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The Reduction of EPSC Amplitude in CA1 Pyramidal Neurons by the Peroxynitrite Donor SIN-1 Requires Ca2+ Influx Via Postsynaptic Non-L-Type Voltage Gated Calcium Channels

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Abstract

The peroxynitrite free radical (ONOO−) modulation of miniature excitatory postsynaptic currents (mEPSCs) and spontaneous excitatory postsynaptic currents (sEPSCs) was investigated in rat CA1 pyramidal neurons using the whole-cell patch clamp technique. SIN-1(3-morpholino-sydnonimine), which can lead the simultaneous generation of superoxide anion and nitric oxide, and then form the highly reactive species ONOO−, induced dose-dependent inhibition in amplitudes of both mEPSCs and sEPSCs. The SIN-1 action on mEPSC amplitude was completely blocked by U0126, a selective MEK inhibitor, suggesting that MEK contributed to the action of ONOO− on mEPSCs. The effect of SIN-1 was completely occluded either in the presence of the calcium chelator EGTA or the non-selective calcium channel antagonist Cd2+. Furthermore, the application of nifedipine (20 μM), the L-type calcium channel blocker, had no effect on the ONOO−-induced decrease in mEPSC amplitude, excluding a role for L-type voltage-gated Ca2+ channels in this process. SIN-1 inhibited the frequency of sEPSCs but had no effect on mEPSC frequency, which suggested a presynaptic action potential-dependent the action of ONOO− at CA1 pyramidal neuron synapses. The best-known glutamatergic input to CA1 pyramidal neurons is via Schaffer collaterals from CA3 area. However, no changes were observed in slices treated with SIN-1 on the spontaneous firing rates of CA3 pyramidal neurons. These findings suggested that SIN-1 inhibited glutamatergic synaptic transmission of CA1 pyramidal neurons by a postsynaptic non-L-type voltage gated calcium channel-dependent mechanism.

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References

  1. Beckman JS, Beckman TW, Chen J, Marshall PA, Freeman BA (1990) Apparent hydroxyl radical production by peroxynitrite: implications for endothelial injury from nitric oxide and superoxide. Proc Natl Acad Sci USA 87:1620–1624

    Article  CAS  PubMed  Google Scholar 

  2. Salgo MG, Bermudez E, Squadrito GL, Pryor WA (1995) Peroxynitrite causes DNA damage and oxidation of thiols in rat thymocytes [corrected]. Arch Biochem Biophys 322:500–505

    Article  CAS  PubMed  Google Scholar 

  3. Szabo C (1996) DNA strand breakage and activation of poly-ADP ribosyltransferase: a cytotoxic pathway triggered by peroxynitrite. Free Radic Biol Med 21:855–869

    Article  CAS  PubMed  Google Scholar 

  4. Salgo MG, Stone K, Squadrito GL, Battista JR, Pryor WA (1995) Peroxynitrite causes DNA nicks in plasmid pBR322. Biochem Biophys Res Commun 210:1025–1030

    Article  CAS  PubMed  Google Scholar 

  5. Szabo C, Ischiropoulos H, Radi R (2007) Peroxynitrite: biochemistry, pathophysiology and development of therapeutics. Nat Rev Drug Discov 6:662–680

    Article  CAS  PubMed  Google Scholar 

  6. Radi R (1998) Peroxynitrite reactions and diffusion in biology. Chem Res Toxicol 11:720–721

    Article  CAS  PubMed  Google Scholar 

  7. Koppenol WH, Moreno JJ, Pryor WA, Ischiropoulos H, Beckman JS (1992) Peroxynitrite, a cloaked oxidant formed by nitric oxide and superoxide. Chem Res Toxicol 5:834–842

    Article  CAS  PubMed  Google Scholar 

  8. Lanone S, Mebazaa A, Heymes C, Henin D, Poderoso JJ, Panis Y, Zedda C, Billiar T, Payen D, Aubier M, Boczkowski J (2000) Muscular contractile failure in septic patients: role of the inducible nitric oxide synthase pathway. Am J Respir Crit Care Med 162:2308–2315

    Article  CAS  PubMed  Google Scholar 

  9. Campelo MWS, Oriá RB, de França Lopes LG, de Castro Brito GA, dos Santos AA, de Vasconcelos RC, da Silva FON, Nobrega BN, Bento-Silva MT, de Vasconcelos PRL (2012) Preconditioning with a novel metallopharmaceutical NO donor in anesthetized rats subjected to brain ischemia/reperfusion. Neurochem Res 37:749–758

    Article  CAS  PubMed  Google Scholar 

  10. Love S (1999) Oxidative stress in brain ischemia. Brain Pathol 9:119–131

    Article  CAS  PubMed  Google Scholar 

  11. Juurlink B, Paterson P (1998) Review of oxidative stress in brain and spinal cord injury: suggestions for pharmacological and nutritional management strategies. J Spinal Cord Med 21:309–334

    CAS  PubMed  Google Scholar 

  12. Butterfield DA, Reed T, Newman SF, Sultana R (2007) Roles of amyloid β-peptide-associated oxidative stress and brain protein modifications in the pathogenesis of Alzheimer’s disease and mild cognitive impairment. Free Radic Biol Med 43:658–677

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  13. Prakash J, Yadav SK, Chouhan S, Singh SP (2013) Neuroprotective role of Withania somnifera root extract in Maneb–Paraquat induced mouse model of parkinsonism. Neurochem Res 38:972–980

    Article  CAS  PubMed  Google Scholar 

  14. Behl C, Skutella T, Frank LH, Post A, Widmann M, Newton CJ, Holsboer F (1997) Neuroprotection against oxidative stress by estrogens: structure–activity relationship. Mol Pharmacol 51:535–541

    CAS  PubMed  Google Scholar 

  15. Heck S, Lezoualc’h F, Engert S, Behl C (1999) Insulin-like growth factor-1-mediated neuroprotection against oxidative stress is associated with activation of nuclear factor κB. J Biol Chem 274:9828–9835

    Article  CAS  PubMed  Google Scholar 

  16. Kraus RL, Pasieczny R, Lariosa-Willingham K, Turner MS, Jiang A, Trauger JW (2005) Antioxidant properties of minocycline: neuroprotection in an oxidative stress assay and direct radical-scavenging activity. J Neurochem 94:819–827

    Article  CAS  PubMed  Google Scholar 

  17. Chen M, Jiang P, Lu J, Xiang ZH, Jiao BH (2010) The correlation of asymmetrical dimethylarginine level and oxidative stress to the onset of Alzheimer’s disease. Acta pharmaceutica Sinica 45:1001–1005

    CAS  PubMed  Google Scholar 

  18. Guix FX, Wahle T, Vennekens K, Snellinx A, Chavez-Gutierrez L, Ill-Raga G, Ramos E, Guardia-Laguarta C, Lleo A, Arimon M, Berezovska O, Munoz FJ, Dotti CG, De Strooper B (2012) Modification of gamma-secretase by nitrosative stress links neuronal aging to sporadic Alzheimer’s disease. EMBO Mol Med 4:660–673

    Article  CAS  PubMed Central  PubMed  Google Scholar 

  19. Guix FX, Ill-Raga G, Bravo R, Nakaya T, de Fabritiis G, Coma M, Miscione GP, Villa-Freixa J, Suzuki T, Fernandez-Busquets X, Valverde MA, de Strooper B, Munoz FJ (2009) Amyloid-dependent triosephosphate isomerase nitrotyrosination induces glycation and tau fibrillation. Brain 132:1335–1345

    Article  PubMed  Google Scholar 

  20. Drechsel DA, Estevez AG, Barbeito L, Beckman JS (2012) Nitric oxide-mediated oxidative damage and the progressive demise of motor neurons in ALS. Neurotox Res 22:251–264

    Article  CAS  PubMed  Google Scholar 

  21. Gunther M, Al Nimer F, Gahm C, Piehl F, Mathiesen T (2012) iNOS-mediated secondary inflammatory response differs between rat strains following experimental brain contusion. Acta Neurochir 154:689–697

    Article  PubMed  Google Scholar 

  22. Dohi K, Ohtaki H, Inn R, Ikeda Y, Shioda HS, Aruga T (2003) Peroxynitrite and caspase-3 expression after ischemia/reperfusion in mouse cardiac arrest model. Acta neurochir Supplement 86:87–91

    CAS  Google Scholar 

  23. Jiang J, Wang W, Sun YJ, Hu M, Li F, Zhu DY (2007) Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood-brain barrier damage. Eur J Pharmacol 561:54–62

    Article  CAS  PubMed  Google Scholar 

  24. Bemeur C, Ste-Marie L, Montgomery J (2007) Increased oxidative stress during hyperglycemic cerebral ischemia. Neurochem Int 50:890–904

    Article  CAS  PubMed  Google Scholar 

  25. Ma YH, Su N, Chao XD, Zhang YQ, Zhang L, Han F, Luo P, Fei Z, Qu Y (2012) Thioredoxin-1 attenuates post-ischemic neuronal apoptosis via reducing oxidative/nitrative stress. Neurochem Int 60:475–483

    Article  CAS  PubMed  Google Scholar 

  26. Bruno MA, Cuello AC (2012) Cortical peroxynitration of nerve growth factor in aged and cognitively impaired rats. Neurobiol Aging 33:1927–1937

    Article  CAS  PubMed  Google Scholar 

  27. Taylor CP, Meldrum BS (1995) Na+ channels as targets for neuroprotective drugs. Trends Pharmacol Sci 16:309–316

    Article  CAS  PubMed  Google Scholar 

  28. Haigney MC, Lakatta EG, Stern MD, Silverman HS (1994) Sodium channel blockade reduces hypoxic sodium loading and sodium-dependent calcium loading. Circulation 90:391–399

    Article  CAS  PubMed  Google Scholar 

  29. Calabresi P, Pisani A, Mercuri NB, Bernardi G (1995) On the mechanisms underlying hypoxia-induced membrane depolarization in striatal neurons. Brain 118:1027–1038

    Article  PubMed  Google Scholar 

  30. Huang CC, Chan SH, Hsu KS (2004) 3-Morpholinylsydnonimine inhibits glutamatergic transmission in rat rostral ventrolateral medulla via peroxynitrite formation and adenosine release. Mol Pharmacol 66:492–501

    Article  CAS  PubMed  Google Scholar 

  31. Moser MB, Moser EI (1998) Functional differentiation in the hippocampus. Hippocampus 8:608–619

    Article  CAS  PubMed  Google Scholar 

  32. Liu ZW, Lei T, Zhang T, Yang Z (2007) Peroxynitrite donor impairs excitability of hippocampal CA1 neurons by inhibiting voltage-gated potassium currents. Toxicol Lett 175:8–15

    Article  CAS  PubMed  Google Scholar 

  33. Pan BX, Zhao GL, Huang XL, Zhao KS (2004) Mobilization of intracellular calcium by peroxynitrite in arteriolar smooth muscle cells from rats. Redox Rep 9:49–55

    Article  CAS  PubMed  Google Scholar 

  34. Pan BX, Zhao GL, Huang XL, Zhao KS (2004) Calcium mobilization is required for peroxynitrite-mediated enhancement of spontaneous transient outward currents in arteriolar smooth muscle cells. Free Radic Biol Med 37:823–838

    Article  CAS  PubMed  Google Scholar 

  35. Torres-Rasgado E, Fouret G, Carbonneau MA, Leger CL (2007) Peroxynitrite mild nitration of albumin and LDL-albumin complex naturally present in plasma and tyrosine nitration rate-albumin impairs LDL nitration. Free Radic Res 41:367–375

    Article  CAS  PubMed  Google Scholar 

  36. Li MH, Cha YN, Surh YJ (2006) Carbon monoxide protects PC12 cells from peroxynitrite-induced apoptotic death by preventing the depolarization of mitochondrial transmembrane potential. Biochem Biophys Res Commun 342:984–990

    Article  CAS  PubMed  Google Scholar 

  37. Kuzkaya N, Weissmann N, Harrison DG, Dikalov S (2005) Interactions of peroxynitrite with uric acid in the presence of ascorbate and thiols: implications for uncoupling endothelial nitric oxide synthase. Biochem Pharmacol 70:343–354

    Article  CAS  PubMed  Google Scholar 

  38. Di S, Malcher-Lopes R, Halmos KC, Tasker JG (2003) Nongenomic glucocorticoid inhibition via endocannabinoid release in the hypothalamus: a fast feedback mechanism. J Neurosci 23:4850–4857

    CAS  PubMed  Google Scholar 

  39. Straiker AJ, Borden CR, Sullivan JM (2002) G-protein alpha subunit isoforms couple differentially to receptors that mediate presynaptic inhibition at rat hippocampal synapses. J Neurosci 22:2460–2468

    CAS  PubMed  Google Scholar 

  40. Richards JD, Dave SH, Chou CH, Mamchak AA, DeFranco AL (2001) Inhibition of the MEK/ERK signaling pathway blocks a subset of B cell responses to antigen. J Immunol 166:3855–3864

    CAS  PubMed  Google Scholar 

  41. Favata MF, Horiuchi KY, Manos EJ, Daulerio AJ, Stradley DA, Feeser WS, Van Dyk DE, Pitts WJ, Earl RA, Hobbs F, Copeland RA, Magolda RL, Scherle PA, Trzaskos JM (1998) Identification of a novel inhibitor of mitogen-activated protein kinase kinase. J Biol Chem 273:18623–18632

    Article  CAS  PubMed  Google Scholar 

  42. Bekkers JM, Stevens CF (1989) NMDA and non-NMDA receptors are co-localized at individual excitatory synapses in cultured rat hippocampus. Nature 341:230–233

    Article  CAS  PubMed  Google Scholar 

  43. Jonas P, Spruston N (1994) Mechanisms shaping glutamate-mediated excitatory postsynaptic currents in the CNS. Curr Opin Neurobiol 4:366–372

    Article  CAS  PubMed  Google Scholar 

  44. Ducrocq C, Blanchard B, Pignatelli B, Ohshima H (1999) Peroxynitrite: an endogenous oxidizing and nitrating agent. Cell Mol Life Sci 55:1068–1077

    Article  CAS  PubMed  Google Scholar 

  45. Schulz R, Dodge KL, Lopaschuk GD, Clanachan AS (1997) Peroxynitrite impairs cardiac contractile function by decreasing cardiac efficiency. Am J Physiol 272:H1212–H1219

    CAS  PubMed  Google Scholar 

  46. Sweatt JD (2004) Mitogen-activated protein kinases in synaptic plasticity and memory. Curr Opin Neurobiol 14:311–317

    Article  CAS  PubMed  Google Scholar 

  47. Kelleher RJ 3rd, Govindarajan A, Tonegawa S (2004) Translational regulatory mechanisms in persistent forms of synaptic plasticity. Neuron 44:59–73

    Article  CAS  PubMed  Google Scholar 

  48. Li J, Li W, Liu W, Altura BT, Altura BM (2007) Peroxynitrite induces apoptosis and decline in intracellular free Mg with concomitant elevation in [Ca2+]I in rat aortic smooth muscle cells: possible roles of extracellular and intracellular magnesium ions in peroxynitrite-induced cell death. Drug Metab Lett 1:85–89

    Article  CAS  PubMed  Google Scholar 

  49. Malan D, Levi RC, Alloatti G, Marcantoni A, Bedendi I, Gallo MP (2003) Cyclic AMP and cyclic GMP independent stimulation of ventricular calcium current by peroxynitrite donors in guinea pig myocytes. J Cell Physiol 197:284–296

    Article  CAS  PubMed  Google Scholar 

  50. Kong SK, Yim MB, Stadtman ER, Chock PB (1996) Peroxynitrite disables the tyrosine phosphorylation regulatory mechanism: Lymphocyte-specific tyrosine kinase fails to phosphorylate nitrated cdc2(6-20)NH2 peptide. Proc Natl Acad Sci USA 93:3377–3382

    Article  CAS  PubMed  Google Scholar 

  51. Wadiche JI, Jahr CE (2001) Multivesicular release at climbing fiber-Purkinje cell synapses. Neuron 32:301–313

    Article  CAS  PubMed  Google Scholar 

  52. Prange O, Murphy TH (1999) Analysis of multiquantal transmitter release from single cultured cortical neuron terminals. J Neurophysiol 81:1810–1817

    CAS  PubMed  Google Scholar 

  53. Wall MJ, Usowicz MM (1998) Development of the quantal properties of evoked and spontaneous synaptic currents at a brain synaps. Nat Neurosci 1:675–682

    Article  CAS  PubMed  Google Scholar 

  54. Freund TF, Buzsaki G (1996) Interneurons of the hippocampus. Hippocampus 6:347–470

    Article  CAS  PubMed  Google Scholar 

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Acknowledgments

This work was partly supported by the National Natural Science Foundation of China (31000509) and Tianjin Research Program of Application Foundation and Advanced Technology (10JCZDJC19100).

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None declared.

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Authors and Affiliations

  1. College of Medicine, Nankai University, Tianjin, 300071, China

    Liu Zhaowei, Xie Yongling & Yang Zhuo

  2. College of Life Science, Nankai University, Tianjin, 300071, China

    Yang Jiajia

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  1. Liu Zhaowei
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  2. Xie Yongling
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  3. Yang Jiajia
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Correspondence to Yang Zhuo.

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Zhaowei, L., Yongling, X., Jiajia, Y. et al. The Reduction of EPSC Amplitude in CA1 Pyramidal Neurons by the Peroxynitrite Donor SIN-1 Requires Ca2+ Influx Via Postsynaptic Non-L-Type Voltage Gated Calcium Channels. Neurochem Res 39, 361–371 (2014). https://doi.org/10.1007/s11064-013-1233-7

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