title: Indomethacin preconditioning induces ischemic tolerance by modifying zinc availability in the brain.
abstract: Intracellular zinc overload causes neuronal injury during the course of neurological disorders, whereas mild levels of zinc are beneficial to neurons. Previous reports indicated that non-steroidal anti-inflammatory drugs, including indomethacin and aspirin, can reduce the risk of ischemic stroke. This study found that chronic pretreatment of rats with indomethacin, a non-selective cyclooxygenase inhibitor, provided tolerance to ischemic injuries in an animal model of stroke by eliciting moderate zinc elevation in neurons. Consecutive intraperitoneal injection of indomethacin (3mg/kg/day for 28 days) led to modest increases in intraneuronal zinc as well as synaptic zinc content, with no significant stimulation of neuronal death. Furthermore, indomethacin induced the expressions of intracellular zinc homeostatic and neuroprotective proteins, rendering the brain resistant against ischemic damages and improving neurological outcomes. However, administration of a zinc-chelator, N,N,N',N'-tetra(2-picolyl)ethylenediamine (TPEN; 15 mg/kg/day), immediately after indomethacin administration eliminated the beneficial actions of the drug. Therefore, indomethacin preconditioning can modulate intracellular zinc availability, contributing to ischemic tolerance in the brain after stroke.
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea; Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea. Electronic address: jlee@amc.seoul.kr.
authors.forename: Joo-Yong
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Shin Bi
authors.initials: SB
authors.lastname: Oh
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Jung-Jin
authors.initials: JJ
authors.lastname: Hwang
authors.affiliation: Asan Institute for Life Sciences, Asan Medical Center, Seoul 138-736, Republic of Korea.
authors.forename: Nayoung
authors.initials: N
authors.lastname: Suh
authors.affiliation: The School of Pharmacy, Sungkyunkwan University, Suwon 440-746, Republic of Korea.
authors.forename: Dong-Gyu
authors.initials: DG
authors.lastname: Jo
authors.affiliation: Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jong S
authors.initials: JS
authors.lastname: Kim
authors.affiliation: Department of Neurology, University of Ulsan College of Medicine, Seoul 138-736, Republic of Korea.
authors.forename: Jae-Young
authors.initials: JY
authors.lastname: Koh
mesh_terms: D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000008:administration & dosage*; D001921:Brain / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D002352:Carrier Proteins / Q000378:metabolism; D016923:Cell Death / Q000187:drug effects; D002614:Chelating Agents / Q000494:pharmacology; D004195:Disease Models, Animal; D004334:Drug Administration Schedule; D005029:Ethylenediamines / Q000494:pharmacology; D018840:HSP70 Heat-Shock Proteins / Q000378:metabolism; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000378:metabolism; D007213:Indomethacin / Q000008:administration & dosage*; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy* / Q000378:metabolism / Q000473:pathology; D008297:Male; D008668:Metallothionein / Q000378:metabolism; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D051381:Rats; D017207:Rats, Sprague-Dawley; D013997:Time Factors; D015032:Zinc / Q000378:metabolism*
chemical_list: D000894:Anti-Inflammatory Agents, Non-Steroidal; D002352:Carrier Proteins; D002614:Chelating Agents; D005029:Ethylenediamines; D018840:HSP70 Heat-Shock Proteins; C497443:Hif1a protein, mouse; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C017800:zinc-binding protein; D008668:Metallothionein; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine; D007213:Indomethacin
keywords: Chemical preconditioning; Neuroprotection; Non-steroidal anti-inflammatory drug; Stroke; Zinc homeostasis; Zinc transporter