Effects Of PACAP Research Articles

Investigation of PACAP38 and PAC1 Receptor Expression in Human Retinoblastoma and the Effect of PACAP38 Administration on Human Y-79 Retinoblastoma Cells.

Retinoblastoma represents the most prevalent malignant neoplasm affecting the eyes in childhood. The clear-cut origin of retinoblastoma has not yet been determined; however, based on experiments, it has been suggested that RB1 loss in cone photoreceptors causes retinoblastoma. Pituitary adenylate-cyclase activating polypeptide (PACAP) is a pleiotropic neuropeptide which has been shown to be affected in certain tumorous transformations, such as breast, lung, kidney, pancreatic, colon, and endocrine cancers. This study aimed to investigate potential changes in both PACAP38 and PAC1 receptor (PAC1R) expression in human retinoblastoma and the effect of PACAP38 administration on the survival of a human retinoblastoma cell line (Y-79). We analyzed human enucleation specimens removed because of retinoblastoma for PACAP38 and PAC1R immunostaining and the effect of PACAP38 on the survival of the Y-79 cell line. We described for the first time that human retinoblastoma cells from patients showed only perinuclear, dot-like immunopositivity for both PACAP38 and PAC1R, irrespective of laterality, genetic background, or histopathological features. Nanomolar (100 nM and 500 nM) PACAP38 concentrations had no effect on the viability of Y-79 cells, while micromolar (2 µM and 6 µM) PACAP38 significantly decreased tumor cell viability. These findings, along with general observations from animal studies showing that PACAP38 has strong anti-apoptotic, anti-inflammatory, and antioxidant effects on ocular tissues, together suggest that PACAP38 and its analogs are promising candidates in retinoblastoma therapy.

Comparison of pituitary adenylate cyclase-activating polypeptide (PACAP, ADCYAP1) gene polymorphisms among patients with methamphetamine addiction, methamphetamine-induced psychosis and healthy controls

ObjectiveRecent studies have shown the role of the PACAPergic system in addiction and psychotic disorders. Studies also show the close association of methamphetamine with psychosis. In our study, we aim to compare the distribution of PACAP rs2856966, rs2231181, and rs1610037 gene polymorphisms, as determined according to literature research, among the patients with methamphetamine addiction (MA), patients with methamphetamine-induced psychosis (MIP), and healthy controls (HC), and to investigate the associations of these polymorphisms with MA and MIP. MethodsIn all, 173 patients diagnosed with MA, 120 patients diagnosed with MIP, and 104 HC without any history of substance abuse were included. Inter-group PACAP rs2856966, rs2231181, and rs1610037 genotypes were examined. ResultsThe rs2231181 CC genotype was determined to increase the risk of MA by 2708 times (β=2708, P=0.010) and the risk of MIP by 2786 times (β=2786, P=0.010). The rs1610037 GG genotype was observed to increase the risk of MA by 9322 times (β=9322, P<0.001) and the risk of MIP by 6579 times (β=6579, P=0.004). ConclusionThrough the PACAPergic system, new treatment interventions specific to MIP and for reducing relapses in MA can be developed. Moreover, treatments to be developed through the PACAPergic system may also be beneficial in preventing the neurotoxicity caused by methamphetamine, by the effect of PACAP on neural development.

Comparative study of effects of NAd and PACAP on contractile and electrical activities in human colon.

Comparative study of effects of NAd and PACAP on contractile and electrical activities in human colon.

PACAP attenuates hepatic lipid accumulation through the FAIM/AMPK/IRβ axis during overnutrition

ObjectivePituitary adenylate cyclase-activating polypeptide (PACAP) was reported to attenuate hepatic lipid accumulation in overnutrition-related metabolic disorder, mediated by up-regulation of fas apoptosis inhibitory molecule (FAIM). However, how PACAP regulates FAIM in metabolic tissues remains to be addressed. Here we investigated the underlying mechanism on the role of PACAP in ameliorating metabolic disorder and examined the potential therapeutic effects of PACAP in preventing the progression of metabolic associated fatty liver disease (MAFLD). MethodsMouse models with MAFLD induced by high-fat diet were employed. Different doses of PACAP were intraperitoneally administrated. Western blot, luciferase assay, lentiviral-mediated gene manipulations and animal metabolic phenotyping analysis were performed to explore the signaling pathway involved in PACAP function. ResultsPACAP ameliorated the excessive hepatic lipid accumulation and inhibited lipogenesis in HFD-fed C57BL/6J mice. Mechanistically, PACAP activated the FAIM-AMPK-IRβ axis to inhibit the expression of lipid synthesis genes, and FAIM mediated the effects of PACAP. FAIM suppression via lentiviral-mediated shRNA inhibited the activation of AMPK, whereas FAIM overexpression promoted AMPK activation. PACAP increased the promoter activity of FAIM gene through activating PKA-CREB signaling pathway. ConclusionOur work demonstrated that the administration of PACAP represented a feasible approach for treating hepatic lipid accumulation in MAFLD. The findings reveal the molecular mechanism that PACAP increase FAIM expression and activates the FAIM/AMPK/IRβ signaling axis, thus inhibits lipogenesis to mediate its beneficial effects.

Long-term protective effect of PACAP in a fetal alcohol syndrome (FAS) model

Prenatal ethanol exposure provokes teratogenic effects, due to oxidative stress and massive neuronal apoptosis in the developing brain that result in lifelong behavioral abnormalities. PACAP exerts anti-oxidative and neuroprotective activities on neuronal cells, and prevents ethanol neurotoxicity. The present study focused on the ability of PACAP to protect the brain of 30-day-old mice (P30) from prenatal alcohol exposure induced oxidative damage and toxicity. Pregnant mice were divided randomly into 4 groups, i.e. control group, ethanol group (1.5 g/kg ip daily injection), PACAP group (5 μg intrauterine daily injection) and an ethanol plus PACAP group. Offspring prenatally exposed to ethanol had decreased body weight and reduced cell survival. Moreover, production of ROS was sharply enhanced in the brain of prenatal ethanol-exposed animals, associated with an elevation in the activity of the antioxidant enzymes, and an increase of oxidative damages as shown by the accumulation of the lipid oxidation marker malondialdehyde and of protein carbonyl compounds. Intrauterine administration of PACAP during the gestational period restored the endogenous antioxidant system, prevented ROS overproduction and promoted the survival of dissociated cells from animals prenatally exposed to ethanol. Behavioral tests revealed that P30 animals exposed to ethanol during the prenatal period exhibited reduced motor activity, altered exploratory interest and increased anxiety. However, PACAP treatment significantly attenuated these behavioral impairments. This study demonstrates that PACAP exerts a potent neuroprotective effect against alcohol toxicity during brain development, and indicates that PACAP and/or PACAP analogs might be a useful tool for treatment of alcohol intoxication during pregnancy.

PACAP antagonizes oxldl-induced lipid-/triglyceride accumulation and VPAC1-expression in human M2-MΦ.

Background and Aims: PACAP (pituitary adenylate cyclase-activating polypeptide) deficiency is proatherogenic in hypercholesterolemic mice and inhibits oxidized-low density lipoprotein (oxLDL)-induced TNF-α release, as well as foam cell formation in macrophages (MΦ). PACAP receptors, i.e. VIP receptor type 1 and 2 (VPAC1; VPAC2) and PACAP selective receptor PAC1 have been reported in MΦ of different tissues. The aim of this study is to examine the effects of PACAP38 on oxLDL-mediated lipid accumulation with respect to PACAP-receptor VPAC1 expression in human M1/M2-MΦ.

Effects of Pacap on Schwann Cells: Focus on Nerve Injury.

Schwann cells, the most abundant glial cells of the peripheral nervous system, represent the key players able to supply extracellular microenvironment for axonal regrowth and restoration of myelin sheaths on regenerating axons. Following nerve injury, Schwann cells respond adaptively to damage by acquiring a new phenotype. In particular, some of them localize in the distal stump to form the Bungner band, a regeneration track in the distal site of the injured nerve, whereas others produce cytokines involved in recruitment of macrophages infiltrating into the nerve damaged area for axonal and myelin debris clearance. Several neurotrophic factors, including pituitary adenylyl cyclase-activating peptide (PACAP), promote survival and axonal elongation of injured neurons. The present review summarizes the evidence existing in the literature demonstrating the autocrine and/or paracrine action exerted by PACAP to promote remyelination and ameliorate the peripheral nerve inflammatory response following nerve injury.

Effects of PACAP-38 and an analog, acetyl-[Ala15, Ala20] PACAP-38-propylamide, on memory consolidation in the detection of spatial novelty task in rats

PACAP-38 (P38) is a pleiotropic peptide that exerts multiple peripheral and central actions, including neurotrophic, neuroprotective and anti-inflammatory actions. Previous studies have suggested an improvement of memory in rats that have received a single systemic injection of P38. In a therapeutic perspective, we used an analog, acetyl-[Ala15, Ala20]PACAP-38-propylamide (ALG), to improve both stability and affinity for PAC1 receptors vs. endogen PACAP. We investigated the effect of P38 and ALG on memory consolidation using a spatial novelty detection (SND) task in which rats had to memorize a configuration of objects to identify that, during a test session, a familiar object has been moved to a new location. Rats received an intravenous injection of P38 or ALG after the last training session. In Experiment 1, P38 (30 µg/kg) improved spatial memory consolidation allowing detection of novelty vs. saline injection. In Experiment 2, we confirmed this effect and showed that P38 restored the performance similar to what was found using non-injected rats. This suggests that, contrary to ALG, P38 exerted a promesiant rather than an anxiety-related effect whereas ALG did not show similar action. We also examined whether P38 effect involved an interaction with NR2B-containing NMDA receptors (NMDARs) by administrating ifenprodil (IFE; a selective NR2B-containing NMDAR antagonist) alone or in combination with P38 or ALG. The results suggested that P38 action on memory involved NR2B-containing NMDARs. Lastly, brain-derived neutrophic factor (BDNF) modulation appeared to be not related to the behavioral performance in the SND task. Overall, the results indicate that P38 exerted a beneficial effect on memory consolidation in a non-associative task, whereas ALG did not have this action.

Stability Test of PACAP in Eye Drops

PACAP is a neuropeptide with widespread distribution and diverse biological functions. It has strong cytoprotective effects mediated mainly through specific PAC1 receptors. Experimental data show protective effects of PACAP in the retina and cornea in several pathological conditions. Although intravitreal injections are a common practice in some ocular diseases, delivery of therapeutic agents in the form of eye drops would be more convenient and would lead to fewer side effects. We have previously shown that PACAP, in the form of eye drops, is able to pass through the ocular barriers and can exert retinoprotective effects. As eye drops represent a promising form of administration of PACAP in ocular diseases, it is important to investigate the stability of PACAP in solutions used in eye drops. In this study, the stability of PACAP1-27 and PACAP1-38 in eye drops was measured in four common media and a commercially available artificial tear solution at both room temperature and +4 °C. Mass spectrometry results show that the highest stability was gained with PACAP1-38 in water and 0.9% saline solution at +4 °C, representing 80–90% drug persistence after 2 weeks. PACAP1-38 in the artificial tear showed very fast degradation at room temperature, but was stable at +4 °C. In summary, PACAP1-38 has higher stability than PACAP1-27, with highest stability at +4 °C in water solution, but both peptides in each medium can be stored for relatively longer periods without significant degradation. These data can provide reference for future therapeutic use of PACAP in eye drops.

Pituitary adenylate cyclase-activating polypeptide-induced PAC1 receptor internalization and recruitment of MEK/ERK signaling enhance excitability of dentate gyrus granule cells.

Pituitary adenylate cyclase activating polypeptide (PACAP; ADCYAP1) is a pleiotropic neuropeptide widely distributed in both the peripheral and central nervous systems. PACAP and its specific cognate PAC1 receptor (ADCYAP1R1) play critical roles in the homeostatic maintenance of multiple physiological and behavioral systems. Notably, maladaptations in the PACAPergic system have been associated with several psychopathologies related to fear and anxiety. PAC1 receptor transcripts are highly expressed in granule cells of the dentate gyrus (DG). Here, we examined the direct effects of PACAP on DG granule cells in brain slices using whole cell patch recordings in current clamp mode. PACAP significantly increased the intrinsic excitability of DG granule cells via PAC1 receptor activation. This increased excitability was not mediated by adenylyl cyclase/cAMP or phospholipase C/PKC activation, but instead via activation of an extracellular signal-regulated kinase (ERK) signaling pathway initiated through PAC1 receptor endocytosis/endosomal signaling. PACAP failed to increase excitability in DG granule cells pretreated with the persistent sodium current blocker riluzole, suggesting that the observed PACAP effects required this component of the inward sodium current.

Neuroprotective Potential of Pituitary Adenylate Cyclase Activating Polypeptide in Retinal Degenerations of Metabolic Origin.

Pituitary adenylate cyclase-activating polypeptide (PACAP1-38) is a highly conserved member of the secretin/glucagon/VIP family. The repressive effect of PACAP1-38 on the apoptotic machinery has been an area of active research conferring a significant neuroprotective potential onto this peptide. A remarkable number of studies suggest its importance in the etiology of neurodegenerative disorders, particularly in relation to retinal metabolic disorders. In our review, we provide short descriptions of various pathological conditions (diabetic retinopathy, excitotoxic retinal injury and ischemic retinal lesion) in which the remedial effect of PACAP has been well demonstrated in various animal models. Of all the pathological conditions, diabetic retinopathy seems to be the most intriguing as it develops in 75% of patients with type 1 and 50% of patients with type 2 diabetes, with concomitant progression to legal blindness in about 5%. Several animal models have been developed in recent years to study retinal degenerations and out of these glaucoma and age-related retina degeneration models bear human recapitulations. PACAP neuroprotection is thought to operate through enhanced cAMP production upon binding to PAC1-R. However, the underlying signaling network that leads to neuroprotection is not fully understood. We observed that (i) PACAP is not equally efficient in the above conditions; (ii) in some cases more than one signaling pathways are activated; (iii) the coupling of PAC1-R and signaling is stage dependent; and (iv) PAC1-R is not the only receptor that must be considered to interpret the effects in our experiments. These observations point to a complex signaling mechanism, that involves alternative routes besides the classical cAMP/protein kinase A pathway to evoke the outstanding neuroprotective action. Consequently, the possible contribution of the other two main receptors (VPAC1-R and VPAC2-R) will also be discussed. Finally, the potential medical use of PACAP in some retinal and ocular disorders will also be reviewed. By taking advantage of, low-cost synthesis technologies today, PACAP may serve as an alternative to the expensive treatment modelities currently available in ocular or retinal conditions.

Protective effect of PACAP-38 on retinal pigmented epithelium in an in vitro and in vivo model of diabetic retinopathy through EGFR-dependent mechanism

Diabetic retinopathy (DR) is one of the most common microvascular complications of diabetes.In the last years, several in vivo studies have demonstrated the protective role of pituitary adenylate cyclase-activating peptide (PACAP-38) to counteract several alterations occurring during DR. Recently, different studies have demonstrated that some PACAP-38 effects are mediated by EGFR trans-activation, although no data exist regarding the link between this peptide and EGFR in DR.The aim of the present study has been to investigate whether retinal effect of PACAP-38 against high glucose damage is mediated by EGFR phosphorylation. Diabetes was induced by a single injection of streptozotocin (STZ) in rats. After 1 week, a group of animals was treated with a single intravitreal injection of 100 μM PACAP-38 or saline solution. Immunohistochemistry and western blot analysis have demonstrated that intravitreal injection of PACAP-38 induced p-EGFR over-expression in retina of diabetic rats. Several pathogenic mechanisms may contribute to diabetic retinopathy including BRB alteration. To better clarify the relationship between PACAP-38 and EGFR, we have also carried out a study on ARPE-19 cells, representing a model in vitro of outer BRB. Our results have shown that PACAP-38 treatment improved cell viability in ARPE-19 cells exposed to hyperglycemic/hypoxic insult mimicking tissue microenvironment occurring in DR.Binding to PAC1R, peptide induces EGFR phosphorylation via PKA-signaling cascade stimulation.EGFR trans-activation triggers MAPK/ERK signaling pathway involved in cell survival and proliferation.In conclusion, data have suggested that PACAP-38 acts through EGFR phosphorylation in DR and this effect particularly occurs on RPE layer.

PACAP stimulates insulin secretion by PAC1 receptor and ion channels in β-cells

Pituitary Adenylate Cyclase-Activating Polypeptide (PACAP) plays a crucial role in the endocrine system. The present study aimed to investigate the effect of PACAP38 on insulin secretion and the underlying mechanism in rat pancreatic β-cells. The insulin secretion results showed that PACAP38 stimulated insulin secretion in a glucose- and dose-dependent manner. The insulinotropic effect was mediated by PAC1 receptor, but not by VPAC1 and VPAC2 receptors. Inhibition of adenylyl cyclase and protein kinase A suppressed PACAP38-augmented insulin secretion. Glucose-regulated insulin secretion is dependent on a series of electrophysiological activities. Current-clamp technology suggested that PACAP38 prolonged action potential duration. Voltage-clamp recordings revealed that PACAP38 blocked voltage-dependent potassium currents, and this effect was reversed by inhibition of PAC1 receptor, adenylyl cyclase, or protein kinase A. Activation of Ca2+ channels by PACAP38 was also observed, which could be antagonized by the PAC1 receptor antagonist. In addition, calcium-imaging analysis indicated that PACAP38 increased intracellular Ca2+ concentration, which was decreased by PAC1 receptor antagonist. These findings demonstrate that PACAP38 stimulates glucose-induced insulin secretion mainly by acting on PAC1 receptor, inhibiting voltage-dependent potassium channels, activating Ca2+ channels and increasing intracellular Ca2+ concentration. Further, PACAP blocks voltage-dependent potassium currents via the adenylyl cyclase/protein kinase A signaling pathway.

Comparison of the effects of PACAP-38 and its analog, acetyl-[Ala15, Ala20] PACAP-38-propylamide, on spatial memory, post-learning BDNF expression and oxidative stress in rat

We compared the effects of single intraveinous injection of pituitary adenylate cyclase-activating polypeptide-38 (P38) to those of its analog, acetyl-[Ala15, Ala20]PACAP-38-propylamide (P38-alg) on spatial memory in the Morris water maze (MWM) using a weak massed-learning procedure, post-training brain derived neurotrophic factor (BDNF) and post-training oxidative stress biomarker assays in male Wistar rats. Acquisition of the MWM task following P38 (30 μg/kg) and P38-alg (30 μg/kg) treatments was similar to control group (Saline: 0.9% NaCl) and there was no interaction between treatments and performance. However, in the probe test, P38-treated group showed a specific interest for the target quadrant whereas the two other groups exhibited less focused place searching behavior. Moreover, P38 had an anxiogenic effect as measured by the distribution of swimming at the periphery of the pool. The swimming test resulted in a decrease in BDNF contents in the hippocampus. P38 but not P38-alg treatment restored BDNF expression. In terms of oxidative stress, both P38 and P38-alg treatments had antioxidative effects. The activity of antioxidative enzymes in the neocortex was increased. However only P38 reduced the levels of carbonylated proteins (CP). These data show that P38 and P38-alg have different behavioral and neurobiological effects. Thus, P38-alg and other analogs with specific functional profiles, inducing beneficial central effects (e.g. neuroprotection) while minimizing undesired peripheral effects may be useful for potential therapeutical use.

Transport of the pituitary adenylate cyclase-activating polypeptide across the blood-brain barrier: implications for migraine

BackgroundPituitary adenylate cyclase-activating polypeptide (PACAP) is widely distributed in the nervous system and is involved in migraine pathophysiology. Understanding the function of the blood-brain barrier (BBB) in relation to PACAP is important to the understand the mechanisms behind PACAP-induced migraine attacks, but also to develop antimigraine drugs targeting the PACAP receptors Here, we aim to review the transport ability of PACAP across the BBB.MethodsWe performed a systematic literature search on PubMed to identify studies reporting original data on PACAP and BBB. The search was finalized in July 2017.ResultsThe literature search identified 96 papers of which 11 contained relevant data. In addition, two papers were known to be relevant and were included. A total of 13 papers studies were included in the final analysis. Preclinical studies (n = 10) suggest the existence of specific PACAP transport systems across the BBB, while human PACAP studies failed to show vasodilator effect of PACAP on the cerebral arteries from the lumen (n = 3).ConclusionPACAP38 is transported over the BBB actively, while PACAP27 cross the BBB by diffusion over the membrane, but after crossing the endothelial membrane both isoforms are either rapidly degraded or efflux back from brain to blood. Thus, a direct central action of the PACAPs is unlikely. This is supported by studies showing selective PACAP effect on extra-cerebral arteries.

Effects of PACAP on the secretions of tear and saliva in mouse

Effects of PACAP on the secretions of tear and saliva in mouse

The differential effects of neuroleptic drugs and PACAP on the expression of BDNF mRNA and protein in a human glioblastoma cell line

Despite numerous studies, the molecular mechanisms underpinning the action of antipsychotic drugs remain not fully understood. It has been suggested that, in addition to the modulation of monoaminergic neurotransmission, antipsychotic drugs can also affect the expression of neurotrophic factors in the brain. The present study examines the effects of a first-generation neuroleptic drug (FGA; haloperidol) and two second-generation neuroleptic drugs (SGAs; olanzapine and amisulpride) on the expression and levels of brain-derived neurotrophic factor (BDNF) in an astrocyte-like T98G glioblastoma cell line. The effects of these drugs were compared to the action of PACAP38, a neuropeptide with well-known BDNF-mediated neuroprotective effects. The tested neuroleptics differentially regulated the mRNA expression and protein level of BDNF depending on concentration and incubation time. Real-time PCR analysis demonstrates that, of the three tested neuroleptics, both haloperidol and olanzapine at a concentration of 5 µM (but not at 20 µM) increased BDNF mRNA expression with similar efficacy after 72-hour incubation. In order to confirm the observed changes in the mRNA expression of BDNF, a protein expression assay was performed. The exposure of cells to 5 μM olanzapine alone for 72 hours increased BDNF concentration in the culture medium by 29%. Additionally, PACAP significantly up-regulated BDNF mRNA expression in T98G cells and the obtained results correlated positively with the increased production of BDNF protein, 22% above control values. Our findings show that olanzapine, similarly to exogenous PACAP38, increased BDNF mRNA expression and protein release, which can contribute to its neuroprotective mechanism of action in the cells of non-neuronal origin. The results of the paper show that olanzapine, similarly to exogenous PACAP38, increased BDNF mRNA expression and protein release, which can contribute to its neuroprotective mechanism of action in the cells of nonneuronal origin. The results of the present paper confirm the findings that BDNF may represent the key target for olanzapine and PACAP.

THE IN VITRO EFFECTS OF PACAP ON BACE1 ACTIVITY, TAU PHOSPHORYLATION AND SYNAPTIC FUNCTION

PACAP is reduced the brains and cerebrospinal fluids of Alzheimer’s disease (AD) patients (Han et al 2014 Neurology. 82(19):1724-8; Han et al 2015 JAMA Neurol. 72(3):333-9). PACAP reduced Aβ-induced toxicity in primary cultured mouse neurons and the neuroprotective effects could be attributed to the mitochondrial function enhancement (Han et al 2014 Neurobiol Aging. 35(9):2064-71). Furthermore in mouse brain, PACAP enhanced the production of sAPPα while decreased Aβ species, suggesting a shift of the APP metabolism from beta-secretase predominant pathway to alpha-secretase predominant pathway (Rat et al 2011.FASEB J.25 (9):3208-18.). However, the effect of PACAP on beta-secretase activity was not measured; the effects of PACAP on other key factors in AD pathogenesis had never been elucidated. In this study, we tested the effects of PACAP on three critical molecular events implicated in AD disease: beta-secretase activity, Tau phosphorylation and synaptic function. Primary cultured mouse neurons were established as described previously (Han et al 2014 Neurobiol Aging. 35(9):2064-71). At 14 days, after treating with PACAP for 72 hours, we measured BACE1 activity using BACE1 FRET assay kit (Panvera, Life Technologies) with a customized protocol. The steady state fluorescent units (RFU) were fit into Michaelis-Menten curve to analyse Km and Vmax. The cultured neurons were incubated with Aβ42 with or without PACAP for 72 hours before we proceeded to test Tau phosphorylation using Western blot or test EPSCs using patch clamp. PACAP38 decreased BACE1 Vmax by 30%, suggesting a reduction of enzyme capacity. PACAP38 increased BACE1 Km, suggesting a weakened affinity of BACE1, which may result from a post-translational modification. Treating cultured mouse neurons with Aβ42 oligomers increased tau phosphorylation at the site of threonine 523, which is equivalent to threonine 231 in human tau. PACAP38 reduced Aβ42-induced T523 hyperphosphorylation. The primary cultured mouse neurons developed spontaneous excitatory postsynaptic currents (EPSC), which was reduced by Aβ42 oligomer due to its toxic effect on synapse. PACAP38 prevents the reduction of EPSC induced by Aβ42. Exogenous PACAP decreased beta-secretase activity, reduced tau protein phosphorylation at least in specific site and protected synaptic function in cultured primary mouse neurons.

Activation of the HPA axis and depression of feeding behavior induced by restraint stress are separately regulated by PACAPergic neurotransmission in the mouse

We measured serum CORT elevation in wild-type and PACAP-deficient C57BL/6N male mice after acute (1 h) or prolonged (2–3 h) daily restraint stress for 7 d. The PACAP dependence of CORT elevation was compared to that of stress-induced hypophagia. Daily restraint induced unhabituated peak CORT elevation, and hypophagia/weight loss, of similar magnitude for 1, 2, and 3 h of daily restraint, in wild-type mice. Peak CORT elevation, and hypophagia, were both attenuated in PACAP-deficient mice for 2 and 3 h daily restraint. Hypophagia induced by 1-h daily restraint was also greatly reduced in PACAP-deficient mice, however CORT elevation, both peak and during recovery from stress, was unaffected. Thus, hypothalamic PACAPergic neurotransmission appears to affect CRH gene transcription and peptide production, but not CRH release, in response to psychogenic stress. A single exposure to restraint sufficed to trigger hypophagia over the following 24 h. PACAP deficiency attenuated HPA axis response (CORT elevation) to prolonged (3 h) but not acute (1 h) single-exposure restraint stress, while hypophagia induced by either a single 1 h or a single 3 h restraint were both abolished in PACAP-deficient mice. These results suggest that PACAP’s actions to promote suppression of food intake following an episode of psychogenic stress is unrelated to the release of CRH into the portal circulation to activate the pituitary-adrenal axis. Furthermore, demonstration of suppressed food intake after a single 1-h restraint stress provides a convenient assay for investigating the location of the synapses and circuits mediating the effects of PACAP on the behavioral sequelae of psychogenic stress.

Igf1 and Pacap rescue cerebellar granule neurons from apoptosis via a common transcriptional program

A shift of the delicate balance between apoptosis and survival-inducing signals determines the fate of neurons during the development of the central nervous system and its homeostasis throughout adulthood. Both pathways, promoting or protecting from apoptosis, trigger a transcriptional program. We conducted whole-genome expression profiling to decipher the transcriptional regulatory elements controlling the apoptotic/survival switch in cerebellar granule neurons following the induction of apoptosis by serum and potassium deprivation or their rescue by either insulin-like growth factor-1 (Igf1) or pituitary adenylyl cyclase-activating polypeptide (Pacap). Although depending on different upstream signaling pathways, the survival effects of Igf1 and Pacap converged into common transcriptional cascades, thus suggesting the existence of a general transcriptional program underlying neuronal survival.