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Please use this identifier to cite or link to this item: http://hdl.handle.net/1942/9434

Title: Substance P protects spiral ganglion neurons from apoptosis via PKC-Ca2+-MAPK/ERK pathways
Authors: Lallemend, F
Lefebvre, PP
Hans, G
RIGO, Jean-Michel
Van De Water, TR
Moonen, G
Malgrange, B.
Issue Date: 2003
Publisher: BLACKWELL PUBLISHING LTD
Citation: JOURNAL OF NEUROCHEMISTRY, 87(2). p. 508-521
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(O-2)(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, Go6976 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 4beta-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.
Notes: Univ Liege, Res Ctr Cellular & Mol Neurobiol, Liege, Belgium. Univ Liege, Dept Otorhinolaryngol, Liege, Belgium. Univ Liege, Dept Neurol, Liege, Belgium. Univ Miami, Sch Med, Dept Otolaryngol, Miami, FL USA.
URI: http://hdl.handle.net/1942/9434
DOI: 10.1046/j.1471-4159.2003.02014.x
ISI #: 000185596100024
ISSN: 0022-3042
Category: A1
Type: Journal Contribution
Appears in Collections: Research publications

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