31 research outputs found
Protective Intestinal Effects of Pituitary Adenylate Cyclase Activating Polypeptide
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 infl uences secretion of intestinal glands, blood
fl ow, and smooth muscle contraction. PACAP is a well-known cytoprotective peptide
with strong anti-apoptotic, anti-infl ammatory, 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 ischemiaâreperfusion 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 fi nding 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 infl ammatory 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 proinfl ammatory
cytokines. We completed the present review with recent clinical results obtained
in patients suffering from infl ammatory 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 infl ammatory events of the intestine
Histological Evaluation of Diabetic Neurodegeneration in the Retina of Zucker Diabetic Fatty (ZDF) Rats
In diabetes, retinal dysfunctions exist prior to clinically detectable vasculopathy, however the pathology behind these functional deficits is still not fully established. Previously, our group published a detailed study on the retinal histopathology of type 1 diabetic (T1D) rat model, where specific alterations were detected. Although the majority of human diabetic patients have type 2 diabetes (T2D), similar studies on T2D models are practically absent. To fill this gap, we examined Zucker Diabetic Fatty (ZDF) rats - a model for T2D - by immunohistochemistry at the age of 32 weeks. Glial reactivity was observed in all diabetic specimens, accompanied by an increase in the number of microglia cells. Prominent outer segment degeneration was detectable with changes in cone opsin expression pattern, without a decrease in the number of labelled elements. The immunoreactivity of AII amacrine cells was markedly decreased and changes were detectable in the number and staining of some other amacrine cell subtypes, while most other cells examined did not show any major alterations. Overall, the retinal histology of ZDF rats shows a surprising similarity to T1D rats indicating that despite the different evolution of the disease, the neuroretinal cells affected are the same in both subtypes of diabetes
Effects of PACAP on intracellular signaling pathways in human retinal pigment epithelial cells exposed to oxidative stress
Abstract The integrity of retinal pigment epithelial cells is critical for photoreceptor survival and vision. Pituitary adenylate cyclase activating polypeptide (PACAP) exerts retinoprotective effects against several types of injuries in vivo, including optic nerve transection, retinal ischemia, excitotoxic injuries, UVA-induced lesion, and diabetic retinopathy. In a recent study, we have proven that PACAP is also protective in oxidative stress-induced injury in human pigment epithelial cells (ARPE-19 cells). The aim of the present study was to investigate the possible mechanisms of this protection. ARPE cells were exposed to a 24-h hydrogen peroxide treatment. Expressions of kinases and apoptotic markers were studied by complex array kits and Western blot. Oxidative stress induced the activation of several apoptotic markers, including Bad, Bax, HIF-1α, several heat shock proteins, TNF-related apoptosis-inducing ligand, and Fas-associated protein with death domain, while PACAP treatment decreased them. The changes in the expression of MAP kinases showed that PACAP activated the protective ERK1/2 and downstream CREB, and decreased the activation of the pro-apoptotic p38MAPK and c-Jun N-terminal kinase, an effect opposite to that observed with only oxidative stress. Furthermore, PACAP increased the activation of the protective Akt pathway. In addition, the effects of oxidative stress on several other signaling molecules were counteracted by PACAP treatment (Chk2, Yes, Lyn, paxillin, p53, PLC, STAT4, RSK). These play a role in cell death, cell cycle, inflammation, adhesion, differentiation and proliferation. In summary, PACAP, acting at several levels, influences the balance between pro-and antiapoptotic factors in favor of anti-apoptosis, thereby providing protection in oxidative stress-induced injury of human retinal pigment epithelial cells
Mice deficient in pituitary adenylate cyclase activating polypeptide (PACAP) are more susceptible to retinal ischemic injury in vivo
Pituitary adenylate cyclase activating polypeptide (PACAP) is a neuroprotective peptide exerting protective effects in neuronal injuries. We have provided evidence that PACAP is neuroprotective in several models of retinal degeneration in vivo. Our previous studies showed that PACAP treatment ameliorated the damaging effects of chronic hypoperfusion modeled by permanent bilateral carotid artery occlusion. We have also demonstrated in earlier studies that treatment with PACAP antagonists further aggravates retinal lesions. It has been shown that PACAP deficient mice have larger infarct size in cerebral ischemia. The aim of this study was to compare the degree of retinal damage in wild type and PACAP deficient mice in ischemic retinal insult. Mice underwent 10 min of bilateral carotid artery occlusion followed by 2-wk reperfusion period. Retinas were then processed for histol. anal. It was found that PACAP deficient mice had significantly greater retinal damage, as shown by the thickness of the whole retina, the morphometric anal. of the individual retinal layers, and the cell nos. in the inner nuclear and ganglion cell layers. Exogenous PACAP administration could partially protect against retinal degeneration in PACAP deficient mice. These results clearly show that endogenous PACAP reacts as a stress-response peptide that is necessary for endogenous protection against different retinal insults. [on SciFinder(R)
Changes in metabolic and muscle damage indicators following a single bout of jump training on stair versus at level
We hypothesized that stair-jump exercise would induce less muscle damage and greater acute metabolic responses than level-jumps
The Protective Role of PAC1-Receptor Agonist Maxadilan in BCCAO-Induced Retinal Degeneration
A number of studies have proven that pituitary adenylate cyclase activating polypeptide (PACAP) is protective in neurodegenerative diseases. Permanent bilateral common carotid artery occlusion (BCCAO) causes severe degeneration in the rat retina. In our previous studies, protective effects were observed with PACAP1-38, PACAP1-27 and VIP, but not with their related peptides, glucagon or secretin in BCCAO. All three PACAP receptors (PAC1, VPAC1, VPAC2) appear in the retina. Molecular and immunohistochemical analysis demonstrated that the retinoprotective effects are most probably mainly mediated by the PAC1 receptor. The aim of the present study was to investigate the retinoprotective effects of a selective PAC1-receptor agonist maxadilan in BCCAO-induced retinopathy. Wistar rats were used in the experiment. After performing BCCAO, the right eye was treated with intravitreal maxadilan (0.1 ΌM or 1 ΌM), while the left eye was injected with vehicle. Sham-operated rats received the same treatment. Two weeks after the operation, retinas were processed for standard morphometric- and molecular analysis. Intravitreal injection of 0.1 ΌM or 1 ΌM maxadilan caused significant protection in the thickness of most retinal layers and the number of cells in the GCL compared to the BCCAO-operated eyes. In addition, 1 ΌM maxadilan application was more effective than 0.1 ΌM maxadilan treatment in the ONL, INL, IPL, and the entire retina (OLM-ILM). Maxadilan treatment significantly decreased cytokine expressions (CINC-1, IL-1α and L-selectin) in ischemia. In summary, our histological and molecular analysis showed that maxadilan, a selective PAC1 receptor agonist, has a protective role in BCCAO-induced retinal degeneration, further supporting the role of PAC1 receptor conveying the retinoprotective effects of PACAP
PACAP is an endogenous protective factor - insights from PACAP-deficient mice
Pituitary adenylate cyclase-activating polypeptide (PACAP) is a
widespread neuropeptide with a diverse array of biological
functions. Not surprisingly, the lack of endogenous PACAP
therefore results in a variety of abnormalities. One of the
important effects of PACAP is its neuroprotective and general
cytoprotective role. PACAP protects neurons and other tissues
against ischemic, toxic, and traumatic lesions. Data obtained
from PACAP-deficient mice provide evidence that endogenous
PACAP also has protective functions. Mice lacking PACAP are more
vulnerable to different in vitro and in vivo insults. The
present review summarizes data on the increased sensitivity of
PACAP-deficient mice against harmful stimuli. Mice lacking PACAP
respond with a higher degree of injury in cerebral ischemia,
autoimmune encephalomyelitis, and axonal lesion. Retinal
ischemic and excitotoxic injuries also produce increased cell
loss in PACAP-deficient mice. In peripheral organs, kidney cell
cultures from PACAP-deficient mice are more sensitive to
oxidative stress and in vitro hypoxia. In vivo, PACAP-deficient
mice have a negative histological outcome and altered cytokine
response in kidney and small intestine ischemia/reperfusion
injury. Large intestinal inflammation, toxic lesion of the
pancreas, and doxorubicin-induced cardiomyopathy are also more
severe with a lack of endogenous PACAP. Finally, an increased
inflammatory response has been described in subacute endotoxin-
induced airway inflammation and in an oxazolone-induced allergic
contact dermatitis model. In summary, lack of endogenous PACAP
leads to higher vulnerability in a number of injuries in the
nervous system and peripheral organs, supporting the hypothesis
that PACAP is part of the endogenous cytoprotective machinery