title: Neuroprotection by urokinase plasminogen activator in the hippocampus.
abstract: Tissue plasminogen activator (tPA) and urokinase plasminogen activator (uPA), which are both used for thrombolytic treatment of acute ischemic stroke, are serine proteases that convert plasminogen to active plasmin. Although recent experimental evidences have raised controversy about the neurotoxic versus neuroprotective roles of tPA in acute brain injury, uPA remains unexplored in this context. In this study, we evaluated the effect of uPA on neuronal death in the hippocampus of mice after kainate-induced seizures. In the normal brain, uPA was localized to both nuclei and cytosol of neurons. Following severe kainate-induced seizures, uPA completely disappeared in degenerating neurons, whereas uPA-expressing astrocytes substantially increased, suggesting reactive astrogliosis. uPA-knockout mice were more vulnerable to kainate-induced neuronal death than wild-type mice. Consistent with this, inhibition of uPA by intracerebral injection of the uPA inhibitor UK122 increased the level of neuronal death. In contrast, prior administration of recombinant uPA significantly attenuated neuronal death. Collectively, these results indicate that uPA renders neurons resistant to kainate-induced excitotoxicity. Moreover, recombinant uPA suppressed cell death in primary cultures of hippocampal neurons exposed to H2O2, zinc, or various excitotoxins, suggesting that uPA protects against neuronal injuries mediated by the glutamate receptor, or by oxidation- or zinc-induced death signaling pathways. Considering that tPA may facilitate neurodegeneration in acute brain injury, we suggest that uPA, as a neuroprotectant, might be beneficial for the treatment of acute brain injuries such as ischemic stroke.
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Eunsil
authors.initials: E
authors.lastname: Cho
authors.forename: Kyung Jin
authors.initials: KJ
authors.lastname: Lee
authors.forename: Jung-Woo
authors.initials: JW
authors.lastname: Seo
authors.forename: Catherine Jeonghae
authors.initials: CJ
authors.lastname: Byun
authors.forename: Sun-Ju
authors.initials: SJ
authors.lastname: Chung
authors.forename: Dae Chul
authors.initials: DC
authors.lastname: Suh
authors.forename: Peter
authors.initials: P
authors.lastname: Carmeliet
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
authors.forename: Jong S
authors.initials: JS
authors.lastname: Kim
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
mesh_terms: D000208:Acute Disease; D000818:Animals; D004827:Epilepsy / Q000139:chemically induced / Q000188:drug therapy* / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000633:toxicity; D006624:Hippocampus / Q000187:drug effects* / Q000473:pathology; D007608:Kainic Acid / Q000633:toxicity; D051379:Mice; D057507:Mice, 129 Strain; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D009474:Neurons / Q000187:drug effects* / Q000473:pathology; D018696:Neuroprotective Agents / Q000494:pharmacology*; D014568:Urokinase-Type Plasminogen Activator / Q000494:pharmacology*
chemical_list: D018690:Excitatory Amino Acid Agonists; D018696:Neuroprotective Agents; D014568:Urokinase-Type Plasminogen Activator; D007608:Kainic Acid