Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways

François Lallemend, P. P. Lefebvre, G. Hans, J. M. Rigo, T. R. Van De Water, G. Moonen, B. Malgrange

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

In the current study, we have investigated the ability of substance P (SP) to protect 3-day-old (P3) rat spiral ganglion neurons (SGNs) from trophic factor deprivation (TFD)-induced cell death. The presence of SP high affinity neurokinin-1 receptor (NK1) transcripts was detected in the spiral ganglion and the NK1 protein localized to SGNs both ex vivo and in vitro. Treatment with SP increased cytoplasmic Ca2+ in SGNs, further arguing for the presence of functional NK1 on these neurons. Both SP and the agonist [Sar 9,Met(O2)11]-SP significantly decreased SGN cell death induced by TFD, with no effect on neurite outgrowth. The survival promoting effect of SP was blocked by the NK1 antagonist, WIN51708. Both pan-caspase inhibitor BOC-D-FMK and SP treatments markedly reduced activation of caspases and DNA fragmentation in trophic factor deprived-neurons. The neuroprotective action of SP was antagonised by specific inhibitors of second messengers, including 1.2.bis-(O-aminophenoxy)-ethane-N,N,N′,N′ -tetraacetic acid (BAPTA-AM) to chelate cytosolic Ca2+, the protein kinase C (PKC) inhibitors bisindolylmaleimide I, Gö6976 and LY333531 and the MAPK/ERK inhibitor U0126. In contrast, nifedipine, a specific inhibitor of L-type Ca2+ channel, and LY294002, a phosphatidylinositol-3-OH kinase (PI3K) inhibitor, had no effect on SP trophic support of SGNs. Moreover, activation of endogenous PKC by 4β-phorbol 12-myristate 13-acetate (PMA) also reduced the loss of trophic factor-deprived SGNs. Thus, NK1 expressed by SGNs transmit a survival-promoting regulatory signal during TFD-induced SGN cell death via pathways involving PKC activation, Ca2+ signalling and MAPK/ERK activation, which can be accounted for by an inhibition of caspase activation.

Original languageEnglish (US)
Pages (from-to)508-521
Number of pages14
JournalJournal of neurochemistry
Volume87
Issue number2
DOIs
StatePublished - Oct 1 2003

Keywords

  • Apoptosis
  • Neuroprotection
  • NK1
  • Spiral ganglion neurons
  • Substance P

ASJC Scopus subject areas

  • Biochemistry
  • Cellular and Molecular Neuroscience

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    Lallemend, F., Lefebvre, P. P., Hans, G., Rigo, J. M., Van De Water, T. R., Moonen, G., & Malgrange, B. (2003). Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca 2+-MAPK/ERK pathways. Journal of neurochemistry, 87(2), 508-521. https://doi.org/10.1046/j.1471-4159.2003.02014.x