Inhibitory effect of PACAP on caspase activity in neuronal apoptosis: a better understanding towards therapeutic applications in neurodegenerative diseases.
Programmed cell death, which is part of the normal development of the central nervous system, is also implicated in various neurodegenerative disorders. Cysteine-dependent aspartate-specific proteases (caspases) play a pivotal role in the cascade of events leading to apoptosis. Many factors that inhibit cell death have now been identified, but the underlying mechanisms are not fully understood. Pituitary adenylate cyclase-activating polypeptide (PACAP) has been shown to exert neurotrophic activities during development and to prevent neuronal apoptosis induced by various insults such as ischemia. Most of the neuroprotective effects of PACAP are mediated through the PAC1 receptor. This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression, which inhibits cytochrome c release and blocks the activation of caspases. The inhibitory effect of PACAP on the apoptotic cascade suggests that selective, stable, and potent PACAP derivatives could potentially be of therapeutic value for the treatment of post-traumatic and/or chronic neurodegenerative processes.
Dejda
Agnieszka
A
INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, Mont-Saint-Aignan, France.
Jolivel
Valérie
V
Bourgault
Steve
S
Seaborn
Tommy
T
Fournier
Alain
A
Vaudry
Hubert
H
Vaudry
David
D
D000818:Animals; D017209:Apoptosis / Q000502:physiology*; D061945:Caspase Inhibitors; D020169:Caspases / Q000378:metabolism; D004789:Enzyme Activation; D006801:Humans; D008928:Mitochondria / Q000378:metabolism; D019636:Neurodegenerative Diseases / Q000378:metabolism* / Q000473:pathology / Q000628:therapy*; D009474:Neurons / Q000166:cytology / Q000502:physiology*; D018696:Neuroprotective Agents / Q000378:metabolism / Q000627:therapeutic use; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide / Q000378:metabolism / Q000627:therapeutic use; D053218:Receptors, Death Domain / Q000378:metabolism; D015398:Signal Transduction / Q000502:physiology
D061945:Caspase Inhibitors; D018696:Neuroprotective Agents; D051219:Pituitary Adenylate Cyclase-Activating Polypeptide; D053218:Receptors, Death Domain; D020169:Caspases