Indomethacin preconditioning induces ischemic tolerance by modifying zinc availability in the brain

• Published in: Neurobiology of disease Vol. 81; pp. 186 - 195
• Main Authors: Lee, Joo-Yong, Oh, Shin Bi, Hwang, Jung-Jin, Suh, Nayoung, Jo, Dong-Gyu, Kim, Jong S, Koh, Jae-Young
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 01.09.2015; Elsevier
• Subjects: Animals; Anti-Inflammatory Agents, Non-Steroidal - administration & dosage; Brain - drug effects; Brain - metabolism; Brain - pathology; Carrier Proteins - metabolism; Cell Death - drug effects; Chelating Agents - pharmacology; Chemical preconditioning; Disease Models, Animal; Drug Administration Schedule; Ethylenediamines - pharmacology; HSP70 Heat-Shock Proteins - metabolism; Hypoxia-Inducible Factor 1, alpha Subunit - metabolism; Indomethacin - administration & dosage; Infarction, Middle Cerebral Artery - drug therapy; Infarction, Middle Cerebral Artery - metabolism; Infarction, Middle Cerebral Artery - pathology; Male; Metallothionein - metabolism; Neurology; Neurons - drug effects; Neurons - metabolism; Neurons - pathology; Neuroprotection; Non-steroidal anti-inflammatory drug; Rats; Rats, Sprague-Dawley; Stroke; Time Factors; Zinc - metabolism; Zinc homeostasis; Zinc transporter; hypoxia-inducing factor-1α; 2,3,5-triphenyl tetrazolium chloride; ZnT; Neuroprotection; TPEN; TTC; NSAID; MTF-1; CNS; SLC; zinc transporter; N,N′,N′-tetra(2-picolyl)ethylenediamine; solute carrier; non-steroidal anti-inflammatory drug; Hsp70; N-(6-methoxy-8-quinolyl)-p-carboxybenzoylsulphonamide; heat shock protein 70; internal carotid artery; Hif-1α; Zinc homeostasis; MCAO; metal-responsive transcription factor-1; ECA; Stroke; metallothionein-1/2; ICA; cyclooxygenase; COX; TFLZn; central nervous system; MT-1/2; Chemical preconditioning; external carotid artery; middle cerebral artery occlusion; Non-steroidal anti-inflammatory drug; Zinc transporter
• ISSN: 0969-9961; 1095-953X
• DOI: 10.1016/j.nbd.2014.12.019

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 (3 mg/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.