title: Zinc preconditioning protects against neuronal apoptosis through the mitogen-activated protein kinase-mediated induction of heat shock protein 70.
abstract: During brain ischemic preconditioning (PC), mild bursts of ischemia render neurons resistant to subsequent strong ischemic injuries. Previously, we reported that zinc plays a key role in PC-induced neuroprotection in vitro and in vivo. Zinc-triggered p75(NTR) induction transiently activates caspase-3, which cleaves poly(ADP-ribose) polymerase-1 (PARP-1). Subsequently, the PARP-1 over-activation-induced depletion of nicotinamide adenine dinucleotide (NAD(+))/adenosine triphosphate (ATP) after exposures to lethal doses of zinc or N-methyl-D-aspartate is significantly attenuated in cortical neuronal cultures. In the present study, zinc-mediated preconditioning (Zn PC) reduced apoptotic neuronal death that was caused by N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine (TPEN), etoposide, or staurosporine in mouse cortical cells. We focused on heat shock protein 70 (HSP70) because NAD(+)/ATP depletion does not directly cause apoptosis, and HSP70 can inhibit the activation of caspase-9 or caspase-3 by preventing apoptosome formation or cytochrome C release. Zn PC-mediated HSP70 induction was required for neuroprotection against neuronal apoptosis, and geldanamycin-induced HSP70 induction sufficiently blocked neuronal apoptotic cell death. Furthermore, Zn PC-mediated HSP70 induction was blocked by chemical inhibitors of extracellular signal-regulated kinase (ERK) or p38 mitogen-activated protein kinase (MAPK) signaling, but not c-Jun N-terminal protein kinase. Similarly, neuroprotection by Zn PC against TPEN-induced apoptosis was almost completely reversed by the blockade of ERK or p38 MAPK signaling. Our findings suggest that the ERK- or p38 MAPK-mediated induction of HSP70 plays a key role in inhibiting caspase-3 activation during Zn PC.
authors.affiliation: Department of Molecular Biology, Sejong University, Seoul 143-747, South Korea.
authors.forename: Jeong-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, Sejong University, Seoul 143-747, South Korea.
authors.forename: Jong-Min
authors.initials: JM
authors.lastname: Lee
authors.affiliation: Department of Molecular Biology, Sejong University, Seoul 143-747, South Korea.
authors.forename: Ki-Ryeong
authors.initials: KR
authors.lastname: Kim
authors.affiliation: Department of Molecular Biology, Sejong University, Seoul 143-747, South Korea.
authors.forename: Hana
authors.initials: H
authors.lastname: Im
authors.affiliation: Department of Molecular Biology, Sejong University, Seoul 143-747, South Korea. Electronic address: yhkim@sejong.ac.kr.
authors.forename: Yang-Hee
authors.initials: YH
authors.lastname: Kim
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects*; D002478:Cells, Cultured; D005029:Ethylenediamines / Q000633:toxicity; D018840:HSP70 Heat-Shock Proteins / Q000096:biosynthesis*; D019194:Ischemic Preconditioning / Q000379:methods*; D020935:MAP Kinase Signaling System / Q000187:drug effects*; D051379:Mice; D009474:Neurons / Q000187:drug effects* / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000008:administration & dosage; D015032:Zinc / Q000008:administration & dosage* / Q000378:metabolism* / Q000633:toxicity; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D005029:Ethylenediamines; D018840:HSP70 Heat-Shock Proteins; D018696:Neuroprotective Agents; D048051:p38 Mitogen-Activated Protein Kinases; D015032:Zinc; C044387:N,N,N',N'-tetrakis(2-pyridylmethyl)ethylenediamine
keywords: Apoptosis; ERK; HSP70; Ischemic preconditioning; Zinc; p38 MAPK