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Inhibitory Effect of PACAP on Caspase Activity in Neuronal Apoptosis: A Better Understanding Towards Therapeutic Applications in Neurodegenerative Diseases

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Abstract

Programmed cell death, which is part of the normal development of the central nervous system, is also implicated in various neurodegenerative disorders. Cysteine-dependent aspartate-specific proteases (caspases) play a pivotal role in the cascade of events leading to apoptosis. Many factors that inhibit cell death have now been identified, but the underlying mechanisms are not fully understood. Pituitary adenylate cylase-activating polypeptide (PACAP) has been shown to exert neurotrophic activities during development and to prevent neuronal apoptosis induced by various insults such as ischemia. Most of the neuroprotective effects of PACAP are mediated through the PAC1 receptor. This receptor activates a transduction cascade of second messengers to stimulate Bcl-2 expression, which inhibits cytochrome c release and blocks the activation of caspases. The inhibitory effect of PACAP on the apoptotic cascade suggests that selective, stable, and potent PACAP derivatives could potentially be of therapeutic value for the treatment of post-traumatic and/or chronic neurodegenerative processes.

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References

  • Acehan, D., Jiang, X., Morgan, D. G., Heuser, J. E., Wang, X., & Akey, C. W. (2002). Three-dimensional structure of the apoptosome: implications for assembly, procaspase-9 binding, and activation. Molecular Cell, 9, 423–432.

    PubMed  CAS  Google Scholar 

  • Adams, J. M., & Cory, S. (1998). The Bcl-2 protein family: Arbiters of cell survival. Science, 281, 1322–1326.

    PubMed  CAS  Google Scholar 

  • Ahmad, M., Srinivasula, S. M., Wang, L., et al. (1997). CRADD, a novel human apoptotic adaptor molecule for caspase-2, and FasL/tumor necrosis factor receptor-interacting protein RIP. Cancer Research, 57, 615–619.

    PubMed  CAS  Google Scholar 

  • Allais, A., Burel, D., Isaac, E. R., et al. (2007). Altered cerebellar development in mice lacking pituitary adenylate cyclase-activating polypeptide. European Journal of Neuroscience, 25, 2604–2618.

    PubMed  Google Scholar 

  • Allen, J. W., Eldadah, B. A., Huang, X., Knoblach, S. M., & Faden, A. I. (2001). Multiple caspases are involved in beta-amyloid-induced neuronal apoptosis. Journal of Neuroscience Research, 65, 45–53.

    PubMed  CAS  Google Scholar 

  • Alnemri, E. S., Livingston, D. J., Nicholson, D. W., et al. (1996). Human ICE/CED-3 protease nomenclature. Cell, 87, 171.

    PubMed  CAS  Google Scholar 

  • Arimura, A. (1998). Perspectives on pituitary adenylate cyclase activating polypeptide (PACAP) in the neuroendocrine, endocrine, and nervous systems. Japanese Journal of Physiology, 48, 301–331.

    PubMed  CAS  Google Scholar 

  • Aubert, N., Basille, M., Falluel-Morel, A., et al. (2005). PACAP protects granule cells against apoptosis induced by hypoxia in monkey cerebellum slices. Regulatory Peptides, 130, 156.

    Google Scholar 

  • Aubert, N., Falluel-Morel, A., Vaudry, D., et al. (2006). PACAP and C2-ceramide generate different AP-1 complexes through a MAP-kinase-dependent pathway: Involvement of c-Fos in PACAP-induced Bcl-2 expression. Journal of Neurochemistry, 99, 1237–1250.

    PubMed  CAS  Google Scholar 

  • Banks, W. A., Kastin, A. J., Komaki, G., & Arimura, A. (1993). Passage of pituitary adenylate cyclase activating polypeptide1–27 and pituitary adenylate cyclase activating polypeptide1–38 across the blood–brain barrier. Journal of Pharmacology and Experimental Therapeutics, 26777, 690–696.

    Google Scholar 

  • Basille, M., Gonzalez, B. J., Fournier, A., & Vaudry, H. (1994). Ontogeny of pituitary adenylate cyclase-activating polypeptide (PACAP) receptors in the rat cerebellum: A quantitative autoradiographic study. Developmental Brain Research, 82, 81–89.

    PubMed  CAS  Google Scholar 

  • Basille, M., Gonzalez, B. J., Leroux, P., Jeandel, L., Fournier, A., & Vaudry, H. (1993). Localization and characterization of PACAP receptors in the rat cerebellum during development: Evidence for a stimulatory effect of PACAP on immature cerebellar granule cells. Neuroscience, 57, 329–338.

    PubMed  CAS  Google Scholar 

  • Beebe, X., Darczak, D., Davis-Taber, R. A., et al. (2008). Discovery and SAR of hydrazide antagonists of the pituitary adenylate cyclase-activating polypeptide (PACAP) receptor type 1 (PAC(1)-R). Bioorganic & Medicinal Chemistry Letters, 18, 2162–2166.

    CAS  Google Scholar 

  • Bhave, S. V., & Hoffman, P. L. (2004). Phosphatidylinositol 3′-OH kinase and protein kinase A pathways mediate the anti-apoptotic effect of pituitary adenylyl cyclase-activating polypeptide in cultured cerebellar granule neurons: Modulation by ethanol. Journal of Neurochemistry, 88, 359–369.

    Article  PubMed  CAS  Google Scholar 

  • Birk, S., Sitarz, J. T., Petersen, K. A., et al. (2007). The effect of intravenous PACAP38 on cerebral hemodynamics in healthy volunteers. Regulatory Peptides, 140, 185–191.

    PubMed  CAS  Google Scholar 

  • Bourgault, S., Vaudry, D., Botia, B., et al. (2008). Novel stable PACAP analogs with potent activity towards the PAC1 receptor. Peptides, in press, DOI 10.1016/j.peptides.2008.01.022.

  • Braun, J. S., Prass, K., Dirnagl, U., Meisel, A., & Meisel, C. (2007). Protection from brain damage and bacterial infection in murine stroke by the novel caspase-inhibitor Q-VD-OPH. Experimental Neurology, 206, 183–191.

    PubMed  CAS  Google Scholar 

  • Cameron, D. B., Galas, L., Jiang, Y., Raoult, E., Vaudry, D., & Komuro, H. (2007). Cerebellar cortical-layer-specific control of neuronal migration by pituitary adenylate cyclase-activating polypeptide. Neuroscience, 146, 697–712.

    PubMed  CAS  Google Scholar 

  • Cao, G., Luo, Y., Nagayama, T., et al. (2002). Cloning and characterization of rat caspase-9: implications for a role in mediating caspase-3 activation and hippocampal cell death after transient cerebral ischemia. Journal of Cerebral Blood Flow and Metabolism, 22, 534–546.

    PubMed  CAS  Google Scholar 

  • Cavallaro, S., Copani, A., D’Agata, V., et al. (1996). Pituitary adenylate cyclase activating polypeptide prevents apoptosis in cultured cerebellar granule neurons. Molecular Pharmacology, 50, 60–66.

    PubMed  CAS  Google Scholar 

  • Chang, J. Y., Korolev, V. V., & Wang, J. Z. (1996). Cyclic AMP and pituitary adenylate cyclase-activating polypeptide (PACAP) prevent programmed cell death of cultured rat cerebellar granule cells. Neuroscience Letters, 206, 181–184.

    PubMed  CAS  Google Scholar 

  • Chang, H. Y., & Yang, X. (2000). Proteases for cell suicide: Functions and regulation of caspases. Microbiology and Molecular Biology Reviews, 64, 821–846.

    PubMed  CAS  Google Scholar 

  • Chauvier, D., Lecoeur, H., Langonne, A., et al. (2005). Upstream control of apoptosis by caspase-2 in serum-deprived primary neurons. Apoptosis, 10, 1243–1259.

    PubMed  CAS  Google Scholar 

  • Chen, J., Nagayama, T., Jin, K., et al. (1998). Induction of caspase-3-like protease may mediate delayed neuronal death in the hippocampus after transient cerebral ischemia. Journal of Neuroscience, 18, 4914–4928.

    PubMed  CAS  Google Scholar 

  • Chen, Y., Samal, B., Hamelink, C. R., et al. (2006). Neuroprotection by endogenous and exogenous PACAP following stroke. Regulatory Peptides, 137, 4–19.

    PubMed  CAS  Google Scholar 

  • Chen, W. H., & Tzeng, S. F. (2005). Pituitary adenylate cyclase-activating polypeptide prevents cell death in the spinal cord with traumatic injury. Neuroscience Letters, 384, 117–121.

    PubMed  CAS  Google Scholar 

  • Clark, R. S. B., Kochanek, P. M., Chen, M., et al. (1999). Increases in Bcl-2 and cleavage of caspase-1 and caspase-3 in human brain after head injury. FASEB Journal, 13, 813–821.

    PubMed  CAS  Google Scholar 

  • Clark, R. S. B., Kochanek, P. M., Watkins, S. C., et al. (2000). Caspase-3 mediated neuronal death after traumatic brain injury in rats. Journal of Neurochemistry, 74, 740–753.

    PubMed  CAS  Google Scholar 

  • Datta, S. R., Dudek, H., Tao, X., et al. (1997). Akt phosphorylation of BAD couples survival signals to the cell-intrinsic death machinery. Cell, 91, 231–241.

    PubMed  CAS  Google Scholar 

  • Davoli, M. A., Fourtounis, J., Tam, J., et al. (2002). Immunohistochemical and biochemical assessment of caspase-3 activation and DNA fragmentation following transient focal ischemia in the rat. Neuroscience, 115, 125–136.

    PubMed  CAS  Google Scholar 

  • Dejda, A., Sokolowska, P., & Nowak, J. Z. (2005). Neuroprotective potential of three neuropeptides PACAP, VIP and PHI. Pharmacological Reports, 57, 307–320.

    PubMed  CAS  Google Scholar 

  • Deveraux, Q. L., Takahashi, R., Salvesen, G. S., & Reed, J. C. (1997). X-linked IAP is a direct inhibitor of cell-death proteases. Nature, 388, 300–304.

    PubMed  CAS  Google Scholar 

  • Doberer, D., Gschwandtner, M., Mosgoeller, W., Bieglmayer, C., Heinzl, H., & Petkov, V. (2007). Pulmonary and systemic effects of inhaled PACAP38 in healthy male subjects. European Journal of Clinical Investigation, 37, 665–672.

    PubMed  CAS  Google Scholar 

  • Dohi, K., Mizushima, H., Nakajo, S., et al. (2002). Pituitary adenylate cyclase-activating polypeptide (PACAP) prevents hippocampal neurons from apoptosis by inhibiting JNK/SAPK and p38 signal transduction pathways. Regulatory Peptides, 109, 83–88.

    PubMed  CAS  Google Scholar 

  • Downward, J. (1999). How BAD phosphorylation is good for survival. Nature Cell Biology, 1, 33–35.

    Google Scholar 

  • Duan, H., & Dixit, V. M. (1997). RAIDD is a new ‘death’ adaptor molecule. Nature, 385, 86–89.

    PubMed  CAS  Google Scholar 

  • Ellis, H. M., & Horvitz, H. R. (1986). Genetic control of programmed cell death in the nematode C. elegans. Cell, 44, 817–829.

    PubMed  CAS  Google Scholar 

  • Engidawork, E., Gulesserian, T., Yoo, B. C., Cairns, N., & Lubec, G. (2001). Alterations of caspases and apoptosis-related proteins in brains of patients with Alzheimer’s disease. Biochemical and Biophysical Research Communications, 281, 84–93.

    PubMed  CAS  Google Scholar 

  • Falluel-Morel, A., Aubert, N., Vaudry, D., et al. (2004). Opposite regulation of the mitochondrial apoptotic pathway by C2-ceramide and PACAP through a MAP-kinase-dependent mechanism in cerebellar granule cells. Journal of Neurochemistry, 91, 1231–1243.

    PubMed  CAS  Google Scholar 

  • Farkas, O., Tamas, A., Zsombok, A., et al. (2004). Effects of pituitary adenylate cyclase-activating polypeptide in a rat model of traumatic brain injury. Regulatory Peptides, 123, 69–75.

    PubMed  CAS  Google Scholar 

  • Fink, K. B., Andrews, L. J., Butler, W. E., et al. (1999). Reduction of post-traumatic brain injury and free radical production by inhibition of the caspase-1 cascade. Neuroscience, 94, 1213–1218.

    PubMed  CAS  Google Scholar 

  • Friedlander, R. M., Brown, R. H., Gagliardini, V., Wang, J., & Yuan, J. (1997). Inhibition of ICE slows ALS in mice. Nature, 338, 31.

    Google Scholar 

  • Gao, Z., Tian, Y., Wang, J., et al. (2007). A dimeric Smac/diablo peptide directly relieves caspase-3 inhibition by XIAP. Dynamic and cooperative regulation of XIAP by Smac/Diablo. Journal of Biological Chemistry, 282, 30718–30727.

    PubMed  CAS  Google Scholar 

  • Gonzalez, B. J., Basille, M., Vaudry, D., Fournier, A., & Vaudry, H. (1997). Pituitary adenylate cyclase-activating polypeptide promotes cell survival and neurite outgrowth in rat cerebellar neuroblasts. Neuroscience, 78, 419–430.

    PubMed  CAS  Google Scholar 

  • Graf, D., Bode, J. G., & Haussinger, D. (2007). Caspases and receptor cleavage. Archives of Biochemistry and Biophysics, 462, 162–170.

    PubMed  CAS  Google Scholar 

  • Guo, Y., Srinivasula, S. M., Druilhe, A., Fernandes-Alnemri, T., & Alnemri, E. S. (2002). Caspase-2 induces apoptosis by releasing proapoptotic proteins from mitochondria. Journal of Biological Chemistry, 277, 13430–13437.

    PubMed  CAS  Google Scholar 

  • Hakem, R., Hakem, A., Duncan, G. S., et al. (1998). Differential requirement for caspase 9 in apoptotic pathway in vivo. Cell, 94, 339–352.

    PubMed  CAS  Google Scholar 

  • Han, P., & Lucero, M. T. (2005). Pituitary adenylate cyclase activating polypeptide reduces A-type K+ currents and caspase activity in cultured adult mouse olfactory neurons. Neuroscience, 134, 745–756.

    PubMed  CAS  Google Scholar 

  • Hara, H., Fink, K., Endres, M., et al. (1997). Attenuation of transient focal cerebral ischemic injury in transgenic mice expressing a mutant ICE inhibitory protein. Journal of Cerebral Blood Flow and Metabolism, 17, 370–375.

    PubMed  CAS  Google Scholar 

  • Harada, J., & Sugimoto, M. (1999). Activation of caspase-3 in b-amyloid-induced apoptosis of cultured rat cortical neurons. Brain Research, 842, 311–323.

    PubMed  CAS  Google Scholar 

  • Hengartner, M. O., Ellis, R. E., & Horvitz, H. R. (1992). Caenorhabditis elegans gene ced-9 protects cells from programmed cell death. Nature, 356, 494–499.

    PubMed  CAS  Google Scholar 

  • Hermel, E., Gafni, J., Propp, S. S., et al. (2004). Specific caspase interactions and amplification are involved in selective neuronal vulnerability in Huntington’s disease. Cell Death and Differentiation, 11, 424–438.

    PubMed  CAS  Google Scholar 

  • Hitomi, J., Katayama, T., Eguchi, Y., et al. (2004a). Involvement of caspase-4 in endoplasmic reticulum stress-induced apoptosis and Ab-induced cell death. Journal of Cell Biology, 165, 347–356.

    PubMed  CAS  Google Scholar 

  • Hitomi, J., Katayama, T., Taniguchi, M., Honda, A., Imaizumi, K., & Tohyama, M. (2004b). Apoptosis induced by endoplasmic reticulum stress depends on activation of caspase-3 via caspase-12. Neuroscience Letters, 357, 127–130.

    PubMed  CAS  Google Scholar 

  • Inoue, H., Tsukita, K., Iwasato, T., et al. (2003). The crucial role of caspase-9 in the disease progression of a transgenic ALS mouse model. EMBO Journal, 22, 6665–6674.

    PubMed  CAS  Google Scholar 

  • Journot, L., Villalba, M., & Bockaert, J. (1998). PACAP-38 protects cerebellar granule cells from apoptosis. Annals of the New York Academy of Sciences, 865, 100–110.

    PubMed  CAS  Google Scholar 

  • Kang, S. J., Wang, S., Hara, H., et al. (2000). Dual role of caspase-11 in mediating activation of caspase-1 and caspase-3 under pathological conditions. Journal of Cell Biology, 149, 613–622.

    PubMed  CAS  Google Scholar 

  • Kang, S. J., Wang, S., Kuida, K., & Yuan, J. (2002). Distinct downstream pathways of caspase-11 in regulating apoptosis and cytokine maturation during septic shock response. Cell Death and Differentiation, 9, 1115–1125.

    PubMed  CAS  Google Scholar 

  • Katahira, M., Yone, K., Arishima, Y., et al. (2003). The neuroprotective effects of PACAP on spinal cord injury (SCI) in rats. Regulatory Peptides, 115, 49.

    Google Scholar 

  • Kerr, J. F., Wyllie, A. H., & Currie, A. R. (1972). Apoptosis: A basic biological phenomenon with wide-ranging implications in tissue kinetics. British Journal of Cancer, 26, 239–257.

    PubMed  CAS  Google Scholar 

  • Kischkel, F. C., Hellbardt, S., Behrmann, I., et al. (1995). Cytotoxicity-dependent APO-1 (Fas/CD95)-associated proteins form a death-inducing signaling complex (DISC) with the receptor. EMBO Journal, 14, 5579–5588.

    PubMed  CAS  Google Scholar 

  • Klevenyi, P., Andreassen, O., Ferrante, R. J., Schleicher, J. R., Jr., Friendlander, R. M., & Beal, M. F. (1999). Transgenic mice expressing a dominant negative mutant interleukin-1beta converting enzyme show resistance to MPTP neurotoxicity. Neuroreport, 10, 635–638.

    PubMed  CAS  Google Scholar 

  • Kluck, R. M., Bossy-Wetzel, E., Green, D. R., & Newmeyer, D. D. (1997). The release of cytochrome c from mitochondria: A primary site for Bcl-2 regulation of apoptosis. Science, 275, 1132–1136.

    PubMed  CAS  Google Scholar 

  • Knoblach, S. M., Huang, X., VanGelderen, J., Calva-Cerqueira, D., & Faden, A. I. (2005). Selective caspase activation may contribute to neurological dysfunction after experimental spinal cord trauma. Journal of Neuroscience Research, 80, 369–380.

    PubMed  CAS  Google Scholar 

  • Kuida, K., Haydar, T. F., Kuan, C. Y., et al. (1998). Reduced apoptosis and cytochrome c-mediated caspase activation in mice lacking caspase 9. Cell, 94, 325–337.

    PubMed  CAS  Google Scholar 

  • Kuida, K., Zheng, T. S., Na, S., et al. (1996). Decreased apoptosis in the brain and premature lethality in CPP32-deficient mice. Nature, 384, 368–372.

    PubMed  CAS  Google Scholar 

  • Le, D. A., Wu, Y., Huang, Z., et al. (2002). Caspase activation and neuroprotection in caspase-3-deficient mice after in vivo cerebral ischemia and in vitro oxygen glucose deprivation. Proceedings of the National Academy of Sciences of the United States of America, 99, 15188–15193.

    PubMed  CAS  Google Scholar 

  • Lerner, E. A., Ribeiro, J. M., Nelson, R. J., & Lerner, M. R. (1991). Isolation of maxadilan, a potent vasodilatory peptide from the salivary glands of the sand fly Lutzomyia longipalpis. Journal of Biological Chemistry, 266, 11234–11236.

    PubMed  CAS  Google Scholar 

  • Li, M., David, C., Kikuta, T., Somogyvari-Vigh, A., & Arimura, A. (2005). Signaling cascades involved in neuroprotection by subpicomolar pituitary adenylate cyclase-activating polypeptide 38. Journal of Molecular Neuroscience, 27, 91–105.

    PubMed  Google Scholar 

  • Li, M., Maderdrut, J. L., Lertora, J. J., & Batuman, V. (2007). Intravenous infusion of pituitary adenylate cyclase-activating polypeptide (PACAP) in a patient with multiple myeloma and myeloma kidney: a case study. Peptides, 28, 1891–1895.

    PubMed  CAS  Google Scholar 

  • Li, P., Nijhawan, D., Budihardjo, I., et al. (1997). Cytochrome c and dATP-dependent formation of Apaf-1/caspase-9 complex initiates an apoptotic protease cascade. Cell, 91, 479–489.

    PubMed  CAS  Google Scholar 

  • Li, M., Ona, V. O., Chen, M., et al. (2000a). Function role and therapeutic implications of neuronal caspase-1 and -3 in a mouse model of traumatic spinal cord injury. Neuroscience, 99, 333–342.

    PubMed  CAS  Google Scholar 

  • Li, M., Ona, V. O., Guegan, C., et al. (2000b). Functional role of caspase-1 and caspase-3 in ALS transgenic mouse model. Science, 288, 335–339.

    PubMed  CAS  Google Scholar 

  • Liu, H., Chang, D. W., & Yang, X. (2005). Interdimer processing and linearity of procaspase-3 activation. Journal of Biological Chemistry, 280, 11578–11582.

    PubMed  CAS  Google Scholar 

  • Liu, X. H., Kwon, D., Schielke, G. P., Yang, G. Y., Silverstein, F. S., & Barks, J. D. E. (1999). Mice Deficient in Interleukin-1 converting enzyme are resistant to neonatal hypoxic–ischemic brain damage. Journal of Cerebral Blood Flow and Metabolism, 19, 1099–1108.

    PubMed  CAS  Google Scholar 

  • Luo, X., Budihardjo, I., Zou, H., Slaughter, C., & Wang, X. (1998). Bid, a Bcl2 interacting protein, mediates cytochrome c release from mitochondria in response to activation of cell surface death receptors. Cell, 94, 481–490.

    PubMed  CAS  Google Scholar 

  • Luthi, A. U., & Martin, S. J. (2007). The CASBAH: A searchable database of caspase substrates. Cell Death and Differentiation, 14, 641–650.

    PubMed  CAS  Google Scholar 

  • Malagelada, C., Xifro, X., Minano, A., Sabria, J., & Rodriguez-Alvarez, J. (2005). Contribution of caspase-mediated apoptosis to the cell death caused by oxygen-glucose deprivation in cortical cell cultures. Neurobiology of Disease, 20, 27–37.

    PubMed  CAS  Google Scholar 

  • Martin, D. A., Siegel, R. M., Zheng, L., & Lenardo, M. J. (1998). Membrane oligomerization and cleavage activates the caspase-8 (FLICE/MACHalpha1) death signal. Journal of Biological Chemistry, 273, 4345–4349.

    PubMed  CAS  Google Scholar 

  • Masuo, Y., Tokito, F., Matsumoto, Y., Shimamoto, N., & Fujino, M. (1994). Ontogeny of pituitary adenylate cyclase-activating polypeptide (PACAP) and its binding sites in the rat brain. Neuroscience Letters, 170, 43–46.

    PubMed  CAS  Google Scholar 

  • Matsui, T., Ramasamy, K., Ingelsson, M., et al. (2006). Coordinated expression of caspase 8, 3 and 7 mRNA in temporal cortex of Alzheimer disease: Relationship to formic acid extractable abeta42 levels. Journal of Neuropathology and Experimental Neurology, 65, 508–515.

    PubMed  CAS  Google Scholar 

  • Mei, Y. A., Vaudry, D., Basille, M., et al. (2004). PACAP inhibits delayed rectifier potassium current via a cAMP/PKA transduction pathway: Evidence for the involvement of I K in the anti-apoptotic action of PACAP. European Journal of Neuroscience, 19, 1446–1458.

    PubMed  CAS  Google Scholar 

  • Mentlein, R. (1999). Dipeptidyl-peptidase IV (CD26)—role in the inactivation of regulatory peptides. Regulatory Peptides, 85, 9–24.

    PubMed  CAS  Google Scholar 

  • Morio, H., Tatsuno, I., Hirai, A., Tamura, Y., & Saito, Y. (1996). Pituitary adenylate cyclase-activating polypeptide protects rat-cultured cortical neurons from glutamate-induced cytotoxicity. Brain Research, 741, 82–88.

    PubMed  CAS  Google Scholar 

  • Nakagawa, T., Zhu, H., Morishima, N., et al. (2000). Caspase-12 mediates endoplasmic-reticulum-specific apoptosis and cytotoxicity by amyloid-beta. Nature, 403, 98–103.

    PubMed  CAS  Google Scholar 

  • Namura, S., Zhu, J., Fink, K., et al. (1998). Activation and cleavage of caspase-3 in apoptosis induced by experimental cerebral ischemia. Journal of Neuroscience, 18, 3659–3668.

    PubMed  CAS  Google Scholar 

  • Nandha, K. A., Benito-Orfila, M. A., Smith, D. M., Ghatei, M. A., & Bloom, S. R. (1991). Action of pituitary adenylate cyclase-activating polypeptide and vasoactive intestinal polypeptide on the rat vascular system: Effects on blood pressure and receptor binding. Journal of Endocrinology, 129, 69–73.

    Article  PubMed  CAS  Google Scholar 

  • Ni, B., Wu, X., Su, Y., et al. (1998). Transient global forebrain ischemia induces a prolonged expression of the caspase-3 mRNA in rat hippocampal CA1 pyramidal neurons. Journal of Cerebral Blood Flow and Metabolism, 18, 248–256.

    PubMed  CAS  Google Scholar 

  • Niewiadomski, P., Nowak, J. Z., Sedkowska, P., & Zawilska, J. B. (2002). Rapid desensitization of receptors for pituitary adenylate cyclase-activating polypeptide (PACAP) in chick cerebral cortex. Polish Journal of Pharmacology, 54, 717–721.

    PubMed  CAS  Google Scholar 

  • Obeng, E. A., & Boise, L. H. (2005). Caspase-12 and caspase-4 are not required for caspase-dependent endoplasmic reticulum stress-induced apoptosis. Journal of Biological Chemistry, 280, 29578–29587.

    PubMed  CAS  Google Scholar 

  • Ohtaki, H., Nakamachi, T., Dohi, K., et al. (2005). Neuroprotective mechanism of PACAP after focal ischemia in mouse. Regulatory Peptides, 130, 149.

    Google Scholar 

  • Ohtaki, H., Nakamachi, T., Dohi, K., et al. (2006). Pituitary adenylate cyclase-activating polypeptide (PACAP) decreases ischemic neuronal cell death in association with IL-6. Proceedings of the National Academy of Sciences of the United States of America, 103, 7488–7493.

    PubMed  CAS  Google Scholar 

  • Ona, V. O., Li, M., Vonsattel, J. P. G., et al. (1999). Inhibition of caspase-1 slows disease progression in a mouse model of Huntington’s disease. Nature, 399, 263–267.

    PubMed  CAS  Google Scholar 

  • Onoue, S., Endo, K., Ohshima, K., Yajima, T., & Kashimoto, K. (2002a). The neuropeptide PACAP attenuates beta-amyloid (1–42)-induced toxicity in PC12 cells. Peptides, 23, 1471–1478.

    PubMed  CAS  Google Scholar 

  • Onoue, S., Ohshima, K., Endo, K., Yajima, T., & Kashimoto, K. (2002b). PACAP protects neuronal PC12 cells from the cytotoxicity of human prion protein fragment 106–126. FEBS Letters, 522, 65–70.

    PubMed  CAS  Google Scholar 

  • Onyuksel, H., Sejourne, F., Suzuki, H., & Rubinstein, I. (2006). Human VIP-alpha: A long-acting, biocompatible and biodegradable peptide nanomedicine for essential hypertension. Peptides, 27, 2271–2275.

    PubMed  Google Scholar 

  • Peter, M. E., & Krammer, P. H. (2003). The CD95(APO-1/Fas) DISC and beyond. Cell Death and Differentiation, 10, 26–35.

    PubMed  CAS  Google Scholar 

  • Rabuffetti, M., Sciorati, C., Tarozzo, G., Clementi, E., Manfredi, A. A., & Beltramo, M. (2000). Inhibition of caspase-1-like activity by Ac-Tyr-Val-Ala-Asp-chloromethyl ketone induces long-lasting neuroprotection in cerebral ischemia through apoptosis reduction and decrease of proinflammatory cytokines. Journal of Neuroscience, 20, 4398–4404.

    PubMed  CAS  Google Scholar 

  • Racz, B., Gallyas, F., Jr., Kiss, P., et al. (2006). The neuroprotective effects of PACAP in monosodium glutamate-induced retinal lesion involve inhibition of proapoptotic signaling pathways. Regulatory Peptides, 137, 20–26.

    PubMed  CAS  Google Scholar 

  • Rao, R. V., Castro-Obregon, S., Frankowski, H., et al. (2002). Coupling endoplasmic reticulum stress to the cell death program. An Apaf-1-independent intrinsic pathway. Journal of Biological Chemistry, 277, 21836–21842.

    PubMed  CAS  Google Scholar 

  • Reglodi, D., Lubics, A., Tamas, A., Szalontay, L., & Lengvari, I. (2004). Pituitary adenylate cyclase activating polypeptide protects dopaminergic neurons and improves behavioral deficits in a rat model of Parkinson’s disease. Behavioural Brain Research, 151, 303–312.

    PubMed  CAS  Google Scholar 

  • Reglodi, D., Somogyvari-Vigh, A., Vigh, S., Kozicz, T., & Arimura, A. (2000). Delayed systemic administration of PACAP38 is neuroprotective in transient middle cerebral artery occlusion in the rat. Stroke, 31, 1411–1417.

    PubMed  CAS  Google Scholar 

  • Reglodi, D., Tamas, A., Somogyvari-Vigh, A., et al. (2002). Effects of pretreament with PACAP on the infarct size and functional outcome in rat permanent focal cerebral ischemia. Peptides, 23, 2227–2234.

    PubMed  CAS  Google Scholar 

  • Renatus, M., Stennicke, H. R., Scott, F. L., Liddington, R. C., & Salvesen, G. S. (2001). Dimer formation drives the activation of the cell death protease caspase 9. Proceedings of the National Academy of Sciences of the United States of America, 98, 14250–14255.

    PubMed  CAS  Google Scholar 

  • Renolleau, S., Fau, S., Goyenvalle, C., et al. (2007). Specific caspase inhibitor Q-VD-OPh prevents neonatal stroke in P7 rat: A role for gender. Journal of Neurochemistry, 100, 1062–1071.

    PubMed  CAS  Google Scholar 

  • Robberecht, P., Gourlet, P., De Nef, P., et al. (1992). Structural requirements for the occupancy of pituitary adenylate-cyclase-activating-peptide (PACAP) receptors and adenylate cyclase activation in human neuroblastoma NB-OK-1 cell membranes. Discovery of PACAP(6–38) as a potent antagonist. European Journal of Biochemistry, 207, 239–246.

    PubMed  CAS  Google Scholar 

  • Rohn, T. T., Head, E., Nesse, W. H., Cotman, C. W., & Cribbs, D. H. (2001). Activation of caspase-8 in the Alzheimer’s disease brain. Neurobiology of Disease, 8, 1006–1016.

    PubMed  CAS  Google Scholar 

  • Rohn, T. T., Rissman, R. A., Davis, M. C., Kim, Y. E., Cotman, C. W., & Head, E. (2002). Caspase-9 activation and caspase cleavage of tau in the Alzheimer’s disease brain. Neurobiology of Disease, 11, 341–354.

    PubMed  CAS  Google Scholar 

  • Sakamaki, K., Inoue, T., Asano, M., et al. (2002). Ex vivo whole-embryo culture of caspase-8-deficient embryos normalize their aberrant phenotypes in the developing neural tube and heart. Cell Death and Differentiation, 9, 1196–1206.

    PubMed  CAS  Google Scholar 

  • Samantaray, S., Knaryan, V. H., Guyton, M. K., Matzelle, D. D., Ray, S. K., & Banik, N. L. (2007). The parkinsonian neurotoxin rotenone activates calpain and caspase-3 leading to motoneuron degeneration in spinal cord of Lewis rats. Neuroscience, 146, 741–755.

    PubMed  CAS  Google Scholar 

  • Sanchez, I., Xu, C. J., Juo, P., Kakizaka, A., Blenis, J., & Yuan, J. (1999). Caspase-8 is required for cell death induced by expanded polyglutamine repeats. Neuron, 22, 623–633.

    PubMed  CAS  Google Scholar 

  • Sawangjaroen, K., Dallemagne, C. R., Cross, R. B., & Curlewis, J. D. (1992). Effects of pituitary adenylate cyclase-activating polypeptide (PACAP) and vasoactive intestinal polypeptide (VIP) on the cardiovascular system in sheep. Peptides, 13, 1029–1032.

    PubMed  CAS  Google Scholar 

  • Schielke, G. P., Yang, G. Y., Shivers, B. D., & Betz, A. L. (1998). Reduced ischemic brain injury in interleukin-1b converting enzyme-deficient mice. Journal of Cerebral Blood Flow and Metabolism, 18, 180–185.

    PubMed  CAS  Google Scholar 

  • Sherwood, N. M., Krueckl, S. L., & McRory, J. E. (2000). The origin and function of the pituitary adenylate cyclase-activating polypeptide (PACAP)/glucagon superfamily. Endocrine Reviews, 21, 619–670.

    PubMed  CAS  Google Scholar 

  • Shi, G. X., Rehmann, H., & Andres, D. A. (2006). A novel cyclic AMP-dependent Epac-Rit signaling pathway contributes to PACAP38-mediated neuronal differentiation. Molecular and Cellular Biology, 26, 9136–9147.

    PubMed  CAS  Google Scholar 

  • Shibata, M., Hattori, H., Sasaki, T., Gotoh, J., Hamada, J., & Fukuuchi, Y. (2003). Activation of caspase-12 by endoplasmic reticulum stress induced by transient middle cerebral artery occlusion in mice. Neuroscience, 118, 491–499.

    PubMed  CAS  Google Scholar 

  • Shioda, S., Ozawa, H., Dohi, K., et al. (1998). PACAP protects hippocampal neurons against apoptosis: involvement of JNK/SAPK signaling pathway. Annals of the New York Academy of Sciences, 865, 111–117.

    PubMed  CAS  Google Scholar 

  • Springer, J. E., Azbill, R. D., & Knapp, P. E. (1999). Activation of the caspase-3 apoptotic cascade in traumatic spinal cord injury. Nature Medicine, 5, 943–946.

    PubMed  CAS  Google Scholar 

  • Srinivasula, S. M., Ahmad, M., Fernandes-Alnemri, T., & Alnemri, E. S. (1998). Autoactivation of procaspase-9 by Apaf-1-mediated oligomerization. Molecular Cell, 1, 949–957.

    PubMed  CAS  Google Scholar 

  • Stennicke, H. R., Jurgensmeier, J. M., Shin, H., et al. (1998). Pro-caspase-3 is a major physiologic target of caspase-8. Journal of Biological Chemistry, 273, 27084–27090.

    PubMed  CAS  Google Scholar 

  • Stumm, R., Kolodziej, A., Prinz, V., Endres, M., Wu, D. F., & Hollt, V. (2007). Pituitary adenylate cyclase-activating polypeptide is up-regulated in cortical pyramidal cells after focal ischemia and protects neurons from mild hypoxic/ischemic damage. Journal of Neurochemistry, 103, 1666–1681.

    PubMed  CAS  Google Scholar 

  • Sun, C., Song, D., Davis-Taber, R. A., et al. (2007). Solution structure and mutational analysis of pituitary adenylate cyclase-activating polypeptide binding to the extracellular domain of PAC1-RS. Proceedings of the National Academy of Sciences of the United States of America, 104, 7875–7880.

    PubMed  CAS  Google Scholar 

  • Suzuki, H., Noda, Y., Paul, S., Gao, X. P., & Rubinstein, I. (1995). Encapsulation of vasoactive intestinal peptide into liposomes: effects on vasodilation in vivo. Life Sciences, 57, 1451–1457.

    PubMed  CAS  Google Scholar 

  • Tamas, A., Lubics, L., Lengvari, I., & Reglodi, D. (2006a). Protective effects of PACAP in excitotoxic striatal lesion. Annals of the New York Academy of Sciences, 1070, 570–574.

    PubMed  CAS  Google Scholar 

  • Tamas, A., Zsombok, A., Farkas, O., et al. (2006b). Postinjury administration of pituitary adenylate cyclase-activating polypeptide (PACAP) attenuates traumatically induced axonal injury in rats. Journal of Neurotrauma, 23, 686–695.

    PubMed  Google Scholar 

  • Thornberry, N. A., & Lazebnik, Y. (1998). Caspases: Enemies within. Science, 281, 1312–1316.

    PubMed  CAS  Google Scholar 

  • Timmer, J. C., & Salvesen, G. S. (2007). Caspase substrates. Cell Death and Differentiation, 14, 66–72.

    PubMed  CAS  Google Scholar 

  • Tinel, A., & Tschopp, J. (2004). The PIDDosome, a protein complex implicated in activation of caspase-2 in response to genotoxic stress. Science, 304, 843–846.

    PubMed  CAS  Google Scholar 

  • Tokuda, E., Ono, S., Ishige, K., et al. (2007). Dysequilibrium between caspases and their inhibitors in a mouse model for amyotrophic lateral sclerosis. Brain Research, 1148, 234–242.

    PubMed  CAS  Google Scholar 

  • Troy, C. M., Rabacchi, S. A., Friedman, W. J., Frappier, T. F., Brown, K., & Shelanski, M. L. (2000). Caspase-2 mediates neuronal cell death induced by beta-amyloid. Journal of Neuroscience, 20, 1386–1392.

    PubMed  CAS  Google Scholar 

  • Uchida, D., Arimura, A., Somogyvári-Vigh, A., Shioda, S., & Banks, W. A. (1996). Prevention of ischemia-induced death of hippocampal neurons by pituitary adenylate cyclase activating polypeptide. Brain Research, 736, 280–286.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Cottet-Rousselle, C., Basille, M., et al. (2004). Pituitary adenylate cyclase-activating polypeptide inhibits caspase-3 activity but does not protect cerebellar granule neurons against b-amyloid (25–35)induced apoptosis. Regulatory Peptides, 123, 43–49.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Falluel-Morel, A., Basille, M., et al. (2003a). Pituitary adenylate cyclase-activating polypeptide prevents C2-ceramide-induced apoptosis of cerebellar granule cells. Journal of Neuroscience Research, 72, 303–316.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Falluel-Morel, A., Leuillet, S., Vaudry, H., & Gonzalez, B. J. (2003b). Regulators of cerebellar granule cell development act through specific signaling pathways. Science, 300, 1532–1534.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Gonzalez, B. J., Basille, M., Anouar, Y., Fournier, A., & Vaudry, H. (1998). Pituitary adenylate cyclase-activating polypeptide stimulates both c-fos gene expression and cell survival in rat cerebellar granule neurons through activation of the protein kinase A pathway. Neuroscience, 84, 801–812.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Gonzalez, B. J., Basille, M., Fournier, A., & Vaudry, H. (1999). Neurotrophic activity of pituitary adenylate cyclase-activating polypeptide on rat cerebellar cortex during development. Proceedings of the National Academy of Sciences of the United States of America, 96, 9415–9420.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Gonzalez, B. J., Basille, M., et al. (2000a). The neuroprotective effect of pituitary adenylate cyclase-activating polypeptide on cerebellar granule cells is mediated through inhibition of the CED3-related cysteine protease caspase-3/CPP32. Proceedings of the National Academy of Sciences of the United States of America, 97, 13390–13395.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Gonzalez, B. J., Basille, M., Yon, L., Fournier, A., & Vaudry, H. (2000b). Pituitary adenylate cyclase-activating polypeptide and its receptors: From structure to functions. Pharmacological Reviews, 52, 269–324.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Pamantung, T. F., Basille, M., et al. (2002a). PACAP protects cerebellar granule neurons against oxidative stress-induced apoptosis. European Journal of Neuroscience, 15, 1451–1460.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Rousselle, C., Basille, M., et al. (2002b). Pituitary adenylate cyclase-activating polypeptide protects rat cerebellar granule neurons against ethanol-induced apoptotic cell death. Proceedings of the National Academy of Sciences of the United States of America, 99, 6398–6403.

    PubMed  CAS  Google Scholar 

  • Vaudry, D., Stork, P. J., Lazarovici, P., & Eiden, L. E. (2002c). Signaling pathways for PC12 cell differentiation: making the right connections. Science, 296, 1648–1649.

    PubMed  CAS  Google Scholar 

  • Villalba, M., Bockaert, J., & Journot, L. (1997). Pituitary adenylate cyclase-activating polypeptide (PACAP-38) protects cerebellar granule neurons from apoptosis by activating the mitogen-activated protein kinase (MAP kinase) pathway. Journal of Neuroscience, 17, 83–90.

    PubMed  CAS  Google Scholar 

  • Wang, S., Miura, M., Jung, Y. K., Zhu, H., Li, E., & Yuan, J. (1998). Murine caspase-11, an ICE-interacting protease, is essential for the activation of ICE. Cell, 92, 501–509.

    PubMed  CAS  Google Scholar 

  • Wang, G., Qi, Ch., Fan, G. H., Zhou, H. Y., & Chen, S. D. (2005). PACAP protects neuronal differentiated PC12 cells against the neurotoxicity induced by a mitochondrial complex I inhibitor, rotenone. FEBS Letters, 579, 4005–4011.

    PubMed  CAS  Google Scholar 

  • Yakovlev, A. G., Knoblach, S. M., Fan, L., Fox, G. B., Goodnight, R., & Faden, A. I. (1997). Activation of CPP32-like caspases contributes to neuronal apoptosis and neurological dysfunction after traumatic brain injury. Journal of Neuroscience, 17, 7415–7424.

    PubMed  CAS  Google Scholar 

  • Yang, J., Liu, X., Bhalla, K., et al. (1997). Prevention of apoptosis by Bcl-2: Release of cytochrome c from mitochondria blocked. Science, 275, 1129–1132.

    PubMed  CAS  Google Scholar 

  • Yuan, J., & Yankner, B. A. (2000). Apoptosis in the nervous system. Nature, 407, 802–809.

    PubMed  CAS  Google Scholar 

  • Zhang, Y., Leavitt, B. R., van Raamsdonk, J. M., et al. (2006). Huntingtin inhibits caspase-3 activation. EMBO Journal, 25, 5896–5906.

    PubMed  CAS  Google Scholar 

  • Zhou, P., Chou, J., Olea, R. S., Yuan, J., & Wagner, G. (1999). Solution structure of Apaf-1 CARD and its interaction with caspase-9 CARD: A structural basis for specific adaptor/caspase interaction. Proceedings of the National Academy of Sciences of the United States of America, 96, 11265–11270.

    PubMed  CAS  Google Scholar 

  • Zhu, L., Tamvakopoulos, C., Xie, D., et al. (2003). The role of dipeptidyl peptidase IV in the cleavage of glucagon family peptides: In vivo metabolism of pituitary adenylate cyclase activating polypeptide-(1–38). Journal of Biological Chemistry, 278, 22418–22423.

    PubMed  CAS  Google Scholar 

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Acknowledgments

Supported by INSERM (U413), the European Institute for Peptide Research (IFRMP23), the Regional Platform for Cell Imaging (PFRRICHN), the National Research Agency (ANR-06-JCJC-0071), the Institut pour la Recherche sur la Moelle épinière et l′Encéphale (IRME), the Institut de Recherches Scientifiques sur les Boissons (IREB), and the Conseil Régional de Haute-Normandie. A.D. is the recipient of a postdoctoral fellowship from the Fondation pour la Recherche Médicale. V.J. is the recipient of a Convention Industrielle de Formation par la Recherche (CIFRE). S.B. is the recipient of a doctoral studentship from the Natural Sciences and Engineering Research Council of Canada. T.S. is the recipient of a postdoctoral fellowship from INSERM. H.V. is Affiliated Professor at the INRS-Institute Armand-Frappier (Montreal, Canada).

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Authors and Affiliations

  1. INSERM U413, Laboratory of Cellular and Molecular Neuroendocrinology, Mont-Saint-Aignan, France

    Agnieszka Dejda, Valérie Jolivel, Steve Bourgault, Tommy Seaborn, Hubert Vaudry & David Vaudry

  2. European Institute for Peptide Research (IFRMP 23), University of Rouen, 76821, Mont-Saint-Aignan, France

    Agnieszka Dejda, Valérie Jolivel, Steve Bourgault, Tommy Seaborn, Hubert Vaudry & David Vaudry

  3. International Associated Laboratory Samuel de Champlain, Mont-Saint-Aignan, France

    Agnieszka Dejda, Valérie Jolivel, Steve Bourgault, Tommy Seaborn, Alain Fournier, Hubert Vaudry & David Vaudry

  4. Institute for Medical Biology, Polish Academy of Sciences, Lodz, Poland

    Agnieszka Dejda

  5. QUIDD (QUantitative Imaging in Drug Development), 76801, Saint-Etienne-du-Rouvray, France

    Valérie Jolivel

  6. INRS—Institut Armand-Frappier, Institut National de la Recherche Scientifique, 531 boul., des Prairies, H7V 1B7, Canada

    Steve Bourgault & Alain Fournier

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  1. Agnieszka Dejda
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  2. Valérie Jolivel
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  3. Steve Bourgault
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  6. Hubert Vaudry
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  7. David Vaudry
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Correspondence to Hubert Vaudry or David Vaudry.

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Dejda, A., Jolivel, V., Bourgault, S. et al. Inhibitory Effect of PACAP on Caspase Activity in Neuronal Apoptosis: A Better Understanding Towards Therapeutic Applications in Neurodegenerative Diseases. J Mol Neurosci 36, 26–37 (2008). https://doi.org/10.1007/s12031-008-9087-1

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