Oxidative stress is crucially involved in the pathogenesis of neurological diseases such as stroke and degenerative diseases. We previously demonstrated that platelet-derived growth factors (PDGFs) protected neurons from H2O2-induced oxidative stress and indicated the involvement of PI3K-Akt and MAP kinases as an underlying mechanism. Ca2+ overload has been shown to mediate the neurotoxic effects of oxidative stress and excitotoxicity. We examined the effects of PDGFs on H2O2-induced Ca2+ overload in primary cultured neurons to further clarify their neuroprotective mechanism. H2O2-induced Ca2+ overload in neurons in a dose-dependent manner, while pretreating neurons with PDGF-BB for 24 hours largely suppressed it. In a comparative study, the suppressive effects of PDGF-BB were more potent than those of PDGF-AA. We then evaluated calpain activation, which was induced by Ca2+ overload and mediated both apoptotic and nonapoptotic cell death. H2O2-induced calpain activation in neurons in a dose-dependent manner. Pretreatment of PDGF-BB completely blocked H2O2-induced calpain activation. To the best of our knowledge, the present study is the first to demonstrate the mechanism underlying the neuroprotective effects of PDGF against oxidative stress via the suppression of Ca2+ overload and inactivation of calpain and suggests that PDGF-BB may be a potential therapeutic target of neurological diseases. 1. Introduction Oxidative stress and excitotoxicity play important roles in the pathogenesis of a number of neurological diseases, including ischemic infarction, multiple sclerosis, amyotrophic lateral sclerosis, and Alzheimer’s, Huntington’s, and Parkinson’s diseases [1–3]. Ca2+ has been shown to mediate the cytotoxicity of oxidative stress and excitotoxicity, and cellular Ca2+ overload or the perturbation of intracellular Ca2+ compartmentalization induced by these noxious stimuli can cause cytotoxicity and trigger cell death including both apoptotic and necrotic cell death [4–6]; however, these mechanisms of cellular injury have yet to be elucidated in adequate detail to prevent and treat neurological diseases [7, 8]. Calpains are calcium-regulated cysteine proteases that have been implicated in the regulation of cell death pathways including apoptosis and necrosis [9, 10]. An elevated intracellular calcium concentration will hyperactivate calpains. The activation of calpains was shown to be involved in various pathological conditions, including ischemic brain injuries and chronic neurodegenerative diseases, for example, Alzheimer’s disease [9, 11]. Previous
References
[1]
L. M. Sayre, G. Perry, and M. A. Smith, “Oxidative stress and neurotoxicity,” Chemical Research in Toxicology, vol. 21, no. 1, pp. 172–188, 2008.
[2]
P. H. Chan, K. Niizuma, and H. Endo, “Oxidative stress and mitochondrial dysfunction as determinants of ischemic neuronal death and survival,” Journal of Neurochemistry, vol. 109, no. 1, pp. 133–138, 2009.
[3]
S. Gandhi and A. Y. Abramov, “Mechanism of oxidative stress in neurodegeneration,” Oxidative Medicine and Cellular Longevity, vol. 2012, Article ID 428010, 11 pages, 2012.
[4]
C. Krieger and M. R. Duchen, “Mitochondria, Ca2+ and neurodegenerative disease,” European Journal of Pharmacology, vol. 447, no. 2-3, pp. 177–188, 2002.
[5]
S. Orrenius, B. Zhivotovsky, and P. Nicotera, “Regulation of cell death: the calcium-apoptosis link,” Nature Reviews Molecular Cell Biology, vol. 4, no. 7, pp. 552–565, 2003.
[6]
R. Rizzuto, D. de Stefani, A. Raffaello, and C. Mammucari, “Mitochondria as sensors and regulators of calcium signaling,” Nature Review Molecular Cell Biology, vol. 13, no. 9, pp. 566–578, 2012.
[7]
A. Reynolds, C. Laurie, R. Lee Mosley, and H. E. Gendelman, “Oxidative stress and the pathogenesis of neurodegenerative disorders,” International Review of Neurobiology, vol. 82, pp. 297–325, 2007.
[8]
I. Niki？, D. Merkler, C. Sorbara et al., “A reversible form of axon damage in experimental autoimmune encephalomyelitis and multiple sclerosis,” Nature Medicine, vol. 17, no. 4, pp. 495–499, 2011.
[9]
Y. Huang and K. K. W. Wang, “The calpain family and human disease,” Trends in Molecular Medicine, vol. 7, no. 8, pp. 355–362, 2001.
[10]
M. B. Bevers and R. W. Neumar, “Mechanistic role of calpains in postischemic neurodegeneration,” Journal of Cerebral Blood Flow and Metabolism, vol. 28, no. 4, pp. 655–673, 2008.
[11]
P. S. Vosler, Y. Gao, C. S. Brennan et al., “Ischemia-induced calpain activation causes eukaryotic (translation) initiation factor 4G1 (eIF4GI) degradation, protein synthesis inhibition, and neuronal death,” Proceedings of the National Academy of Sciences of the United States of America, vol. 108, no. 44, pp. 18102–18107, 2011.
[12]
C. Volbracht, E. Fava, M. Leist, and P. Nicotera, “Calpain inhibitors prevent nitric oxide-triggered excitotoxic apoptosis,” NeuroReport, vol. 12, no. 17, pp. 3645–3648, 2001.
[13]
S. K. Ray, D. D. Matzelle, E. A. Sribnick, M. K. Guyton, J. M. Wingrave, and N. L. Banik, “Calpain inhibitor prevented apoptosis and maintained transcription of proteolipid protein and myelin basic protein genes in rat spinal cord injury,” Journal of Chemical Neuroanatomy, vol. 26, no. 2, pp. 119–124, 2003.
[14]
K. E. Saatman, J. Creed, and R. Raghupathi, “Calpain as a therapeutic target in traumatic brain injury,” Neurotherapeutics, vol. 7, no. 1, pp. 31–42, 2010.
[15]
K. H. Yamada, D. A. Kozlowski, S. E. Seidl et al., “Targeted gene inactivation of calpain-1 suppresses cortical degeneration due to traumatic brain injury and neuronal apoptosis induced by oxidative stress,” Journal of Biological Chemistry, vol. 287, no. 16, pp. 13182–13193, 2012.
[16]
M. Tallquist and A. Kazlauskas, “PDGF signaling in cells and mice,” Cytokine and Growth Factor Reviews, vol. 15, no. 4, pp. 205–213, 2004.
[17]
M. Sasahara, J. W. U. Fries, E. W. Raines et al., “PDGF B-chain in neurons of the central nervous system, posterior pituitary, and in a transgenic model,” Cell, vol. 64, no. 1, pp. 217–227, 1991.
[18]
H.-J. Yeh, K. G. Ruit, Y.-X. Wang, W. C. Parks, W. D. Snider, and T. F. Deuel, “PDGF a-chain gene is expressed by mammalian neurons during development and in maturity,” Cell, vol. 64, no. 1, pp. 209–216, 1991.
[19]
L. J. Reigstad, J. E. Varhaug, and J. R. Lillehaug, “Structural and functional specificities of PDGF-C and PDGF-D, the novel members of the platelet-derived growth factors family,” The FEBS Journal, vol. 272, no. 22, pp. 5723–5741, 2005.
[20]
T. Egawa-Tsuzuki, M. Ohno, N. Tanaka et al., “The PDGF B-chain is involved in the ontogenic susceptibility of the developing rat brain to NMDA toxicity,” Experimental Neurology, vol. 186, no. 1, pp. 89–98, 2004.
[21]
Y. Ishii, T. Oya, L. Zheng et al., “Mouse brains deficient in neuronal PDGF receptor-β develop normally but are vulnerable to injury,” Journal of Neurochemistry, vol. 98, no. 2, pp. 588–600, 2006.
[22]
J. Shen, Y. Ishii, G. Xu et al., “PDGFR-Β as a positive regulator of tissue repair in a mouse model of focal cerebral ischemia,” Journal of Cerebral Blood Flow and Metabolism, vol. 32, no. 2, pp. 353–367, 2012.
[23]
L. Zheng, Y. Ishii, A. Tokunaga et al., “Neuroprotective effects of PDGF against oxidative stress and the signaling pathway involved,” Journal of Neuroscience Research, vol. 88, no. 6, pp. 1273–1284, 2010.
[24]
Z. Tang, P. Arjunan, C. Lee et al., “Survival effect of PDGF-CC rescues neurons from apoptosis in both brain and retina by regulating GSK3β phosphorylation,” Journal of Experimental Medicine, vol. 207, no. 4, pp. 867–880, 2010.
[25]
Y. Arai, T. Kondo, K. Tanabe et al., “Enhancement of hyperthermia-induced apoptosis by local anesthetics on human histiocytic lymphoma U937 cells,” Journal of Biological Chemistry, vol. 277, no. 21, pp. 18986–18993, 2002.
[26]
Q.-L. Zhao, Y. Fujiwara, and T. Kondo, “Mechanism of cell death induction by nitroxide and hyperthermia,” Free Radical Biology and Medicine, vol. 40, no. 7, pp. 1131–1143, 2006.
[27]
M. Ankarcrona, J. M. Dypbukt, E. Bonfoco et al., “Glutamate-induced neuronal death: a succession of necrosis or apoptosis depending on mitochondrial function,” Neuron, vol. 15, no. 4, pp. 961–973, 1995.
[28]
C. Chinopoulos and V. Adam-Vizi, “Calcium, mitochondria and oxidative stress in neuronal pathology: novel aspects of an enduring theme,” The FEBS Journal, vol. 273, no. 3, pp. 433–450, 2006.
[29]
S.-E. Choi, S.-H. Min, H.-C. Shin, H.-E. Kim, M. W. Jung, and Y. Kang, “Involvement of calcium-mediated apoptotic signals in H2O2-induced MIN6N8a cell death,” European Journal of Pharmacology, vol. 547, no. 1–3, pp. 1–9, 2006.
[30]
K. Funa and M. Sasahara, “The toles of PDGF in development and during neurogenesis in the normal and diseased nervous system,” The Jourmnal of Neuroimmune Pharmacology, 2013.
[31]
B. Cheng, D. C. McMahon, and M. P. Mattson, “Modulation of calcium current, intracellular calcium levels and cell survival by glucose deprivation and growth factors in hippocampal neurons,” Brain Research, vol. 607, no. 1-2, pp. 275–285, 1993.
[32]
R. Kowara, Q. Chen, M. Milliken, and B. Chakravarthy, “Calpain-mediated truncation of dihydropyrimidinase-like 3 protein (DPYSL3) in response to NMDA and H2O2 toxicity,” Journal of Neurochemistry, vol. 95, no. 2, pp. 466–474, 2005.
[33]
C. Liang, “Negative regulation of autophagy,” Cell Death and Differentiation, vol. 17, no. 12, pp. 1807–1815, 2010.
[34]
V. Nimmrich, R. Szabo, C. Nyakas et al., “Inhibition of calpain prevents N-methyl-D-aspartate-induced degeneration of the nucleus basalis and associated behavioral dysfunction,” Journal of Pharmacology and Experimental Therapeutics, vol. 327, no. 2, pp. 343–352, 2008.
[35]
B. D'Orsi, H. Bonner, L. P. Tuffy et al., “Calpains are downstream effectors of bax-dependent excitotoxic apoptosis,” Journal of Neuroscience, vol. 32, no. 5, pp. 1847–1858, 2012.
[36]
Y. Miao Y, L. D. Dong, J. Chen et al., “Involvement of calpain/p35-p25/Cdk5/NMDAR signaling pathway in glutamate-induced neurotoxicity in cultured rat retinal neurons,” PLoS ONE, vol. 7, no. 8, Article ID e42318, 2012.
[37]
H. C. Tseng and M. A. Dichter, “Platelet-derived growth factor-BB pretreatment attenuates excitotoxic death in cultured hippocampal neurons,” Neurobiology of Disease, vol. 19, no. 1-2, pp. 77–83, 2005.
[38]
B. A. Miller and W. Zhang, “TRP channels as mediators of oxidative stress,” Advances in Experimental Medicine and Biology, vol. 704, pp. 531–544, 2011.
[39]
C. F. Valenzuela, A. Kazlauskas, S. J. Brozowski et al., “Platelet-derived growth factor receptor is a novel modulator of type a γ-aminobutyric acid-gated ion channels,” Molecular Pharmacology, vol. 48, no. 6, pp. 1099–1107, 1995.
[40]
C. Fernando Valenzuela, Z. Xiong, J. F. MacDonald et al., “Platelet-derived growth factor induces a long-term inhibition of N-methyl-D-aspartate receptor function,” Journal of Biological Chemistry, vol. 271, no. 27, pp. 16151–16159, 1996.
[41]
B. Cheng and M. P. Mattson, “PDGFs protect hippocampal neurons against energy deprivation and oxidative injury: evidence for induction of antioxidant pathways,” Journal of Neuroscience, vol. 15, no. 11, pp. 7095–7104, 1995.
[42]
K. Iihara, M. Sasahara, N. Hashimoto, Y. Uemura, H. Kikuchi, and F. Hazama, “Ischemia induces the expression of the platelet-derived growth factor-B chain in neurons and brain macrophages in vivo,” Journal of Cerebral Blood Flow and Metabolism, vol. 14, no. 5, pp. 818–824, 1994.
[43]
K. Farrell and R. A. Barker, “Stem cells and regenerative therapies for Parkinson’s disease,” Degenerative Neurological and Neuromuscular Disease, vol. 2, pp. 79–92, 2012.
