Endogenous PACAP acts as a stress response peptide to protect cerebellar neurons from ethanol or oxidative insult

Abstract

The rodent cerebellum is richly supplied with PACAPergic innervation. Exogenous pituitary adenylate cyclase-activating polypeptide (PACAP) increases cerebellar granule cell survival and differentiation in culture, and enhances the number of neuroblasts in the molecular and internal granule cell layers (IGL) when injected postnatally into the cerebellum in vivo. Here, we have investigated the role of endogenous PACAP during cerebellar development by comparing the morphology of normal and PACAP-deficient mouse cerebellum, and the response of cerebellar granule cells from normal and PACAP-deficient mice subjected to neurotoxic insult in culture. There was no difference in cerebellar volume or granule cell number, in 11-day-old wild type versus PACAP-deficient mice. Cultured cerebellar neurons from PACAP-deficient and wild type mice also showed no apparent differences in survival and differentiation either under depolarizing conditions, or non-depolarizing conditions in the presence or absence of either dibutyryl cAMP or 100 nM PACAP. However, cultured cerebellar neurons from PACAP-deficient mice were significantly more sensitive than wild type neurons to ethanol-or hydrogen peroxide-induced toxicity. Differential ethanol toxicity was reversed by addition of 100 nM exogenous PACAP, suggesting that endogenous PACAP has neuroprotective activity in the context of cellular insult or stress. The neuroprotective action of PACAP was mimicked by dibutryl cAMP, indicating that it occurred via activation of adenylate cyclase. These results indicate that PACAP might act to protect the brain from paraphysiological insult, including exposure to toxins or hypoxia.

Regulation of Oxidative Stress by Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) Mediated by PACAP Receptor

“…It is well known that PACAP protects neuronal cells from diverse insults such as hydroxyl peroxide exposure and ischemia (Vaudry et al 2002(Vaudry et al , 2005Ohtaki et al 2006Ohtaki et al , 2008, with recent evidence suggesting that it may also rescue other organs or tissues including kidney (Arimura et al 2005;Li et al 2010;Horvath et al 2010), heart (Gasz et al 2006;Mori et al 2010), inner ear (Racz et al 2010), and endothelial cells (Racz et al 2007). Most injuries lead to the production of ROS and oxidative stress.…”

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

“…In addition to VIP, PACAP can increase its own expression, thus promoting, in an autocrine manner, cerebellar granule cell survival. In this way, short-term PACAP exposure can be turned into a long-term action (Tabuchi et al, 2001a,b;Vaudry et al, 2005). Furthermore, besides its direct action on the intrinsic apoptotic pathway, PACAP promotes the expression of antioxidant proteins (Botia et al, 2008) and transactivation of PAC1-R contributes to the insulin-like growth factor neuroprotective activity (Delcourt et al, 2007).…”

PACAP38 increases vesicular monoamine transporter 2 (VMAT2) expression and attenuates methamphetamine toxicity

“…PACAP38 can attenuate hydrogen peroxide toxicity, while cells from mutant animals that do not express PACAP38 are more sensitive to oxidative damage (Vaudry, et al 2002, Vaudry, et al 2005). PACAP38 has also been shown to protect cells from a diverse array of toxic insults of clinical significance, such as β-amyloid fragements (Alzheimer's), prion protein (Creuztfeldt-Jakob), glycoprotein-120 (HIV), and excitotoxicity (Morio, et al 1996, Brenneman, et al 2002, Onoue, et al 2002a, Onoue, et al 2002b, Atlasz, et al 2006.…”