Pituitary adenylate cyclase-activating polypeptide protects astroglial cells against oxidative stress-induced apoptosis

Abstract

J. Neurochem. (2011) 117, 403–411. Abstract Oxidative stress, associated with a variety of disorders including neurodegenerative diseases, results from accumulation of reactive oxygen species (ROS). Oxidative stress is not only responsible for neuron apoptosis, but can also provoke astroglial cell death. Numerous studies indicate that pituitary adenylate cyclase‐activating polypeptide (PACAP) promotes neuron survival, but nothing is known regarding the action of PACAP on astroglial cell survival. Thus, the purpose of the present study was to investigate the potential glioprotective effect of PACAP on H2O2‐induced astrocyte death. Pre‐treatment of cultured rat astrocytes with nanomolar concentrations of PACAP prevented cell death provoked by H2O2 (300 μM), whereas vasoactive intestinal polypeptide was devoid of protective activity. The effect of PACAP on astroglial cell survival was abolished by the type 1 PACAP receptor antagonist, PACAP6‐38. The protective action of PACAP was blocked by the protein kinase A inhibitor H89, the protein kinase C inhibitor chelerythrine and the mitogen‐activated protein (MAP)‐kinase kinase (MEK) inhibitor U0126. PACAP stimulated glutathione formation, and blocked H2O2‐evoked ROS accumulation and glutathione content reduction. In addition, PACAP prevented the decrease of mitochondrial activity and caspase 3 activation induced by H2O2. Taken together, these data indicate for the first time that PACAP, acting through type 1 PACAP receptor, exerts a potent protective effect against oxidative stress‐induced astrocyte death. The anti‐apoptotic activity of PACAP on astrocytes is mediated through the protein kinase A, protein kinase C and MAPK transduction pathways, and can be accounted for by inhibition of ROS‐induced mitochondrial dysfunctions and caspase 3 activation.

Octadecaneuropeptide ODN prevents hydrogen peroxide-induced oxidative damage of biomolecules in cultured rat astrocytes

“…Here, we observed that the AC inhibitor ddA blocked the inhibitory effect of ODN on H 2 O 2 -induced intracellular ROS accumulation, while the PLC inhibitor U73122 had no effect. These data are in agreement with evidences indicating that activation of the AC/PKA transduction pathway contributes to reduce the cellular ROS levels and to protect cells against oxidative stress in hippocampal cultured neurons [7] and in cultured astrocytes [5,24,31].…”

“…Astroglial cells contain high levels of ROS scavenger molecules and antioxidant enzymes which play a prominent role in the protection of neurons against oxidative stress and associated cell death [4]. Nevertheless, it has recently been reported that astrocyte functionality and viability may be compromised under excessive oxidative stress conditions [12,30,31] and astrocyte apoptosis has been observed in brain injuries caused by trauma or ischemia [8,36]. Therefore, in many pathological conditions, protection of astrocytes from oxidative insult appears essential to prevent neurodegeneration.…”

Protective Intestinal Effects of Pituitary Adenylate Cyclase Activating Polypeptide

“…In diabetic nephropathy, Banki et al [ 40 ] showed that PACAP treatment increased glutathione levels. PACAP also stimulated glutathione formation, and blocked H 2 O 2 -evoked reactive oxygen species (ROS) accumulation and glutathione content reduction in oxidative stressinduced astroglial injury [ 44 ]. In kidney ischemia-reperfusion, similar changes were observed: PACAP treatment decreased MDA levels while increased GSH levels [ 45 ].…”

Hemoglobin-Improved Protection in Cultured Cerebral Cortical Astroglial Cells: Inhibition of Oxidative Stress and Caspase Activation

“…Secondary cultures of rat cortical astrocytes were prepared from 1- or 2-day-old Wistar rats of both sexes as previously described (34). Briefly, cerebral hemispheres were dissected, meninges removed, and tissues collected in DMEM/Ham F12 (2:1; v/v) culture medium supplemented with 2 mM glutamine, 1‰ insulin, 5 mM HEPES, 0.4% glucose (final concentration of glucose in culture media is 4.5 g/L), and 1% of the antibiotic-antimycotic solution.…”