Neuroprotection by NGF in the PC12 in vitro OGD model: Involvement of mitogen-activated protein kinases and gene expression

Rinat Tabakman, Hao Jiang, Iris Shahar, Hadar Arien-Zakay, Robert A. Levine, Philip Lazarovici*

*Corresponding author for this work

Research output: Contribution to journalArticlepeer-review

77 Scopus citations

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 ncuroprotective 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 neurotoxkity and NGF-induced neuroprotection, and to generate novel therapeutic concepts for stroke treatment.

Original languageAmerican English
Pages (from-to)84-96
Number of pages13
JournalAnnals of the New York Academy of Sciences
Volume1053
DOIs
StatePublished - 2005

Keywords

  • Gene expression
  • Ischemia
  • MAPK
  • NGF
  • Neuroprotection
  • PC12

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