The neuropeptide PACAP attenuates β-amyloid (1–42)-induced toxicity in PC12 cells

Onoue, Satomi; Endo, Kazuhira; Ohshima, Keiichi; Yajima, Takeaki; Kashimoto, Kazuhisa

doi:10.1016/s0196-9781(02)00085-2

Cited by 106 publications

(83 citation statements)

References 42 publications

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“…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 can attenuate hydrogen peroxide toxicity, while cells from mutant animals that do not express PACAP38 are more sensitive to oxidative damage (Vaudry, et al 2002, Vaudry, et al 2005). 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.…”

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: Introductionmentioning

confidence: 99%

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

Guillot

Richardson

et al. 2008

Neuropeptides

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“…Various in vitro studies involving exposure to ␤-amyloid (14), ceramide (15,16), hydroxyl peroxide (17), and ethanol (18,19) have indicated that the neurotrophic PACAP signaling pathway is increased or activated by means of phosphorylation of the extracellular signal-regulated kinase (ERK) type of mitogenactivated protein kinase (15)(16)(17), phosphatidylinositol 3Ј-OH kinase (18), and protein kinase A (18,20) but is decreased or inhibited by means of the phosphorylation of cJun N-terminal kinase (JNK) (15) and the caspases cascade (14,17). PACAP suppresses cell death indirectly by the induction of BDNF in neuronal culture by glutamate toxicity (21,22).…”

mentioning

confidence: 99%

Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6

Ohtaki

Nakamachi

Dohi

et al. 2006

Proc. Natl. Acad. Sci. U.S.A.

182

192

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Pituitary adenylate cyclase-activating polypeptide (PACAP) has been reported to decrease ischemic neuronal damage and increase IL-6 secretion in rats. However, the mechanisms underlying neuroprotection are still to be fully elucidated. The present study was designed to investigate the role played by PACAP and IL-6 in mediating neuroprotection after ischemia in a null mouse. Infarct volume, neurological deficits, and cytochrome c in cytoplasm were higher in PACAP ؉/؊ and PACAP ؊/؊ mice than in PACAP ؉/؉ animals after focal ischemia, although the severity of response was ameliorated by the injection of PACAP38. A decrease in mitochondrial bcl-2 was also accentuated in PACAP ؉/؊ and PACAP ؊/؊ mice, but the decrease could be prevented by PACAP38 injection. PACAP receptor 1 (PAC1R) immunoreactivity was colocalized with IL-6 immunoreactivity in neurons, although the intensity of IL-6 immunoreactivity in PACAP ؉/؊ mice was less than that in PACAP ؉/؉ animals. IL-6 levels increased in response to PACAP38 injection, an effect that was canceled by cotreatment with the PAC1R antagonist. However, unlike in wild-type controls, PACAP38 treatment did not reduce the infarction in IL-6 null mice. To clarify the signaling pathway associated with the activity of PACAP and IL-6, phosphorylated STAT (signal transducer and activator of transcription) 3, ERK (extracellular signal-regulated kinase), and AKT levels were examined in PACAP ؉/؊ and IL-6 null mice after ischemia. Lower levels of pSTAT3 and pERK were observed in the PACAP ؉/؊ mice, whereas a reduction in pSTAT3 was recorded in the IL-6 null mice. These results suggest that PACAP prevents neuronal cell death after ischemia via a signaling mechanism involving IL-6.bcl-2 ͉ extracellular signal-regulated kinase ͉ ischemia ͉ pituitary adenylate cyclase-activating polypeptide-specific receptor ͉ signal transducer and activator of transcription 3

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“…In cortical neurons, PACAP can also prevent the neurotoxic effect of other insults such as lipopolysaccharide (Kong et al, 1999), and in mesencephalic dopaminergic neurons PACAP can counteract the neurotoxic effect of 6-hydroxydopamine (Takei et al, 1998). In a study relevant to AD, it was shown that PACAP can protect PC12 cells against death induced by amyloid β-peptide (Onoue et al, 2002). These results again confirm the potential therapeutic benefits of pharmacological modulation of PACAP receptors for neurodegenerative disorders.…”

Section: Pituitary Adenylate Cyclase Activating Peptide (Pacap)mentioning

confidence: 53%

Class II G Protein-Coupled Receptors and Their Ligands in Neuronal Function and Protection

Martin

Maturana²,

Brenneman

et al. 2005

NMM

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G protein-coupled receptors (GPCRs) play pivotal roles in regulating the function and plasticity of neuronal circuits in the nervous system. Among the myriad of GPCRs expressed in neural cells, class II GPCRs which couples predominantly to the Gs-adenylate cyclase-cAMP signaling pathway, have recently received considerable attention for their involvement in regulating neuronal survival. Neuropeptides that activate class II GPCRs include secretin, glucagon-like peptides (GLP-1 and GLP-2), growth hormone-releasing hormone (GHRH), pituitary adenylate cyclase activating peptide (PACAP), corticotropin-releasing hormone (CRH), vasoactive intestinal peptide (VIP), parathyroid hormone (PTH), and calcitonin-related peptides. Studies of patients and animal and cell culture models, have revealed possible roles for class II GPCRs signaling in the pathogenesis of several prominent neurodegenerative conditions including stroke, Alzheimer's, Parkinson's, and Huntington's diseases. Many of the peptides that activate class II GPCRs promote neuron survival by increasing the resistance of the cells to oxidative, metabolic, and excitotoxic injury. A better understanding of the cellular and molecular mechanisms by which class II GPCRs signaling modulates neuronal survival and plasticity will likely lead to novel therapeutic interventions for neurodegenerative disorders.

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The neuropeptide PACAP attenuates β-amyloid (1–42)-induced toxicity in PC12 cells

Cited by 106 publications

References 42 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

Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6

Class II G Protein-Coupled Receptors and Their Ligands in Neuronal Function and Protection

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