Skip to main content
SpringerLink
Log in

Protein kinase Cδ mediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism

  • Organ Toxicity and Mechanisms
  • Published:
Archives of Toxicology Aims and scope Submit manuscript

Abstract

We investigated whether protein kinase C (PKC) is involved in trimethyltin (TMT)-induced neurotoxicity. TMT treatment (2.8 mg/kg, i.p.) significantly increased PKCδ expression out of PKC isozymes (i.e., α, βI, βII, δ, and ς) in the hippocampus of wild-type (WT) mice. Consistently, treatment with TMT resulted in significant increases in cleaved PKCδ expression. Genetic or pharmacological inhibition (PKCδ knockout or rottlerin) was less susceptible to TMT-induced seizures than WT mice. TMT treatment increased glutathione oxidation, lipid peroxidation, protein oxidation, and levels of reactive oxygen species. These effects were more pronounced in the WT mice than in PKCδ knockout mice. In addition, the ability of TMT to induce nuclear translocation of Nrf2, Nrf2 DNA-binding activity, and upregulation of γ-glutamylcysteine ligase was significantly increased in the PKCδ knockout mice and rottlerin (10 or 20 mg/kg, p.o. × 6)-treated WT mice. Furthermore, neuronal degeneration (as shown by nuclear chromatin clumping and TUNEL staining) in WT mice was most pronounced 2 days after TMT. At the same time, TMT-induced inhibition of phosphoinositol 3-kinase (PI3K)/Akt signaling was evident, thereby decreasing phospho-Bad, expression of Bcl-xL and Bcl-2, and the interaction between phospho-Bad and 14-3-3 protein, and increasing Bax expression and caspase-3 cleavage were observed. Rottlerin or PKCδ knockout significantly protected these changes in anti- and pro-apoptotic factors. Importantly, treatment of the PI3K inhibitor LY294002 (0.8 or 1.6 µg, i.c.v.) 4 h before TMT counteracted protective effects (i.e., Nrf-2-dependent glutathione induction and pro-survival phenomenon) of rottlerin. Therefore, our results suggest that down-regulation of PKCδ and up-regulations of Nrf2-dependent glutathione defense mechanism and PI3K/Akt signaling are critical for attenuating TMT neurotoxicity.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6
Fig. 7
Fig. 8
Fig. 9

Similar content being viewed by others

References

  • Bouldin TW, Goines ND, Bagnell CR, Krigman MR (1981) Pathogenesis of trimethyltin neuronal toxicity. Ultrastructural and cytochemical observations. Am J Pathol 104(3):237–249

    CAS  PubMed  PubMed Central  Google Scholar 

  • Braman RS, Tompkins MA (1979) Separation and determination of nanogram amounts of inorganic tin and methyltin compounds in the environment. Anal Chem 51(1):12–19

    Article  CAS  PubMed  Google Scholar 

  • Brown AW, Aldridge WN, Street BW, Verschoyle RD (1979) The behavioral and neuropathologic sequelae of intoxication by trimethyltin compounds in the rat. Am J Pathol 97(1):59–82

    CAS  PubMed  PubMed Central  Google Scholar 

  • Cookson MR, Slamon ND, Pentreath VW (1998) Glutathione modifies the toxicity of trimethyltin and trimethyltin in C6 glioma cells. Arch Toxicol 72(4):197–202

    Article  CAS  PubMed  Google Scholar 

  • Domenicotti C, Marengo B, Nitti M, Verzola D, Garibotto G, Cottalasso D, Poli G, Melloni E, Pronzato MA, Marinari UM (2003a) A novel role of protein kinase C-δ in cell signaling triggered by glutathione depletion. Biochem Pharmacol 66(8):1521–1526

    Article  CAS  PubMed  Google Scholar 

  • Domenicotti C, Marengo B, Verzola D, Gaibotto G, Traverso N, Patrica S, Maloberti G, Cottalasso D, Poli G, Passalacqua M, Melloni E, Pronzato MA, Marinari UM (2003b) Role of PKC-δ activity in glutathione-depleted neuroblastoma cells. Free Radic Biol Med 35(5):504–516

    Article  CAS  PubMed  Google Scholar 

  • Dyer RS, Walsh TJ, Wonderlin WF, Bercegeay M (1982) The trimethyltin syndrome in rats. Neurobehav Toxicol Teratol 4(2):127–133

    CAS  PubMed  Google Scholar 

  • Eyerman DJ, Yamamoto BK (2007) A rapid oxidation and persistent decrease in the vesicular monoamine transporter 2 after methamphetamine. J Neurochem 103:1219–1227

    Article  CAS  PubMed  Google Scholar 

  • Favaron M, Manev H, Siman R, Bertolino M, Szekely AM, DcEarausquin G, Guidotti A, Coata E (1990) Down-regulation of protein kinase C protects cerebellar granule neurons in primary culture from glutamate-induced neuronal death. Proc Natl Acad Sci USA 87(5):1983–1987

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Geloso MC, Corvino V, Michetti F (2011) Trimethyltin-induced hippocampal degeneration as a tool to investigate neurodegenerative processes. Neurochem Int 58(7):729–738

    Article  CAS  PubMed  Google Scholar 

  • Giorgi C, Agnoletto C, Baldini C, Bononi A, Bonora M, Marchi S, Missiroli S, Patergnani S, Poletti F, Rimessi A, Zavan B, Pinton P (2010) Redox control of protein kinase C: cell- and disease-specific aspects. Antioxid Redox Signal 13(7):1051–1085

    Article  CAS  PubMed  Google Scholar 

  • Gopalakrishna R, Jaken S (2000) Protein kinase C signaling and oxidative stress. Free Radic Biol Med 28(9):1349–1361

    Article  CAS  PubMed  Google Scholar 

  • Guglielmetti F, Rattray M, Baldessari S, Butelli E, Samanin R, Bendotti C (1997) Selective up-regulation of protein kinase C epsilon in granule cells after kainic acid-induced seizures in rat. Mol Brain Res 49(1–2):188–196

    Article  CAS  PubMed  Google Scholar 

  • Ishida N, Akaike M, Tsutsumi S, Kanai H, Masui A, Sadamatsu M, Kuroda Y, Watanabe Y, McEwen BS, Kato N (1997) Trimethyltin syndrome as a hippocampal degeneration model: temporal changes and neurochemical features of seizure susceptibility and learning impairment. Neuroscience 81(4):1183–1191

    Article  CAS  PubMed  Google Scholar 

  • Ishii T, Itoh K, Takahashi S, Sato H, Yanagawa T, Katoh Y, Bannai S, Yamamoto M (2000) Transcription factor Nrf2 coordinately regulates a group of oxidative stress-inducible genes in macrophages. J Biol Chem 275(21):16023–16029

    Article  CAS  PubMed  Google Scholar 

  • Kaasinen SK, Goldsteins G, Alhonen L, Janne J, Koistinaho J (2002) Induction and activation of protein kinase Cδ in hippocampus and cortex after kainic acid treatment. Exp Neurol 176(1):203–212

    Article  CAS  PubMed  Google Scholar 

  • Kane MD, Yang CW, Gunasekar PG, Isom GE (1998) Trimethyltin stimulate protein kinase C translocation through receptor-mediated phospholipase C activation in PC12 cells. J Neurochem 70(2):509–514

    Article  CAS  PubMed  Google Scholar 

  • Kanthasamy AG, Kitazawa M, Kanthasamy A, Anantharam V (2003) Role of proteolytic activation of protein kinase Cδ in oxidative stress-induced apoptosis. Antioxid Redox Signal 5(5):609–620

    Article  CAS  PubMed  Google Scholar 

  • Kim HC, Jhoo WK, Bing G, Shin EJ, Wie MB, Kim WK, Ko KH (2000) Phenidone prevents kainate-induced neurotoxicity via antioxidant mechanisms. Brain Res 874(1):15–23

    Article  CAS  PubMed  Google Scholar 

  • Kim HC, Bing G, Jhoo WK, Kim WK, Shin EJ, Park ES, Choi YS, Lee DW, Shin CY, Ryu JR, Ko KH (2002) Oxidative damage causes formation of lipofuscin-like substances in the hippocampus of the senescence-accelerated mouse after kainate treatment. Behav Brain Res 131(1–2):211–220

    Article  CAS  PubMed  Google Scholar 

  • Koczyk D (1996) How does trimethyltin affect the brain: facts and hypotheses. Acta Neurobiol Exp 56(2):587–596

    CAS  Google Scholar 

  • Kwon YS, Ann HS, Nabeshima T, Shin EJ, Kim WK, Jhoo JH, Jhoo WK, Wie MB, Kim YS, Jang KJ, Kim HC (2004) Selegiline potentiates the effects of EGb 761 in response to ischemic brain injury. Neurochem Int 45(1):157–170

    Article  CAS  PubMed  Google Scholar 

  • Lattanzi W, Corvino V, Di Maria V, Michetti F, Geloso MC (2013) Gene expression profiling as a tool to investigate the molecular machinery activated during hippocampal neurodegeneration induced by trimethyltin (TMT) administration. Int J Mol Sci 14(8):16817–16835

    Article  PubMed  PubMed Central  Google Scholar 

  • Lebel CP, Bondy SC (1990) Sensitive and rapid quantitation of oxygen reactive species formation in rat synaptosomes. Neurochem Int 17(3):435–440

    Article  CAS  PubMed  Google Scholar 

  • Lee JM, Calkins MJ, Chan K, Kan YW, Johnson JA (2003) Identification of the NF-E2-related factor-2-dependent genes conferring protection against oxidative stress in primary cortical astrocytes using oligonucleotide microarray analysis. J Biol Chem 278(14):12029–12038

    Article  CAS  PubMed  Google Scholar 

  • Lefebvre d’Hellencourt C, Harry GJ (2005) Molecular profiles of mRNA levels in laser capture microdissected murine hippocampal regions differentially responsive to TMT-induced cell death. J Neurochem 93(1):206–220

    Article  PubMed  Google Scholar 

  • Li W, Khor TO, Xu C, Shen G, Jeong WS, Yu S, Kong AN (2008) Activation of Nrf2-antioxidant signaling attenuates NFκB-inflammatory response and elicits apoptosis. Biochem Pharmacol 76(11):1485–1489

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Liu JX, Liu Y, Tang FR (2011) Pilocarpine-induced status epilepticus alters hippocampal PKC expression in mice. Acta Neurobiol Exp 71(2):220–232

    Google Scholar 

  • Marengo B, De Ciucis C, Ricciarelli R, Passalacqua M, Nitti M, Zingg JM, Marinari UM, Pronzato MA, Domenicotti C (2011) PKCδ sensitizes neuroblastoma cells to l-buthionine-sulfoximine and etoposide inducing reactive oxygen species overproduction and DNA damage. PLoS One 6(2):e1466

    Article  Google Scholar 

  • Mellor H, Parker PJ (1998) The extended protein kinase C superfamily. Biochem J 332(Pt 2):281–292

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Miyamoto A, Nakayama K, Imaki H, Hirose S, Jiang Y, Abe M, Tsukiyama T, Nagahama H, Ohno S, Hatakeyama S, Nakayama KI (2002) Increased proliferation of B cells and auto-immunity in mice lacking protein kinase Cδ. Nature 416(6883):865–869

    Article  CAS  PubMed  Google Scholar 

  • Nagashima R, Sano S, Huong NQ, Shiba T, Ogita K (2010) Enhanced expression of glutathione-S-transferase in the hippocampus following acute treatment with trimethyltin in vivo. J Pharmacol Sci 113(3):267–270

    Article  CAS  PubMed  Google Scholar 

  • Narasimhan M, Mahimainathan L, Rathinam ML, Riar AK, Henderson GI (2011) Overexpression of Nrf2 protects cerebral cortical neurons from ethanol-induced apoptotic death. Mol Pharmacol 80:988–999

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Nishizuka Y (1995) Protein kinase C and lipid signaling for sustained cellular responses. FASEB J 9(7):484–496

    CAS  PubMed  Google Scholar 

  • Ogita K, Nitta Y, Watanabe M, Nakatani Y, Nishiyama N, Sugiyama C, Yoneda Y (2004) In vivo activation of c-Jun N-terminal kinase signaling cascade prior to granule cell death induced by trimethyltin in the dentate gyrus of mice. Neuropharmacology 47(4):619–630

    Article  CAS  PubMed  Google Scholar 

  • Oliver CN, Ahn BW, Moerman EJ, Goldstein S, Stadtman ER (1987) Age-related changes in oxidized proteins. J Biol Chem 262(12):5488–5491

    CAS  PubMed  Google Scholar 

  • Ono M, Akiyama K, Tsutsui K, Kuroda S (1994) Differential changes in the activities of multiple protein kinase C subspecies in the hippocampal-kindled rat. Brain Res 660(1):27–33

    Article  CAS  PubMed  Google Scholar 

  • Pavlakovic G, Eyer CL, Isom GE (1995a) Neuroprotective effects of PKC inhibition against chemical hypoxia. Brain Res 676(1):205–211

    Article  CAS  PubMed  Google Scholar 

  • Pavlakovic G, Kane MD, Eyer CL, Kanthasamay A, Isom GE (1995b) Activation of protein kinase C by trimethyltin: relevance to neurotoxicity. J Neurochem 65(5):2338–2343

    Article  CAS  PubMed  Google Scholar 

  • Reed DJ, Ellis WW, Meck RA (1980) The inhibition of gamma-glutamyl transpeptidase and glutathione metabolism of isolated rat kidney cells by l-(αS, 5S)-α-amino-3-chloro-4, 5-dihydro-5-isoxazoleacetic acid (AT-125; NSC-163501). Biochem Biophys Res Commun 94(4):1273–1277

    Article  CAS  PubMed  Google Scholar 

  • Sasaki H, Sato H, Kuriyama-Matsumura K, Sato K, Maebara K, Wang H, Tamba M, Itoh K, Yamamoto M, Bannai S (2002) Electrophile response element-mediated induction of the cystine/glutamate exchange transporter gene expression. J Biol Chem 277(47):44765–44771

    Article  CAS  PubMed  Google Scholar 

  • Shawky S, Emons H (1998) Distribution pattern of organotin compounds at different trophic levels of aquatic ecosystems. Chemosphere 36(3):523–535

    Article  CAS  PubMed  Google Scholar 

  • Shih AY, Johnson DA, Wong G, Kraft AD, Jiang L, Erb H, Johnson JA, Murphy TH (2003) Coordinate regulation of glutathione biosynthesis and release by Nrf2-expressing glia potently protects neurons from oxidative stress. J Neurosci 23(8):3394–3406

    CAS  PubMed  Google Scholar 

  • Shin EJ, Suh SK, Lim YK, Jhoo WK, Hjelle OP, Ottersen OP, Shin CY, Ko KH, Kim WK, Kim DS, Chun W, Ali S, Kim HC (2005) Ascorbate attenuates trimethyltin-induced oxidative burden and neuronal degeneration in the rat hippocampus by maintaining glutathione homeostasis. Neuroscience 133(3):715–727

    Article  CAS  PubMed  Google Scholar 

  • Shin EJ, Jeong JH, Chung YH, Ko KH, Bach JH, Hong JS, Yoneda Y, Kim HC (2011) Role of oxidative stress in epileptic seizures. Neurochem Int 59(2):122–137

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin EJ, Duong CX, Nguyen XK, Li Z, Bing G, Bach JH, Park DH, Nakayama K, Ali SF, Kanthasamy AG, Cadet JL, Nabeshima T, Kim HC (2012) Role of oxidative stress in methamphetamine-induced dopaminergic toxicity mediated by protein kinase Cδ. Behav Brain Res 232(1):98–113

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Shin EJ, Shin SW, Nguyen TTL, Park DH, Wie MB, Jang CG, Nah SY, Yang BW, Ko SK, Nabeshima T, Kim HC (2014) Ginsenoside Re rescues methamphetamine-induced oxidative damage, mitochondrial dysfunction, microglial activation, and dopaminergic degeneration by inhibiting the protein kinase Cδ gene. Mol Neurobiol 49(3):1400–1421

    Article  CAS  PubMed  Google Scholar 

  • Shuto M, Higuchi K, Sugiyama C, Yoneyama M, Kuramoto N, Nagashima R, Kawada K, Ogita K (2009) Endogenous and exogenous glucocorticoids prevent trimethyltin from causing neuronal degeneration of the mouse brain in vivo: involvement of oxidative stress pathways. J Pharmacol Sci 110(4):424–436

    Article  CAS  PubMed  Google Scholar 

  • Silva AP, Lourenco J, Xapelli S, Ferreira R, Kristiansen H, Woldbye DP, Oliviera CR, Malva JO (2007) Protein kinase C activity blocks neuropeptide Y-mediated inhibition of glutamate release and contributes to excitability of the hippocampus in status epileticus. FASEB J 21(3):671–681

    Article  CAS  PubMed  Google Scholar 

  • Singh A, Boldin-Adamsky S, Thimmulappa RK, Rath SK, Ashush H, Coulter J, Blackford A, Goodman SN, Bunz F, Watson WH, Gabrielson E, Feinstein E, Biswal S (2008) RNAi-mediated silencing of nuclear factor erythroid-2-related factor 2 gene expression in non-small cell lung cancer inhibits tumor growth and increases efficacy of chemotherapy. Cancer Res 68(19):7975–7984

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Sloviter RS, von Knebel Doeberitz C, Walsh TJ, Dempster DW (1986) On the role of seizure activity in the hippocampal damage produced by trimethyltin. Brain Res 367(1–2):169–182

    Article  CAS  PubMed  Google Scholar 

  • Steinberg SF (2004) Distinctive activation mechanisms and functions for protein kinase Cδ. Biochem J 384(Pt3):449–459

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tang FR, Lee WL, Gao H, Chen Y, Loh YT, Chia SC (2004) Expression of different isoforms of protein kinase C in the rat hippocampus after pilocarpine-induced status epilepticus with special reference to CA1 area and the dentate gyrus. Hippocampus 14(1):87–98

    Article  CAS  PubMed  Google Scholar 

  • Terunuma M, Xu J, Vihlani M, Sieghart W, Kittler J, Pangalos M, Haydon PG, Coulter DA, Moss SJ (2008) Deficits in phosphorylation of GABAA receptors by intimately associated protein kinase C activity underlie compromised synaptic inhibition during status epilepticus. J Neurosci 28(2):376–384

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  • Tran HY, Shin EJ, Saito K, Nguyen XK, Chung YH, Jeong JH, Bach JH, Park DH, Yamada K, Nabeshima T, Yoneda Y, Kim HC (2012) Protective potential of IL-6 against trimethyltin-induced neurotoxicity in vivo. Free Radic Biol Med 52(7):1159–1174

    Article  CAS  PubMed  Google Scholar 

  • Ward NE, Pierce DS, Chung SE, Gravitt KR, O’Brien CA (1998) Irreversible inactivation of protein kinase C by glutathione. J Biol Chem 273(20):12558–12566

    Article  CAS  PubMed  Google Scholar 

  • Yang E, Zha J, Jockel J, Boise LH, Thompson CB, Korsmeyer SJ (1995) Bad, a heterodimeric partner for Bcl-XL and Bcl-2, displaces Bax and promotes cell death. Cell 80(2):285–291

    Article  CAS  PubMed  Google Scholar 

  • Yoneyama M, Nishiyama N, Shuto M, Sugiyama C, Kawada K, Seko K, Nagashima R, Ogita K (2008) In vivo depletion of endogenous glutathione facilitates trimethyltin-induced neuronal damage in the dentate gyrus of mice by enhancing oxidative stress. Neurochem Int 52(4–5):761–769

    Article  CAS  PubMed  Google Scholar 

  • Yoshida K (2007) PKCδ signaling: mechanisms of DNA damage response and apoptosis. Cell Signal 19(5):892–901

    Article  CAS  PubMed  Google Scholar 

  • Zha J, Harada H, Yang E, Jockel J, Korsmeyer SJ (1996) Serine phosphorylation of death agonist BAD in response to survival factor results in binding to 14-3-3 not BCL-XL. Cell 87(4):619–628

    Article  CAS  PubMed  Google Scholar 

Download references

Acknowledgments

The English in this document has been checked by at least two professional editors, both native speakers of English (Beverly Hills English, Los Angeles, CA90024, USA). This work was supported by Basic Science Research Program through the National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT and Future Planning (#NRF-2013R1A1A2060894 and #NRF-2013R1A1A1007378), Republic of Korea. Y. Nam and T.-H. T. Tu are involved in BK21 PLUS program, NRF, Republic of Korea.

Conflict of interest

The authors declare that they have no conflict of interest.

Ethical standard

All procedures performed in studies involving animals were in strict accordance with the ethical standards of the Kangwon National University IACUC and the NIH Guide for the Humane Care and Use of Laboratory Animals. This article does not contain any studies with human participants performed by any of the authors.

Author information

Author notes

    Authors and Affiliations

    1. Neuropsychopharmacology and Toxicology Program, College of Pharmacy, Kangwon National University, Chunchon, 200-701, Republic of Korea

      Eun-Joo Shin, Yunsung Nam, Thu-Hien Thi Tu, Yong Kwang Lim & Hyoung-Chun Kim

    2. School of Veterinary Medicine, Kangwon National University, Chunchon, 200-701, Republic of Korea

      Myung-Bok Wie

    3. Department of Anatomy and Cell Biology, Medical School, Kangwon National University, Chunchon, 200-701, Republic of Korea

      Dae-Joong Kim

    4. Department of Pharmacology, College of Medicine, Chung-Ang University, Seoul, 156-756, Republic of Korea

      Ji Hoon Jeong

    Authors
    1. Eun-Joo Shin
      View author publications

      You can also search for this author in PubMed Google Scholar

    2. Yunsung Nam
      View author publications

      You can also search for this author in PubMed Google Scholar

    3. Thu-Hien Thi Tu
      View author publications

      You can also search for this author in PubMed Google Scholar

    4. Yong Kwang Lim
      View author publications

      You can also search for this author in PubMed Google Scholar

    5. Myung-Bok Wie
      View author publications

      You can also search for this author in PubMed Google Scholar

    6. Dae-Joong Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    7. Ji Hoon Jeong
      View author publications

      You can also search for this author in PubMed Google Scholar

    8. Hyoung-Chun Kim
      View author publications

      You can also search for this author in PubMed Google Scholar

    Corresponding author

    Correspondence to Hyoung-Chun Kim.

    Additional information

    Eun-Joo Shin and Yunsung Nam have contributed equally to this work.

    Electronic supplementary material

    Below is the link to the electronic supplementary material.

    Supplementary material 1 (DOCX 40 kb)

    Supplementary material 2 (TIFF 548 kb)

    Rights and permissions

    Reprints and permissions

    About this article

    Check for updates. Verify currency and authenticity via CrossMark

    Cite this article

    Shin, EJ., Nam, Y., Tu, TH.T. et al. Protein kinase Cδ mediates trimethyltin-induced neurotoxicity in mice in vivo via inhibition of glutathione defense mechanism. Arch Toxicol 90, 937–953 (2016). https://doi.org/10.1007/s00204-015-1516-7

    Download citation

    • Received:

    • Accepted:

    • Published:

    • Issue Date:

    • DOI: https://doi.org/10.1007/s00204-015-1516-7

    Keywords

    Search

    Navigation