title: Pyruvate and cilostazol protect cultured rat cortical pericytes against tissue plasminogen activator (tPA)-induced cell death.
abstract: Since even a brief ischemia can cause permanent brain damage, rapid restoration of blood flow is critical to limiting damage. Although intravenous tPA during the acute stage is the treatment of choice for achieving reperfusion, this treatment is sometimes associated with brain hemorrhage. Agents that reduce tPA-related bleeding risk may help expand its therapeutic window. This study assessed whether zinc dyshomeostasis underlies the toxic effect of tPA on brain vascular pericytes; whether pyruvate, an inhibitor of zinc toxicity, protects pericytes against tPA-induced cell death; and whether cilostazol, which protects pericytes against tPA-induced cell death, affects zinc dyshomeostasis associated with tPA toxicity. Cultured pericytes from newborn rat brains were treated with 10-200 μg/ml tPA for 24 h, inducing cell death in a concentration-dependent manner. tPA-induced cell death was preceded by increases in intracellular free zinc levels, and was substantially attenuated by plasminogen activator inhibitor-1 (PAI-1) or TPEN. Pyruvate completely blocked direct zinc toxicity and tPA-induced pericyte cell death. Both cAMP and cilostazol, a PDE3 inhibitor that attenuates tPA-induced pericyte cell death in vitro and tPA-induced brain hemorrhage in vivo, reduced zinc- and tPA-induced pericyte cell death, suggesting that zinc dyshomeostasis may be targeted by cilostazol in tPA toxicity. These findings show that tPA-induced pericyte cell death may involve zinc dyshomeostasis, and that pyruvate and cilostazol attenuate tPA-induced cell death by reducing the toxic cascade triggered by zinc dyshomeostasis. Since pyruvate is an endogenous metabolite and cilostazol is an FDA-approved drug, in vivo testing of both as protectors against tPA-induced brain hemorrhage may be warranted. This article is part of a Special Issue entitled SI: Neuroprotection.
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Ha Na
authors.initials: HN
authors.lastname: Kim
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Tae-Youn
authors.initials: TY
authors.lastname: Kim
authors.affiliation: Department of Ophthalmology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Young Hee
authors.initials: YH
authors.lastname: Yoon
authors.affiliation: Neural Injury Research Lab, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea; Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: jkko@amc.seoul.kr.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
mesh_terms: D000818:Animals; D000941:Antigens / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002478:Cells, Cultured; D002540:Cerebral Cortex / Q000166:cytology*; D002800:Cholinesterase Inhibitors / Q000494:pharmacology; D000077407:Cilostazol; D000242:Cyclic AMP / Q000378:metabolism; D005029:Ethylenediamines / Q000494:pharmacology; D005343:Fibrinolytic Agents / Q000494:pharmacology*; D007770:L-Lactate Dehydrogenase / Q000378:metabolism; D009419:Nerve Tissue Proteins / Q000378:metabolism; D020286:Pericytes / Q000187:drug effects*; D011509:Proteoglycans / Q000378:metabolism; D019289:Pyruvic Acid / Q000494:pharmacology*; D051381:Rats; D017382:Reactive Oxygen Species / Q000378:metabolism; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000378:metabolism; D013777:Tetrazoles / Q000494:pharmacology*; D010959:Tissue Plasminogen Activator / Q000633:toxicity*; D015032:Zinc / Q000494:pharmacology; D000099216:Chondroitin Sulfate Proteoglycan 4
chemical_list: D000941:Antigens; D002800:Cholinesterase Inhibitors; D000077407:Cilostazol; D000242:Cyclic AMP; D005029:Ethylenediamines; D005343:Fibrinolytic Agents; D007770:L-Lactate Dehydrogenase; D009419:Nerve Tissue Proteins; D011509:Proteoglycans; D019289:Pyruvic Acid; D017382:Reactive Oxygen Species; D020796:Receptor, Platelet-Derived Growth Factor alpha; D013777:Tetrazoles; D010959:Tissue Plasminogen Activator; D015032:Zinc; D000099216:Chondroitin Sulfate Proteoglycan 4; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Cilostazol; Pericyte cell death; Pyruvate; Zinc; cAMP; tPA