VIP-related protection against iodoacetate toxicity in pheochromocytoma (PC12) cells: A model for ischemic/hypoxic injury

E. Sigalov, M. Fridkin, D. E. Brenneman, I. Gozes

Research output: Contribution to journalArticlepeer-review

Abstract

To evaluate the protective properties of peptides related functionally and/or structurally to vasoactive intestinal peptide (VIP), PC12 cultures were treated with iodoacetate as a model for neuronal ischemic/hypoxic injury. Brain tissue can be pre-conditioned against lethal ischemia by several mechanisms including sub-lethal ischemia, moderate hypoglycemia, heat shock, and growth factors. In the present study, a superactive VIP lipophilic analog (Stearyl-Norleucine17-VIP; SNV) was used to pre-condition media of PC12 cells. After removal of the conditioned media, the cultures were exposed to iodoaceate, which inhibits glycolysis. Protective efficacy against iodoacetate-induced injury was assessed by the measurements of lactate dehydrogenase (LDH) activity in the media. Treatment with iodoacetate for 2.5 h produced a twofold increase in LDH activity in the media. The protective effect of SNV had an EC50 of 1 pM. Comparison of the preconditioning rime required for full protection by SNV showed no apparent difference between a 15 min and a 2 h incubation period prior to the addition of iodoacetate. Iodoacetate treatment produced a 20% decrease in the RNA transcripts encoding activity-dependent neuroprotective protein (ADNP), a novel glia-derived protein that is regulated by VIP. The iodoacetate-associated reduction in ADNP mRNA was prevented by pre-treatment with SNV. These effects imply that SNV provides a regulatory mechanism for ADNP synthesis during glycolytic stress. Furthermore, a short exposure to SNV provided potent protection from iodoacetate-induced toxicity suggesting that SNV may have therapeutic value in the treatment of ischemic/hypoxic injury.

Original languageEnglish
Pages (from-to)147-154
Number of pages8
JournalJournal of Molecular Neuroscience
Volume15
Issue number3
DOIs
StatePublished - 2000

Funding

FundersFunder number
Institute for the Study of Aging
US-Israel Binational Science Foundation
Bloom's Syndrome Foundation
Israel Science Foundation

    Keywords

    • Activity-dependent neuroprotective protein (ADNP)
    • Iodoacetate
    • Ischemic/hypoxic injury
    • Ischemic/hypoxic tolerance
    • PC12 pheochromocytoma cells
    • Pre-conditioning
    • Stearyl-Norleucine-VIP (SNV)
    • Vasoactive intestinal peptide (VIP)

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