PACAP protects cerebellar granule neurons against oxidative stress‐induced apoptosis

Vaudry, David; Pamantung, Tommy Ferdinandus; Basille, M.; Rousselle, Cécile; Fournier, Alain; Vaudry, Hubert; Beauvillain, Jean-Claudé; Gonzalez, Bruno J.

doi:10.1046/j.1460-9568.2002.01981.x

Cited by 176 publications

(139 citation statements)

References 50 publications

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“…It is also of interest that GLP-1 appears to exert a cytoprotective action not only in β-cells, but also in neurons [130]. Such findings extend on previous studies demonstrating that PACAP, a neuropeptide related in structure to GLP-1, exerts a neuroprotective effect within the brain [131]. On the basis of these observations, it may be speculated that one unexpected and beneficial therapeutic action of GLP-1 may be its ability to protect against β-cell apoptosis associated with autoimmune destruction (type 1 diabetes) or β-cell exhaustion (type 2 diabetes).…”

Section: G Newly Recognized Growth Factor-like Effects Of Glp-1supporting

confidence: 74%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

124

105

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Glucagon-like peptide-1-(7-36)-amide (GLP-1) is a potent blood glucose-lowering hormone now under investigation for use as a therapeutic agent in the treatment of type 2 (adult onset) diabetes mellitus. GLP-1 binds with high affinity to G protein-coupled receptors (GPCRs) located on pancreatic β-cells, and it exerts insulinotropic actions that include the stimulation of insulin gene transcription, insulin biosynthesis, and insulin secretion. The beneficial therapeutic action of GLP-1 also includes its ability to act as a growth factor, stimulating formation of new pancreatic islets (neogenesis) while slowing b-cell death (apoptosis). GLP-1 belongs to a large family of structurally-related hormones and neuropeptides that include glucagon, secretin, GIP, PACAP, and VIP. Biosynthesis of GLP-1 occurs in the enteroendocrine L-cells of the distal intestine, and the release of GLP-1 into the systemic circulation accompanies ingestion of a meal. Although GLP-1 is inactivated rapidly by dipeptidyl peptidase IV (DDP-IV), synthetic analogs of GLP-1 exist, and efforts have been directed at engineering these peptides so that they are resistant to enzymatic hydrolysis. Additional modifications of GLP-1 incorporate fatty acylation and drug affinity complex (DAC) technology to improve serum albumin binding, thereby slowing renal clearance of the peptides. NN2211, LY315902, LY307161, and CJC-1131 are GLP-1 synthetic analogs that reproduce many of the biological actions of GLP-1, but with a prolonged duration of action. AC2993 (Exendin-4) is a naturally occurring peptide isolated from the lizard Heloderma, and it acts as a high affinity agonist at the GLP-1 receptor. This review summarizes structural features and signal transduction properties of GLP-1 and its cognate b-cell GPCR. The usefulness of synthetic GLP-1 analogs as blood glucose-lowering agents is discussed, and the applicability of GLP-1 as a therapeutic agent for treatment of type 2 diabetes is highlighted. Keywords GLP-1; diabetes mellitus; insulin secretion A. INTRODUCTIONGlucagon-like peptide-1-(7-36)-amide (GLP-1, also known as t-GLP-1 or GLIP) is an intestinally-derived insulinotropic hormone that has attracted considerable attention by virtue of its proven ability to act as a blood glucose lowering agent. The efficacy with which GLP-1 lowers concentrations of blood glucose in type 2 diabetic subjects (adult onset diabetes mellitus) has prompted clinical investigations whereby the therapeutic value of GLP-1 as an antidiabetogenic agent has been substantiated. Earlier studies revealed that © 2003 Bentham Science Publishers Ltd. * Address correspondence to this author at the Department of Physiology and Neuroscience, MSB 442, New York University School of Medicine, 550 First Avenue, NY 10016, New York, USA; Tel: 212-263-5434; Fax: 212-689-9060; holzg01@popmail.med.nyu.edu. NIH Public Access Author ManuscriptCurr Med Chem. Author manuscript; available in PMC 2010 July 29. NIH-PA Author ManuscriptNIH-PA Author Manuscript NIH-PA Author ManuscriptGLP-1 is an ...

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Section: G Newly Recognized Growth Factor-like Effects Of Glp-1supporting

confidence: 74%

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Holz¹,

Chepurny²

2003

CMC

124

105

View full text Add to dashboard Cite

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“…PACAP and BMP-2 are known survival factors for ventral mesencephalic DA neurons that can protect from 6-hydroxydopamine and MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine) (32)(33)(34). ANP can counteract oxidative stress and excess NO (35,36), whereas PARM-1 is implicated in suppression of apoptosis (37). The BMP-inducible antagonists follistatin and chordin were also selectively expressed in the VTA, which indicates active BMP-signaling controlled by autoregulatory feedback loops.…”

Section: Resultsmentioning

confidence: 99%

Molecular basis for catecholaminergic neuron diversity

Grimm

Mueller

Hefti

et al. 2004

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

134

141

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Catecholaminergic neurons control diverse cognitive, motor, and endocrine functions and are associated with multiple psychiatric and neurodegenerative disorders. We present global gene-expression profiles that define the four major classes of dopaminergic (DA) and noradrenergic neurons in the brain. Hypothalamic DA neurons and noradrenergic neurons in the locus coeruleus display distinct group-specific signatures of transporters, channels, transcription, plasticity, axon-guidance, and survival factors. In contrast, the transcriptomes of midbrain DA neurons of the substantia nigra and the ventral tegmental area are closely related with <1% of differentially expressed genes. Transcripts implicated in neural plasticity and survival are enriched in ventral tegmental area neurons, consistent with their role in schizophrenia and addiction and their decreased vulnerability in Parkinson's disease. The molecular profiles presented provide a basis for understanding the common and population-specific properties of catecholaminergic neurons and will facilitate the development of selective drugs.C atecholaminergic (CA) neurons producing the neurotransmitters dopamine (DA) and noradrenalin (NA) are organized in anatomically discrete groups and constitute Ϸ1 of 10 7 cells in the vertebrate CNS (1, 2). The most prominent groups of DA neurons reside in the substantia nigra (SN; A9 cell group; Ϸ10,000 neurons in the rat) and the ventral tegmental area (VTA; A10; Ϸ25,000 neurons) of the midbrain. The SN neurons provide the nigrostriatal ascending inputs to the telencephalon and comprise a key component of the extrapyramidal motor system controlling postural reflexes and initiation of movement. DA neurons in the adjacent VTA give rise to mesocortical and mesolimbic pathways that are implicated in control of emotional balance, reward-associated behavior, attention, and memory. Additional groups of DA neurons reside in the medial zona incerta of the hypothalamus (A13; Ϸ900 neurons) and participate in the regulation of endocrine functions. The largest collection of NA neurons resides in the pontine locus coeruleus (LC; Ϸ1,500 neurons). These neurons form a modulatory projection system to most CNS areas and contribute to the regulation of emotional status, sensory perception, arousal, sleepwake patterns, and most autonomic functions.Consistent with their varied functions, the CA neurons are associated with multiple neurodegenerative, psychiatric, and endocrine disorders. Selective degeneration of DA neurons in the SN but not in the VTA or the hypothalamus leads to Parkinson's disease (PD) (3-7), whereas abnormal function of the VTA DA neurons has been linked to schizophrenia, attention deficit, addiction, and hyperactivity disorders (8-11). In addition, dysfunction of hypothalamic DA neurons can cause hyperprolactinemia, an endocrine disorder of the reproductive system (12), whereas changes in the activity of the NA system have been linked to depression as well as sleep disorders (13,14).The drugs currently available for therapy reflec...

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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).…”

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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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PACAP protects cerebellar granule neurons against oxidative stress‐induced apoptosis

Cited by 176 publications

References 50 publications

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Glucagon-Like Peptide-1 Synthetic Analogs: New Therapeutic Agents for Use in the Treatment of Diabetes Mellitus

Molecular basis for catecholaminergic neuron diversity

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

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