Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca2+-MAPK/ERK pathways

J Neurochem. 2003 Oct;87(2):508-21. doi: 10.1046/j.1471-4159.2003.02014.x.

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 [Sar9,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 4 beta-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.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Animals
  • Apoptosis / drug effects*
  • Calcium / metabolism
  • Calcium Signaling / drug effects
  • Cells, Cultured
  • Chelating Agents / pharmacology
  • Cytosol / metabolism
  • MAP Kinase Signaling System / drug effects*
  • MAP Kinase Signaling System / physiology
  • Mitogen-Activated Protein Kinases / metabolism
  • Nerve Growth Factors / pharmacology
  • Neurons / cytology
  • Neurons / drug effects*
  • Neurons / metabolism
  • Neuroprotective Agents / pharmacology
  • Nifedipine / pharmacology
  • Protein Kinase C / metabolism
  • Rats
  • Rats, Wistar
  • Signal Transduction / drug effects
  • Signal Transduction / physiology
  • Spiral Ganglion* / cytology
  • Spiral Ganglion* / metabolism
  • Substance P / biosynthesis
  • Substance P / genetics
  • Substance P / pharmacology*

Substances

  • Chelating Agents
  • Nerve Growth Factors
  • Neuroprotective Agents
  • Substance P
  • Protein Kinase C
  • Mitogen-Activated Protein Kinases
  • Nifedipine
  • Calcium