title: The Kringle-2 domain of tissue plasminogen activator significantly reduces mortality and brain infarction in middle cerebral artery occlusion rats.
abstract: Tissue plasminogen activator (TPA) showed brain-protective activity within the first 15 min after cerebral ischemia in rats. To understand its molecular mechanism, TPA derivates were intracerebroventricularly administered at 15 min before, and 15, 90, 120 min after middle cerebral artery occlusion (MCAO) in rats. The reduction in mortality and cerebral infarction at 24 h was seen only with TPA administered at 15 min after MCAO. The down-regulation of endogenous TPA by the intracerebroventricular injection of TPA was found to be responsible for the protective effect on the integrity of blood-brain barrier after MCAO, as well as for the reduction in mortality and cerebral infarction. Moreover, for the first time we have found that the Kringle-2 domain is essential for the brain-protective activity of TPA.
authors.affiliation: Institute of Molecular Medicine and State Key Laboratory of Pharmaceutical Biotechnology, Nanjing University, Nanjing 210093, P.R. China.
authors.forename: Haitao
authors.initials: H
authors.lastname: Zhang
authors.forename: Feng
authors.initials: F
authors.lastname: Bi
authors.forename: Chunlan
authors.initials: C
authors.lastname: Xiao
authors.forename: Jianxia
authors.initials: J
authors.lastname: Liu
authors.forename: Zhixia
authors.initials: Z
authors.lastname: Wang
authors.forename: Jian-Ning
authors.initials: JN
authors.lastname: Liu
authors.forename: Jing
authors.initials: J
authors.lastname: Zhang
mesh_terms: D000704:Analysis of Variance; D000818:Animals; D001812:Blood-Brain Barrier / Q000187:drug effects; D020520:Brain Infarction / Q000517:prevention & control*; D054022:Cerebrum / Q000187:drug effects / Q000378:metabolism; D016009:Chi-Square Distribution; D004195:Disease Models, Animal; D015870:Gene Expression / Q000187:drug effects; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000378:metabolism; D018082:Kringles; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000235:genetics / Q000378:metabolism; D016328:NF-kappa B / Q000235:genetics / Q000378:metabolism; D020011:Protective Agents / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D017434:Protein Structure, Tertiary; D051381:Rats; D017207:Rats, Sprague-Dawley; D011994:Recombinant Proteins / Q000008:administration & dosage / Q000494:pharmacology / Q000627:therapeutic use; D010959:Tissue Plasminogen Activator / Q000008:administration & dosage / Q000187:drug effects / Q000378:metabolism / Q000494:pharmacology / Q000627:therapeutic use
chemical_list: D016328:NF-kappa B; D020011:Protective Agents; D011994:Recombinant Proteins; C087896:reteplase; D010959:Tissue Plasminogen Activator; D020780:Matrix Metalloproteinase 9