Inhibitory Effect of PACAP on Caspase Activity in Neuronal Apoptosis: A Better Understanding Towards Therapeutic Applications in Neurodegenerative Diseases

Abstract

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.

Protective Effect of PACAP Against Doxorubicin-Induced Cell Death in Cardiomyocyte Culture

“…The importance of the inhibition of the final executor caspase-3 has been emphasized in several studies (Dejda et al 2008). PACAP inhibits caspase activation in cerebellar granule cells (Vaudry et al 2000), in olfactory neurons (Han and Lucero 2005), in PC12 cells (Wang et al 2005), in cortical neurons (Sanchez et al 2009), in the inner ear (Racz et al 2010), and in the salivary gland of an invertebrate species (Pirger et al 2008).…”

Pituitary Adenylate Cyclase-Activating Polypeptide and Its Receptors: 20 Years after the Discovery

“…PACAP also exerts a neuroprotective effect against retinal degeneration induced by carotid occlusion, kainic acid, and monosodium glutamate (Babai et al, 2005(Babai et al, , 2006Seki et al, 2006b;Atlasz et al, 2007Atlasz et al, , 2008. Considering the potential of PACAP for development into neuroprotective agent, stable analogs that can cross the blood-brain barrier are currently designed (Bourgault et al, 2008a;Dejda et al, 2008), and viral vectors for targeted delivery into the brain are being developed (Sanchez et al, 2008). It has been shown that the passage of PACAP38 across the blood brain barrier is transiently increased after ischemia (Somogyvá ri- , and antisense mRNA directed against the PACAP transporter PTS-6 have been successfully used to inhibit PACAP27 efflux (Nonaka et al, 2005;Dogrukol-Ak et al, 2009).…”

Effects of PACAP on Mitochondrial Apoptotic Pathways and Cytokine Expression in Rats Subjected to Renal Ischemia/Reperfusion

“…The most well-studied protective effects are the neurotrophic and neuroprotective effects of the peptide: PACAP stimulates neuronal survival during development and against various noxious stimuli in vitro and in vivo (Dejda et al 2008;Kovesdi et al 2008;Scharf et al 2008;Tominaga et al 2008). However, PACAP has been shown to exert similar actions in non-neuronal cells, such as endothelial cells, cardiomyocytes, and lymphocytes, where PACAP is an antiapoptotic agent (Gasz et al 2006;Racz et al 2007;Delgado and Ganea 2000).…”