovascular ischemic therapy is evolving. In this review we focus on the basic science of the penumbral concept and identification using various imaging modalities (PET, MRI, and CT) in animal models and human studies. Another article in this supplement addresses the clinical implication and the current understanding and application of this concept into clinical practice of endovascular ischemic stroke therapy. Neurology

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In a rat embolic stroke (eMCAO) model, the effects of 100% normobaric hyperoxia (NBO) with delayed recombinant tissue plasminogen activator (tPA) administration on ischemic lesion size and safety were assessed by diffusion- and perfusion (PWI)-weighted magnetic resonance imaging. NBO or room air (Air) by a face mask was started at 30 mins posteMCAO and continued for 3.5 h. Tissue plasminogen activator or saline was started at 3 h posteMCAO. Types and location of hemorrhagic transformation were assessed at 24 h and a spectrophotometric hemoglobin assay quantified hemorrhage volume at 10 h. In NBO-treated animals the apparent diffusion coefficient/PWI mismatch persisted during NBO treatment. Relative to Air groups, NBO treatment significantly reduced 24 h infarct volumes by approximately 30% and approximately 15% with or without delayed tPA, respectively (P<0.05). There were significantly more hemorrhagic infarction type 2 hemorrhages in Air/tPA versus Air/saline animals (P<0.05). Compared with Air/tPA, the combination of NBO with tPA did not increase hemorrhage volume at 10 h (4.0+/-2.4 versus 6.6+/-2.6 microL, P=0.065) or occurrence of confluent petechial hemorrhages at 24 h (P>0.05), respectively. Our results suggest that early NBO treatment in combination with tPA at a later time point may represent a safe and effective strategy for acute stroke treatment.

PaCO 2 (mm Hg) PaO 2 (mm Hg) MABP (mm Hg) Air/saline (n = 6) Baseline 36.7 ± 3.3 76 ± 10 95 ± 9 90 mins 36.0 ± 3.5 67 ± 10 95 ± 12 180 mins 34.4 ± 5.4 69 ± 8 9 7 ± 10 270 mins 34.6 ± 5.5 75 ± 7 9 9 ± 7 NBO/saline (n = 6) Baseline 37.1 ± 1.9 70 ± 7 9 8 ± 13 90 mins 47. Air, room air; NBO, normobaric hyperoxia; MABP, mean arterial blood pressure; tPA, tissue plasminogen activator. There was no difference in physiological parameters between corresponding groups of the three experiments, and thus, data were pooled for presentation purposes. *P <0.05 versus air/saline. w P <0.05 versus air groups and baseline.