Ischemic brain injuries: the need for new neuroprotective strategies Ischemic injury occurs when the blood supply to the tissue is cut off. The length of time a tissue can survive under ischemic insults varies, but eventu- ally all ischemic tissues become apoptotic and/or necrotic (Lipton, 1999). The major pathophysiologi- cal effects are caused by the reduction in the oxygen and glucose levels, followed by the renewal of blood supply, responsible for the oxidative damage to the tissue (Mehta et al., 2007). Brain tissue has a com- plex differential sensitivity towards ischemic insult. Astrocytes can survive from energy deprivation for a prolonged period and are most sensitive to the burst of reactive oxygen species, on the other hand neurons are highly sensitive to oxygen and glucose deprivation (Hertz, 2008). Therefore, global brain ischemia triggers a complex series of biochemical and molecular mechanisms that impairs the neu- Neuroprotection by human umbilical cord blood- derived progenitors in ischemic brain injuries H. ARIEN-ZAKAY 1,2 , S. LECHT 1 , A. NAGLER 2 , P. LAZAROVICI 1 1 The School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel; 2 Division of Hematology and Cord Blood Bank, Chaim Sheba Medical Center, Tel-Hashomer, Israel ABSTRACT Stem cells have an extremely high potential to treat many devastating diseases, including neuronal injuries. Albeit the need for human neuronal stem cells, their quantities are very limited by relying on early human embryos as the main source. Therefore, progenitors of other origins, such as human umbilical cord blood (CB) are being considered. In the last decade, various populations isolated from the CB were reported to differentiate in vitro towards a neural phenotype. The conditions to induce the cell differentiation are not conclusive and may include addition of chemicals, cytokines and growth factors, including the nerve growth factor (NGF). Some CB cells were found to express the TrkA-NGF receptor, suggesting an endogenous role for this growth factor also in the CB environment. The ability of CB and derived stem cell populations to protect against neurological deficits was shown, both in vitro and in vivo, in models of ischemic brain injuries. In rodent models of stroke, heatstroke, brain trauma and brain damage at birth, CB cells either by intravenous injection or intrastriatal transplantation, were found to reduce the infarct size and the neurological deficits caused by the injury. The restorative effects of CB were suggested to be mediated by mechanisms other than cell replacement. Some of the proposed mechanisms involve reduced inflammation, nerve fiber reorgani- zation by trophic actions, increased cell survival and enhanced angiogenesis. Furthermore, treatment with CB was found to have a therapeutic window of days compared with the present 3-6 hour window for the treatment of stroke with clinically available tools such as recombinant tissue plasminogen activator. Considering the encouraging results with whole CB and derived cells transplantation in ischemic injury models and since CB is widely available and have been used clinically, they may be an excellent source of cells for treatment of human brain ischemic disorders. Key words Human umbilical cord blood • Stemcells • Neuronal • NGF • Neuroprotection • Ischemia • Brain trauma • Stroke Corresponding Author: Philip Lazarovici, The School of Pharmacy Institute for Drug Research, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem, Israel - Tel.: 972 2 6758 729 - Fax: 972 2-6757 490 - Email: philipl@ekmd.huji.ac.il Archives Italiennes de Biologie, 149: 233-245, 2011.