PACAP/PAC1R activation promotes group 2 innate lymphoid cells-dependent allergic rhinitis via ERK pathway.

There is a deficit of pituitary adenylate cyclase-activating polypeptide (PACAP) in patients with neuropathologically confirmed Alzheimer dementia. However, whether this deficit is associated with the earlier stages of Alzheimer disease (AD) is unknown. This study was conducted to clarify the association between PACAP biomarkers and preclinical, mild cognitive impairment (MCI), and dementia stages of AD in postmortem brain tissue. To examine PACAP and PACAP receptor levels in postmortem brain tissues and cerebrospinal fluid from cognitively and neuropathologically normal control individuals, patients with MCI due to AD (MCI-AD), and individuals with AD; analyze the relationship between PACAP, cognitive, and pathologic features; and propose a model to assess these relationships. We measured PACAP and its receptor (PAC1) levels using enzyme-linked immunoassay. A total of 35 cases were included. All the brain tissue and cerebrospinal fluid samples were selected from Banner Sun Health Research Institute Brain and Body Donation Program. All cognitive test results were in record with the Arizona Alzheimer's Consortium. A comparison of PACAP and PAC1 levels among the healthy controls, MCI-AD, and AD dementia groups, as well as a systematic correlation analysis between PACAP level, cognitive performance, and pathologic severity. The PACAP levels in cerebrospinal fluid, the superior frontal gyrus, and the middle temporal gyrus were inversely related to dementia severity. The PACAP levels in cerebrospinal fluid correlated with the Mattis Dementia Rating Scale score (Pearson r = 0.50; P = .03) and inversely correlated with total amyloid plaques (Pearson r = -0.48; P < .01) and tangles (Pearson r = -0.55; P = .01) in the brain. The PACAP in the superior frontal gyrus and middle temporal gyrus correlated with the Stroop Color-Word Interference Test (Pearson r = 0.58; P < .01) and the Auditory Verbal Learning Test-Total Learning (Pearson r = 0.33; P = .02), respectively. The PACAP in the primary visual cortex did not correlate with the Judgment of Line orientation test (P = .14). Furthermore, the PAC1 level in the superior frontal gyrus showed an upregulation in MCI-AD but not in AD. The pharmacodynamic model of the PACAP-PAC1 interaction best predicted cognitive function in the superior frontal gyrus, but it was less predictive in the middle temporal gyrus and failed to be predictive in the primary visual cortex. Deficits in PACAP are associated with clinical severity in the MCI and dementia stages of AD. Additional studies are needed to clarify the role of PACAP deficits in the predisposition to, pathogenesis of, and treatment of AD.

Influence of pinealectomy on levels of PACAP and cAMP in the chicken brain.

Decreased synovial fluid pituitary adenylate cyclase-activating polypeptide (PACAP) levels may reflect disease severity in post-traumatic knee osteoarthritis after anterior cruciate ligament injury

We conducted a systematic review and meta-analysis to explore the relationship between blood pituitary adenylate cyclase-activating polypeptide (PACAP) levels and migraine. PACAP is involved in the onset of migraine, but the results from clinical studies on PACAP level variations across different periods of migraine are conflicting. We systematically searched for observational studies that reported PACAP levels in people with migraine and non-migraine controls published in English from the PubMed, Web of Science, and Ovid electronic databases, or in Chinese from the Chinese National Knowledge Infrastructure and the WanFang Med database. The Newcastle-Ottawa Quality Assessment Scale was used to assess the quality of the included studies. The quality of evidence for each outcome was assessed according to the Grading of Recommendations, Assessment, Development, and Evaluation (GRADE) guidelines. Of the 514 identified studies, 8 were eligible for inclusion. There was a "very low" level of evidence suggesting that the PACAP level is negatively correlated with migraine disease duration in adults with migraine (summary = -0.35, 95% confidence interval [CI] -0.49 to -0.22) and that the PACAP is higher in people with migraine during the ictal period than in the interictal period (standardized mean difference = 0.41, 95% CI 0.17 to 0.66) for both adults and children with migraine. Adult patients with episodic migraine (weighted mean difference [WMD] = -9.58 pg/mL, 95% CI -13.41 to -5.75 pg/mL) or chronic migraine (WMD = -10.93 pg/mL, 95% CI -15.57 to -6.29 pg/mL) had lower blood PACAP levels than non-migraine controls during the interictal period, supported by a "low" or "very low" quality of evidence, respectively, according to the GRADE rules. There is a very low certainty of evidence suggesting that the PACAP level is negatively correlated with migraine disease duration of adults with migraine and it varies greatly among different periods of migraine of both adults and children with migraine.

Pituitary adenylate cyclase-activating polypeptide (PACAP) is a pleiotropic and multifunctional neuropeptide having neurotrophic, neuroprotective, and general cytoprotective actions in a variety of tissues based on its anti-apoptotic, anti-inflammatory, and antioxidant effects. Several studies have demonstrated its cardioprotective effects in vitro and in various animal models. However, few data are available on the presence of PACAP in human cardiac tissues and its role in the pathomechanism and progression of different cardiac disorders, particularly heart failure. Earlier, our research group has shown PAC1 receptor immunoreactivity in human heart tissue samples and we have found significantly elevated PACAP27- and PACAP38-like immunoreactivity in ischemic cardiac samples compared to valvular abnormalities with radioimmunoassay. In the last few years, numerous studies examined the presence and the changes of PACAP levels in different human tissue samples and biological fluids to show alterations in different physiological and pathological conditions. Therefore, the aim of the present study was to measure the alterations of blood PACAP levels in chronic heart failure caused by primary dilated cardiomyopathy or ischemic cardiomyopathy and to examine the possible relationship between serum levels of PACAP, N-terminal prohormone of brain natriuretic peptide (NT-proBNP), and systolic left ventricular function, the most reliable biomarkers of heart failure. In the group of mild heart failure patients, a significant strong negative correlation was detected. Furthermore, in moderate heart failure, we found a significant moderate negative correlation between PACAP and NT-proBNP levels only in ischemic subgroup. Positive correlation was found between serum PACAP level and ejection fraction only in patients with heart failure due to ischemic cardiomyopathy but not in patients with primary dilated cardiomyopathy. In summary, remarkable differences were observed between the ischemic and non-ischemic heart failure suggesting that PACAP might play an important role in the pathomechanism and progression of ischemic heart failure and it might be a potential biomarker of cardiac diseases in the future.

Post-traumatic stress disorder (PTSD) affects approximately 5–10% of all individuals and is more predominant in women (Breslau, 2001). Advances in treatment and prevention will require identifying biomarkers to aid early diagnosis and understanding the mechanisms underlying maladaptive responses to trauma. In a highly traumatized, urban civilian population, we have recently reported that women (but not men) that had been diagnosed with PTSD had higher blood PACAP (pituitary adenylate cyclase-activating polypeptide) levels (Ressler et al, 2011) (Figure 1a). The high PACAP levels were correlated with physiological measures of the acoustic startle reflex, which have previously also been associated with PTSD risk. In addition, to further understand the responsiveness of the PACAP system to emotionally relevant cues and ovarian hormones, we showed that mRNA levels of the receptor for PACAP–PAC1R, are increased in the extended amygdala of adult rodents following classical fear conditioning and as a function of estrogen exposure. These findings suggested that PACAP might be involved in the symptoms characteristic of women diagnosed with PTSD. Figure 1 Relationship between the pituitary adenylate cyclase-activating polypeptide (PACAP)–PAC1 receptor (PAC1R) system and post-traumatic stress disorder (PTSD). (a) Females, but not males with high plasma PACAP38 levels show more PTSD symptoms. (b) ... To further genetically probe this association, we analyzed the PACAP (Adcyap1) gene and its receptor-PAC1 (Adcyap1r1). Only the Adcyap1r1 SNP (rs2267735) was found to be associated with PTSD diagnosis in women (again not in males) (Figure 1b). Although note that this SNP association was not replicated in a less traumatized cohort (Chang et al., 2012). At the epigenetic level, we also found that differential methylation of the Adcyap1r1 gene was associated with PTSD symptoms (Figure 1c). Given the approximately 2 : 1 sex-bias in PTSD prevalence, we find it exciting that the Adcyap1r1 SNP is within a predicted estrogen response element (ERE). Furthermore, in a postmortem sample, we found that females had differential cortical expression of Adcyap1r1 mRNA levels as a function of their genotype. Notably, a recent follow-up study finds that the same genetic risk is associated with higher acoustic startle in traumatized boys and girls before puberty, suggesting that the estrogen effect may be age-dependent (Jovanovic et al, 2012). Looking to the future, the association between PTSD and the PACAP–PAC1 receptor system in traumatized populations warrants further investigation on several important levels. For example, longitudinal prospective studies are needed to ascertain whether peripheral PACAP levels would serve as a robust predictive biomarker of eventual PTSD diagnosis. The PACAP–PAC1 receptor system has been studied for its role in stress responsiveness (Vaudry et al, 2009; Stroth et al, 2011), and as such presents a convergence between the stress and learning components of PTSD that should be investigated further. The genetic observation of a predicted ERE supports other findings that hormonal mechanisms may underlie the sex-bias in PTSD prevalence (Ferree et al, 2011; Lebron-Milad and Milad, 2012), but replications of this finding are necessary. Finally, learning is accompanied by epigenetic modifications at key genetic loci (Zovkic and Sweatt, 2012), and probing the epigenetic signatures at the Adcyap1and Adcyap1r1 genes as a result of previous traumatic experience or hormonal condition presents fertile ground for empirical analysis (Figure 1). In summary, the relationship between PTSD and the PACAP–PAC1 receptor system affords us the opportunity to address PTSD from the perspectives of stress physiology, endocrinology, epigenetics, and predictive biomarkers using human samples and animal models—a truly multi-pronged attack that may be required for understanding complex neuropsychiatric disorders.

Objective: Pituitary adenylate-cyclase activating polypeptide (PACAP) and vasoactive intestinal peptide (VIP) are two neuropeptides that exhibit anti-inflammatory and neuroprotective properties, modulating the production of cytokines and chemokines, and the behavior of immune cells. However, the relationship between PACAP and VIP levels and Parkinson’s disease (PD) are not clear. The aim of the current study was to evaluate serum PACAP and VIP levels in PD patients and to analysis the correlation between neuropeptide levels and non-motor symptoms.Methods: In this cross-sectional study, we enrolled 72 patients with idiopathic PD and 71 healthy volunteers. Serum PACAP and VIP levels were measured using an enzyme-linked immunosorbent assay (ELISA) kit. Non-motor symptoms were assessed with the Non-Motor Symptoms Scale (NMSS) for PD, including total and single-item scores.Results: The serum PACAP levels of PD patients were significantly lower than those of healthy controls [(76.02 ± 43.78) pg/ml vs. (154.96 ± 76.54) pg/ml, P < 0.001]; and the serum VIP levels of PD patients were also significantly lower than those of healthy controls [(109.56 ± 15.39) pg/ml vs. (136.46 ± 24.16) pg/ml, P < 0.001]. PACAP levels were inversely correlated only with the score on NMSS item five, assessing Attention/memory (r = −0.276, P < 0.05) and lower serum PACAP levels were detected in the cognitive dysfunction subgroup than in the cognitively intact subgroup [(61.87 ± 32.66) pg/ml vs. (84.51 ± 47.59) pg/ml, P < 0.05]; meanwhile, VIP levels were inversely correlated with the NMSS total score (r = −0.285, P < 0.05) and the single-item scores for item one, assessing Cardiovascular (r = −0.257, P < 0.05) and item three, assessing Mood/cognition (r = −0.373, P < 0.05), and lower serum VIP levels were detected in the anxiety subgroup and depression subgroup than in the non-anxiety subgroup and non-depression subgroup, respectively [(107.45 ± 15.40) pg/ml vs. (116.41 ± 13.67) pg/ml, P < 0.05]; [(104.45 ± 15.26) pg/ml vs. (113.43 ± 14.52) pg/ml, P < 0.05].Conclusion: The serum PACAP and VIP levels of PD patients were significantly lower than those of healthy controls. The non-motor symptoms significantly negatively correlated with serum PACAP level was cognitive dysfunction, while mood disorder was significantly correlated with serum VIP level.

Pituitary adenylate cyclase activating polypeptide (PACAP) is an endogenous neuropeptide widely distributed throughout the body, including the gastrointestinal tract. Several effects have been described in human and animal intestines. Among others, PACAP influences secretion of intestinal glands, blood flow, and smooth muscle contraction. PACAP is a well-known cytoprotective peptide with strong anti-apoptotic, anti-inflammatory, and antioxidant effects. The present review gives an overview of the intestinal protective actions of this neuropeptide. Exogenous PACAP treatment was protective in a rat model of small bowel autotransplantation. Radioimmunoassay (RIA) analysis of the intestinal tissue showed that endogenous PACAP levels gradually decreased with longer-lasting ischemic periods, prevented by PACAP addition. PACAP counteracted deleterious effects of ischemia on oxidative stress markers and cytokines. Another series of experiments investigated the role of endogenous PACAP in intestines in PACAP knockout (KO) mice. Warm ischemia–reperfusion injury and cold preservation models showed that the lack of PACAP caused a higher vulnerability against ischemic periods. Changes were more severe in PACAP KO mice at all examined time points. This finding was supported by increased levels of oxidative stress markers and decreased expression of antioxidant molecules. PACAP was proven to be protective not only in ischemic but also in inflammatory bowel diseases. A recent study showed that PACAP treatment prolonged survival of Toxoplasma gondii infected mice suffering from acute ileitis and was able to reduce the ileal expression of proinflammatory cytokines. We completed the present review with recent clinical results obtained in patients suffering from inflammatory bowel diseases. It was found that PACAP levels were altered depending on the activity, type of the disease, and antibiotic therapy, suggesting its probable role in inflammatory events of the intestine.

Introduction Pituitary adenylate cyclase-activating polypeptide (PACAP) is a cardioprotective neuropeptide. It has previously been shown that plazma PACAP level increases in myocardial infarction and decompensated heart failure, whereas it decreases in chronic heart failure. Patient material and method We examined blood samples from patients (n=46) undergoing pulmonary vein isolation for atrial fibrillation. We collected 5 ml blood samples from the femoral vein at the beginning, from the right atrium before the septal puncture, from the left atrium before and after the ablation, from the femoral vein at the end of the procedure and the next day from the cubital vein. PACAP levels were determined by ELISA. Patients were divided into intact (n=29) and scarred (n=17) left atrial groups by electroanatomical map. PACAP levels were compared in the total population and in the two groups and correlated with left atrial size and different comorbidity data. Results Significantly higher levels of PACAP were detected in atrial blood and in post-operative femoral vein samples compared to peripheral blood collected at the beginning and 1 day after the procedure. We measured decreased PACAP levels in the left atrium after ablation compared to samples from left atrium before the ablation. Although we found lower PACAP levels in the left atrium after ablation in patients with scarred atrium compared to the intact group, the PACAP levels showed significant elevation in the femoral vein after the ablation in patients with intact atria. Conclusions Our study was the first to show a difference between PACAP levels in atrial and peripheral blood samples. The elevated PACAP levels measured in atrial samples may be due to myocytes and neurons, whose PACAP production decreases depending on the degree of scarring following ablation-induced injury in the left atrium. Transient systemic elevation of PACAP levels is demonstrated in the periphery, suggesting a potential biomarker role for PACAP in these pathologies.

Signaling pathways and promoter regions that mediate pituitary adenylate cyclase activating polypeptide (PACAP) self-regulation in gonadotrophs

The correlation of serum and synovial fluid (SF) pituitary adenylate cyclase-activating polypeptide (PACAP) levels with disease progression of primary knee osteoarthritis (OA) was explored. Radiographic severity of OA was determined by Kellgren–Lawrence (K-L) grades. PACAP levels were measured by ELISA before treatment, and 4 and 8 wk following hyaluronic acid (HA) injection. Levels of IL-1β and MMP-3 were also detected. The numeric pain scale (NPS), revised Oxford Knee Score (OKS), and American Knee Society Score (AKSS) were employed to evaluate to symptomatic severity. Receiver-operating-characteristic (ROC) curve analysis was carried out to compare the diagnostic value of PACAP, IL-1β, and MMP-3 for the K-L grade. PACAP concentrations in SF but not serum were significantly lower in OA patients compared with controls. SF PACAP levels were negatively associated with K-L grades and higher NPS as well as worse AKSS and OKS. Further analysis demonstrated that PACAP concentration in SF was negatively correlated with expressions of IL-1β as well as MMP-3 and may act as a marker for radiographic progression along with MMP-3. Last, we found SF PACAP levels exhibited an incremental trend after HA injection. These findings confirmed the crucial role of PACAP deficiency in the development of primary knee OA.

Migraine is one of the most disabling diseases that continues to pose a significant societal burden. Although there are now treatment options for people with migraine, it remains challenging to identify them as clinical features are diverse and complex, and there are no validated diagnostic or treatment prediction biomarkers. Identification is based on either diagnostic coding or the use of certain acute headache abortive treatments. However, socioeconomic disparities can contribute to under-diagnosis and under-treatment of migraine. Thus, efforts to find biomarkers to identify individuals with migraine and which variables could explain migraine-related chronification and disability are warranted. We aimed to investigate the levels of migraine inducing neuropeptides; calcitonin gene-related peptide (CGRP) and pituitary adenylate cyclase-activating polypeptide (PACAP) in peripheral blood samples as potential biomarkers of migraine. We developed highly sensitive assays for CGRP and PACAP on the MSD S-PLEX assay platform and used them for bioanalysis of preclinical and clinical samples. Wildtype and neuropeptide challenged mice and rats were profiled using the developed assay. To follow-up, commercially obtained plasma samples from healthy controls and migraineurs were initially profiled. Subsequently, we profiled plasma samples from people with migraine (during and after a headache attack and healthy controls. Both MSD S-PLEX assays were transferred to Celerion where they were validated for analysis of clinical samples. Using the highly sensitive PACAP assay, we were able to reliably measure circulating levels of endogenous and administrated PACAP38in mouse and rat plasma. Additionally, using the highly sensitive CGRP assay, we were able to reliably measure circulating levels of endogenous and administrated CGRP in mouse and rat plasma. Furthermore, in the initial human samples, circulating CGRP and PACAP levels were not significantly different in healthy controls compared to people with migraine patients. However, ≥50% people with migraine showed increased circulating CGRP and PACAP levels during their attack period compared to post attack. Overall, people with migraine showed a 3 - 396% increase in one or both neuropeptides during their attack period compared to post attack. Circulating plasma CGRP and PACAP levels in healthy control subjects were consistent with previously measured levels. Our highly sensitive PACAP and CGRP assays were successful in measuring circulating levels of endogenous PACAP38 and CGRP in mouse and rat plasma. Our highly sensitive PACAP and CGRP assays were qualified for measurement of human CGRP and PACAP in healthy control and migraine samples. Plasma CGRP and PACAP levels are elevated in migraineurs during an attack period, and the increased plasma neuropeptide levels during an attack may help the differentiation of migraineurs from non-Migraineurs, or amongst people with migraines to help identify the best treatment for each patient.

Pituitary adenylate cyclase-activating polypeptide (PACAP) in fetal cord blood

Elevated circulating pituitary adenylate cyclase-activating polypeptide (PACAP) levels have been demonstrated to be associated with clinical outcomes of severe traumatic brain injury. The current study aimed to confirm whether elevated plasma PACAP levels are predictive of clinical outcomes of aneurysmal subarachnoid hemorrhage (aSAH). One hundred and eighteen aSAH patients and 118 controls were recruited. Plasma PACAP concentrations were determined using enzyme-linked immunosorbent assay. Patients were followed up until death or completion of 6 months after aSAH. An unfavorable outcome was defined as Glasgow Outcome Scale score of 1-3. The admission PACAP levels were significantly elevated in all patients (296.6 ± 119.7 pg/ml) compared with controls (77.1 ± 17.9 pg/ml, P < 0.001). Plasma PACAP levels were independently associated with clinical severity indicated by World Federation of Neurological Surgeons (WFNS) score (t = 4.745, P < 0.001) and Fisher score (t = 4.239, P < 0.001) using a multivariate linear regression. PACAP was identified as an independent predictor for 6-month mortality [odds ratio (OR), 1.014; 95% confidence interval (CI), 1.005-1.030; P < 0.001] and 6-month unfavorable outcome (OR, 1.012; 95% CI, 1.006-1.028; P < 0.001) and 6-month overall survival (hazard ratio, 1.016; 95% CI, 1.008-1.023; P < 0.001) using a binary logistic regression analysis and a Cox's proportional hazard analysis, respectively. PACAP had similar predictive values compared with WFNS score and Fisher score according to the receiver operating characteristic curve analysis. Higher plasma PACAP levels are associated with clinical severity and long-term prognosis of aSAH patients, and PACAP has potential to be a good prognostic biomarker of aSAH.

The aim of the present article was to investigate the influence of gonadectomy on pituitary adenylate cyclase-activating polypeptide (PACAP) levels in different brain areas. In males, there seems to be an inverse relationship between gonadotropins and PACAP in the brain in the acute phase of castration: PACAP levels decreased in almost all brain areas examined within the first week after castration. In females, such pattern was observed in the hypothalamus, brain stem, and temporal cortex. In the pituitary, levels decreased only on the first day after ovariectomy, and later, as in the thalamus, increases were observed. Although the pattern of change showed gender differences, our results provide further evidence that levels of gonadotropins and possibly gonadotropin-releasing hormone influence PACAP levels and that PACAP is involved in the regulation of gonadal functions.