Effects of PACAP on in vitro and in vivo neuronal cell death, platelet aggregation, and production of reactive oxygen radicals

Reglődi, Dóra; Fábián, Zsolt; Tamás, Andrea; Lubics, Andrea; Szeberényi, József; Alexy, Tamás; Tóth, Kálmán; Márton, Zsolt; Borsiczky, Balázs; Röth, Erzsébet; Szalontay, Luca; Lengvári, Istvàn

doi:10.1016/j.regpep.2004.05.012

Cited by 34 publications

(25 citation statements)

References 38 publications

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“…Among its roles as a neurotransmitter and determinant of neuronal phenotype, it has several general neuroprotective actions: decreased oxidative stress, increased output of neurotrophic compounds by astrocytes, prevention of inflammation, and the attenuation of apoptosis (Delgado, et al 2002, Vaudry, et al 2002, Delgado, et al 2003, Vaudry, et al 2003, Reglodi, et al 2004a, Yang, et al 2006, Masmoudi-Kouki, et al 2007). In reference to midbrain dopamine pathways, PACAP38 has demonstrated neuroprotective properties in the 6-hydroxydopamine model of Parkinson's disease and PAC1, the receptor with the highest affinity for PACAP38, is present in high concentration in the nigrostriatal cell bodies and terminals (Vaudry, et al 2000, Reglodi, et al 2004b).…”

Section: Discussionmentioning

confidence: 99%

“…Many studies investigating PACAP38 as a neuroprotective agent have utilized either a cell culture system or a direct infusion into the central nervous system immediately before or a short time after a challenge (Morio, et al 1996, Reglodi, et al 2000, Brenneman, et al 2002, Dohi, et al 2002, Onoue, et al 2002a, Onoue, et al 2002b, Reglodi, et al 2004a). However, most intriguing from the standpoint of neurological therapeutic development is that systemic administration of PACAP38 can have central nervous system effects by crossing the bloodbrain barrier (BBB) via a saturable transporter (Banks, et al 1993, Dogrukol-Ak, et al 2004).…”

Section: Discussionmentioning

confidence: 99%

“…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. Furthermore, PACAP38 has in vivo neuroprotective activity as well in models of traumatic brain injury, and focal as well as global ischemia (Uchida, et al 1996, Reglodi, et al 2002, Farkas, et al 2004, Reglodi, et al 2004a. These properties make PACAP38 and its signaling pathways interesting therapeutic targets for the treatment and prevention of neurological disease.…”

Section: Introductionmentioning

confidence: 99%

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

Guillot

Richardson

et al. 2008

Neuropeptides

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Pituitary adenylyl cyclase activating polypeptide, 38 amino acids (PACAP38) is a brain-gut peptide with diverse physiological functions and is neuroprotective in several models of neurological disease. In this study, we show that systemic administration of PACAP38, which is transported across the blood-brain barrier, greatly reduces the neurotoxicity of methamphetamine (METH). Mice treated with PACAP38 exhibited an attenuation of striatal dopamine loss after METH exposure as well as greatly reduced markers of oxidative stress. PACAP38 treatment also prevented striatal neuroinflammation after METH administration as measured by overexpression of glial fibrillary acidic protein (GFAP), an indicator of astrogliosis, and glucose transporter 5 (GLUT5), a marker of microgliosis. In PACAP38 treated mice, the observed protective effects were not due to an altered thermal response to METH. Since the mice were not challenged with METH until 28 days after PACAP38 treatment, this suggests the neuroprotective effects are mediated by regulation of gene expression. At the time of METH administration, PACAP38 treated animals exhibited a preferential increase in the expression and function of the vesicular monoamine transporter (VMAT2). Genetic reduction of VMAT2 has been shown to increase the neurotoxicity of METH, thus we propose that the increased expression of VMAT2 may underlie the protective actions of PACAP38 against METH. The ability of PACAP38 to increase VMAT2 expression suggests that PACAP38 signaling pathways may constitute a novel therapeutic approach to treat and prevent disorders of dopamine storage.

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

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

Guillot

Richardson

et al. 2008

Neuropeptides

View full text Add to dashboard Cite

show abstract

“…These studies suggest that PACAP has anti-oxidant effects via indirect action of mechanism, through stimulating endogenous antioxidant capacity. This hypothesis is also supported by the observation that direct scavenging action of PACAP can only be observed at very high (micromolar) concentrations of the peptide [ 46 ].…”

Section: Effects Of Exogenous Pacap In Small Bowel Ischemia-reperfusimentioning

confidence: 64%

Protective Intestinal Effects of Pituitary Adenylate Cyclase Activating Polypeptide

Horváth

Illés

Heimesaat

et al. 2016

Current Topics in Neurotoxicity

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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 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 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.

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“…However, the results remained unsatisfactory due in part to the molecular selectivity of the blood-brain barrier (BBB), which prevented the crossing of most drugs investigated for the treatment of this disease, or because they only targeted one aspect of the disease. In this context, the pituitary adenylate cyclase-activating polypeptide (PACAP) is a promising molecule for the development of a therapeutic strategy to cure a neurodegenerative disease such as PD, because it crosses the BBB and exhibits anti-apoptotic, anti-inflammatory and anti-oxidant activities (Nishimoto et al, 2007;Ravni et al, 2006;Reglodi et al, 2004a;Shioda et al, 2006). Indeed, PACAP has been shown to exert neuroprotective effects in experimental models of neurodegeneration, cerebral ischemia and brain injuries (Deguil et al, 2007;Lazarovici et al, 2012;Lee and Seo, 2014;Rat et al, 2011;Reglodi et al, 2011;Tamas et al, 2012).…”

Section: Introductionmentioning

confidence: 99%

Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model

et al. 2016

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Effects of PACAP on in vitro and in vivo neuronal cell death, platelet aggregation, and production of reactive oxygen radicals

Cited by 34 publications

References 38 publications

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

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

Protective Intestinal Effects of Pituitary Adenylate Cyclase Activating Polypeptide

Characterizations of a synthetic pituitary adenylate cyclase-activating polypeptide analog displaying potent neuroprotective activity and reduced in vivo cardiovascular side effects in a Parkinson's disease model

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