Abstract |
The neuropeptide PACAP ( pituitary adenylate cyclase activating polypeptide) and its receptors are widely expressed in the nervous system including the retina. PACAP has well-known neuroprotective effects in neuronal cultures in vitro and against different insults in vivo. Recently, we have shown that PACAP1-38 is neuroprotective against monosodium glutamate ( MSG)-induced retinal degeneration. Studying the molecular mechanisms of this protection has revealed that PACAP1-38 stimulates anti-apoptotic mechanisms such as phosphorylation of ERK1/2 and inhibits pro-apoptotic signaling molecules such as JNK1/2, p38MAPK, caspase-3 and the translocation of mitochondrial cytochrome c and apoptosis inducing factor in glutamate-treated retinas in vivo. In the present study we investigated the effects of PACAP1-38 on a further signal transduction pathway possibly involved in the protective effect of intravitreal PACAP1-38 administration against apoptotic retinal degeneration induced by neonatal MSG treatment. The focus of the present study was the protein kinase A (PKA)-Bad-14-3-3 transduction pathway. In vivo MSG treatment led to a reduction in the levels of anti-apoptotic molecules (phospho-PKA phospho-Bad, Bcl-xL and 14-3-3 proteins) in the retina. Co-treatment with PACAP1-38 counteracted these effects: the level of phospho-PKA, phospho-Bad, Bcl-xL and 14-3-3 were increased. All effects of PACAP1-38 were inhibited by the PACAP antagonist PACAP6-38. In summary, our results show that PACAP1-38 activates the PKA-Bad-14-3-3 pathway which is inhibited by MSG treatment. Our results also provide new insights into the signaling mechanisms possibly involved in the PACAP-mediated anti-apoptotic effects.
|
Authors | Boglárka Rácz, Ferenc Gallyas Jr, Péter Kiss, Andrea Tamás, Andrea Lubics, István Lengvári, Erzsébet Röth, Gábor Tóth, Orsolya Hegyi, Zsófia Verzál, Csaba Fabricsek, Dóra Reglódi |
Journal | Neurotoxicity research
(Neurotox Res)
Vol. 12
Issue 2
Pg. 95-104
(Sep 2007)
ISSN: 1029-8428 [Print] United States |
PMID | 17967733
(Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
|
Chemical References |
- 14-3-3 Proteins
- Enzyme Inhibitors
- Pituitary Adenylate Cyclase-Activating Polypeptide
- bcl-Associated Death Protein
- Glutamic Acid
- Cyclic AMP-Dependent Protein Kinases
|
Topics |
- 14-3-3 Proteins
(metabolism)
- Animals
- Animals, Newborn
- Cyclic AMP-Dependent Protein Kinases
(metabolism)
- Drug Interactions
- Enzyme Inhibitors
(pharmacology)
- Glutamic Acid
- Models, Biological
- Pituitary Adenylate Cyclase-Activating Polypeptide
(metabolism, pharmacology)
- Rats
- Rats, Wistar
- Retinal Diseases
(chemically induced, metabolism)
- Signal Transduction
(drug effects, physiology)
- bcl-Associated Death Protein
(metabolism)
|