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Cellular mechanisms associated with spontaneous and ciliary neurotrophic factor-cAMP-induced survival and axonal regeneration of adult retinal ganglion cells.
- Source :
-
The Journal of neuroscience : the official journal of the Society for Neuroscience [J Neurosci] 2004 Dec 01; Vol. 24 (48), pp. 10806-15. - Publication Year :
- 2004
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Abstract
- We have shown previously that intraocular elevation of cAMP using the cAMP analog 8-(4-chlorophenylthio)-cAMP (CPT-cAMP) failed to promote axonal regeneration of axotomized adult retinal ganglion cells (RGCs) into peripheral nerve (PN) grafts but significantly potentiated ciliary neurotrophic factor (CNTF)-induced axonal regeneration. Using the PN graft model, we now examine the mechanisms underlying spontaneous and CNTF/CPT-cAMP-induced neuronal survival and axonal regrowth. We found that blockade of the cAMP pathway executor protein kinase A (PKA) using the cell-permeable inhibitor KT5720 did not affect spontaneous survival and axonal regeneration but essentially abolished the CNTF/CPT-cAMP-induced RGC survival and axonal regeneration. Blockade of CNTF signaling pathways such as phosphotidylinositol 3-kinase (PI3K)/akt by 2-(4-morpholinyl)-8-phenyl-4H-1-benzopyran-4-one (LY294002), mitogen-activated protein kinase (MAPK)/extracellular signal-regulated kinase (ERK) by 2-(2-diamino-3-methoxyphenyl-4H-1-benzopyran-4-one (PD98059), or Janus kinase (JAK)/signal transducer and activators of transcription (STAT3) by tyrphostin AG490 also blocked the CNTF/CPT-cAMP-dependent survival and regeneration effects. PKA activity assay and Western blots showed that KT5720, LY294002, and PD98059 almost completely inhibited PKA, PI3K/akt, and MAPK/ERK signal transduction, respectively, whereas AG490 substantially decreased JAK/STAT3 signal transduction. Intraocular injection of CPT-cAMP resulted in a small PKA-dependent increase in CNTF receptor alpha mRNA expression in the retinas, an effect that may facilitate CNTF action on survival and axonal regeneration. Surprisingly, in the absence of CNTF/CPT-cAMP, LY294002, PD98059, and AG490, but not KT5720, significantly enhanced spontaneous RGC survival, suggesting differential roles of these pathways in RGC survival under different conditions. Our data suggest that CNTF/CPT-cAMP-induced RGC survival and axonal regeneration are a result of multiple pathway actions, with PKA as an essential component, but that these pathways can function in an antagonistic manner under different conditions.
- Subjects :
- Animals
Axons drug effects
Axons physiology
Carbazoles pharmacology
Cell Survival drug effects
Chromones pharmacology
Ciliary Neurotrophic Factor antagonists & inhibitors
Ciliary Neurotrophic Factor pharmacology
Cyclic AMP pharmacology
Cyclic AMP-Dependent Protein Kinases antagonists & inhibitors
DNA-Binding Proteins antagonists & inhibitors
Flavonoids pharmacology
Indoles pharmacology
MAP Kinase Signaling System drug effects
Morpholines pharmacology
Optic Nerve Injuries enzymology
Optic Nerve Injuries physiopathology
Peroneal Nerve transplantation
Phosphoinositide-3 Kinase Inhibitors
Protein Serine-Threonine Kinases antagonists & inhibitors
Protein-Tyrosine Kinases antagonists & inhibitors
Proto-Oncogene Proteins antagonists & inhibitors
Proto-Oncogene Proteins c-akt
Pyrroles pharmacology
Rats
Rats, Inbred F344
Receptor, Ciliary Neurotrophic Factor biosynthesis
Receptor, Ciliary Neurotrophic Factor drug effects
Receptor, Ciliary Neurotrophic Factor genetics
Retinal Ganglion Cells drug effects
STAT3 Transcription Factor
Signal Transduction drug effects
Thionucleotides pharmacology
Trans-Activators antagonists & inhibitors
Tyrphostins pharmacology
Up-Regulation
Ciliary Neurotrophic Factor physiology
Cyclic AMP analogs & derivatives
Cyclic AMP-Dependent Protein Kinases physiology
Nerve Regeneration drug effects
Retinal Ganglion Cells physiology
Signal Transduction physiology
Subjects
Details
- Language :
- English
- ISSN :
- 1529-2401
- Volume :
- 24
- Issue :
- 48
- Database :
- MEDLINE
- Journal :
- The Journal of neuroscience : the official journal of the Society for Neuroscience
- Publication Type :
- Academic Journal
- Accession number :
- 15574731
- Full Text :
- https://doi.org/10.1523/JNEUROSCI.3532-04.2004