Neuroprotection by NGF in the PC12 In Vitro OGD Model

Involvement of Mitogen-Activated Protein Kinases and Gene Expression

Authors

  • RINAT TABAKMAN,

    1. Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
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  • HAO JIANG,

    1. William T. Gossett Neurology Laboratories, Henry Ford Health System, Detroit, Michigan 48202, USA
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  • IRIS SHAHAR,

    1. Functional Genomics Unit, Sheba Medical Center, Tel Hashomer 52621, Israel
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  • HADAR ARIEN-ZAKAY,

    1. Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
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  • ROBERT A. LEVINE,

    1. William T. Gossett Neurology Laboratories, Henry Ford Health System, Detroit, Michigan 48202, USA
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  • PHILIP LAZAROVICI

    Corresponding author
    1. Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel
      Address for correspondence: Prof. Philip Lazarovici, Ph.D., Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. Voice: +972-2-6758729, +972-2-6758767; fax: +972-2-6757490. lazph@md.huji.ac.il; pl57@drexel.edu
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Address for correspondence: Prof. Philip Lazarovici, Ph.D., Department of Pharmacology and Experimental Therapeutics, School of Pharmacy, Faculty of Medicine, The Hebrew University of Jerusalem, Jerusalem 91120, Israel. Voice: +972-2-6758729, +972-2-6758767; fax: +972-2-6757490. lazph@md.huji.ac.il; pl57@drexel.edu

Abstract

Abstract: Neurodegenerative disorders and chronic disability due to stroke in the brain or spinal cord afflict a large sector of the population. To investigate the mechanism involved in ischemic stroke and to develop neuroprotective drugs/therapies, in vivo and in vitro, pharmacological models are needed. To investigate the cellular and molecular neuroprotective mechanisms of nerve growth factor (NGF), a member of the nervous system neurotrophin family of growth factors, under ischemia, we used an oxygen-glucose-deprivation (OGD) device and pheochromocytoma PC12 cells exposed to a paradigm of ischemic insult. Pretreatment of the cultures with 50 ng/mL of NGF, 18 h prior to OGD insult, conferred 30% of neuroprotection. Time-course experiments showed marked activation of the ERK, JNK, and p-38 MAPK isoforms during the OGD phase, but not during OGD reperfusion. Pretreatment of the cultures with 50 ng/mL of NGF, 18 h prior to OGD insult, resulted in 50% attenuation of OGD-induced activation of JNK 1, and 20% and 50% attenuation of OGD-induced activation of p-38 α and β, respectively. The effect of NGF on gene expression in the PC12 ischemic model using Affymatrix Rat DNA-Microarray technology indicates that only 6% of the genes are differentially regulated (induced/suppressed) by OGD insult and/or NGF. These findings support the notion that pretreatment with NGF confers neuroprotection from OGD insult, a phenomenon coincidentally related to differential inhibition of MAPK stress kinase isoforms and differential gene expression. This ischemic model may be useful to investigate molecular mechanisms of OGD-induced neurotoxicity and NGF-induced neuroprotection, and to generate novel therapeutic concepts for stroke treatment.

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