PACAP protects neuronal PC12 cells from the cytotoxicity of human prion protein fragment 106-126.
Misfolding of the prion protein yields amyloidogenic isoforms, and it shows exacerbating neuronal damage in neurodegenerative disorders including prion diseases. Pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) potently stimulate neuritogenesis and survival of neuronal cells in the central nervous system. Here, we tested these neuropeptides on neurotoxicity in PC12 cells induced by the prion protein fragment 106-126 [PrP (106-126)]. Concomitant application of neuropeptide with PrP(106-126) (5x10(-5) M) inhibited the delayed death of neuron-like PC12 cells. In particular, PACAP27 inhibited the neurotoxicity of PrP(106-126) at low concentrations (>10(-15) M), characterized by the deactivation of PrP(106-126)-stimulated caspase-3. The neuroprotective effect of PACAP27 was antagonized by the selective PKA inhibitor, H89, or the MAP kinase inhibitor, U0126. These results suggest that PACAP27 attenuates PrP(106-126)-induced delayed neurotoxicity in PC12 cells by activating both PKA and MAP kinases mediated by PAC1 receptor.
Onoue
Satomi
S
Health Science Division, Itoham Foods Inc., Moriya, Ibaraki 302-0104, Japan. onoue@fureai.or.jp
Ohshima
Keiichi
K
Endo
Kosuke
K
Yajima
Takehiko
T
Kashimoto
Kazuhisa
K
D000818:Animals; D053148:Caspase 3; D061945:Caspase Inhibitors; D002470:Cell Survival / Q000187:drug effects; D017868:Cyclic AMP-Dependent Protein Kinases / Q000037:antagonists & inhibitors; D006801:Humans; D020928:Mitogen-Activated Protein Kinases / Q000037:antagonists & inhibitors; D009479:Neuropeptides / Q000494:pharmacology*; D018696:Neuroprotective Agents / Q000494:pharmacology*; D009498:Neurotoxins / Q000494:pharmacology*; D016716:PC12 Cells; D010446:Peptide Fragments / Q000494:pharmacology*; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011328:Prions / Q000494:pharmacology*; D051381:Rats; D015398:Signal Transduction; D014660:Vasoactive Intestinal Peptide / Q000494:pharmacology
C495401:ADCYAP1 protein, human; C495403:Adcyap1 protein, rat; D061945:Caspase Inhibitors; D009479:Neuropeptides; D018696:Neuroprotective Agents; D009498:Neurotoxins; D010446:Peptide Fragments; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D011328:Prions; C082632:prion protein (106-126); D014660:Vasoactive Intestinal Peptide; D017868:Cyclic AMP-Dependent Protein Kinases; D020928:Mitogen-Activated Protein Kinases; C505407:CASP3 protein, human; C505410:Casp3 protein, rat; D053148:Caspase 3