Skip to main content

Advertisement

SpringerLink
Log in

Minocycline reduces oxygen–glucose deprivation-induced PC12 cell cytotoxicity via matrix metalloproteinase-9, integrin β1 and phosphorylated Akt modulation

  • Original Article
  • Published:
Neurological Sciences Aims and scope Submit manuscript

Abstract

Minocycline has shown anti-inflammatory, anti-apoptotic, and antioxidative activities in many models of cerebral ischemia and human acute ischemic stroke. However, the cellular and molecular bases for its neuroprotective effects have not been fully elucidated. In this study, we investigated whether pre-treatment with minocycline could attenuate oxygen–glucose deprivation-induced PC12 cytotoxicity. The activity of matrix metalloproteinase-9 was detected by sodium dodecyl sulfate–polyacrylamide gel electrophoresis zymography. And the expressions of integrin β1, Akt and phosphorylated Akt were analyzed by Western blot. Our results showed that minocycline could ameliorate oxygen–glucose deprivation-induced PC12 cell cytotoxicity at concentrations of 20 nM–20 μM, down-regulate the production and activity of matrix metalloproteinase-9, inhibit the degradation of integrin β1, and up-regulate Akt phosphorylation at optimal concentration of 200 nM. The results may provide a new area for minocycline’s therapeutic intervention for improving the outcomes of cerebral ischemia.

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

Similar content being viewed by others

References

  1. Yong VW, Wells J, Giuliani F, Casha S, Power C, Metz M (2004) The promise of minocycline in neurology. Lancet Neurol 3:744–751

    Article  PubMed  Google Scholar 

  2. Yrjanheikki J, Keinanen R, Pellikka M, Hokfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774

    Article  PubMed  CAS  Google Scholar 

  3. Yrjanheikki J, Tikka T, Keinanen R, Goldsteins G, Chan PH, Koistinaho J (1999) A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proc Natl Acad Sci USA 96:13496–13500

    Article  PubMed  CAS  Google Scholar 

  4. Lampl Y, Boaz M, Gilad R, Lorberboym M, Dabby R, Rapoport A, Anca-Hershkowitz M, Sadeh M (2007) Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69:1404–1410

    Article  PubMed  CAS  Google Scholar 

  5. Fagan SC, Waller JL, Nichols FT, Edwards DJ, Pettigrew LC, Clark WM, Hall CE, Switzer JA, Ergul A, Hess DC (2010) Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 41:2283–2287

    Article  PubMed  CAS  Google Scholar 

  6. Sternlicht MD, Werb Z (2001) How matrix metalloproteinases regulate cell behavior. Annu Rev Cell Dev Biol 17:463–516

    Article  PubMed  CAS  Google Scholar 

  7. Yong VW, Power C, Forsyth P, Edwards DR (2001) Metalloproteinases in biology and pathology of the nervous system. Nat Rev Neurosci 2:502–511

    Article  PubMed  CAS  Google Scholar 

  8. Lee SR, Lo EH (2004) Induction of caspase-mediated cell death by matrix metalloproteinases in cerebral endothelial cells after hypoxia-reoxygenation. J Cereb Blood Flow Metab 24:720–727

    Article  PubMed  CAS  Google Scholar 

  9. Kim GW, Kim HJ, Cho KJ, Kim HW, Cho YJ, Lee BI (2009) The role of MMP-9 in integrin-mediated hippocampal cell death after pilocarpine-induced status epilepticus. Neurobiol Dis 36:169–180

    Article  PubMed  CAS  Google Scholar 

  10. Lee JW, Juliano RL (2000) alpha5beta1 integrin protects intestinal epithelial cells from apoptosis through a phosphatidylinositol 3-kinase and protein kinase B-dependent pathway. Mol Biol Cell 11:1973–1987

    Article  PubMed  CAS  Google Scholar 

  11. Saito A, Hayashi T, Okuno S, Nishi T, Chan PH (2004) Oxidative stress affects the integrin-linked kinase signaling pathway after transient focal cerebral ischemia. Stroke 35:2560–2565

    Article  PubMed  CAS  Google Scholar 

  12. Nakajima T, Wakasa T, Okuma Y, Inanami O, Nomura Y, Kuwahara M, Kawahara K (2006) Dual inhibition of protein phosphatase-1/2a and calpain rescues nerve growth factor-differentiated PC12 cells from oxygen–glucose deprivation-induced cell death. J Neurosci Res 83:459–468

    Article  PubMed  CAS  Google Scholar 

  13. Rajput SK, Siddiqui MA, Kumar V, Meena CL, Pant AB, Jain R, Sharma SS (2011) Protective effects of L-pGlu-(2-propyl)-L-His-L-ProNH2, a newer thyrotropin releasing hormone analog in vitro and in vivo models of cerebral ischemia. Peptides 32:1225–1231

    Article  PubMed  CAS  Google Scholar 

  14. Kawakami Z, Kanno H, Ikarashi Y, Kase Y (2011) Yokukansan, a kampo medicine, protects against glutamate cytotoxicity due to oxidative stress in PC12 cells. J Ethnopharmacol 134:74–81

    Article  PubMed  CAS  Google Scholar 

  15. Zhou XQ, Zeng XN, Kong H, Sun XL (2008) Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci Lett 447:31–36

    Article  PubMed  CAS  Google Scholar 

  16. Miyamoto W, Min HS, Lillehoj HS (2002) Lymphocyte proliferation response during Eimeria tenella infection assessed by a new, reliable, nonradioactive colorimetric assay. Avian Dis 46:10–16

    Article  PubMed  Google Scholar 

  17. Zhang A, Zhang J, Sun P, Yao C, Su C, Sui T, Huang H, Cao X, Ge Y (2010) EIF2alpha and caspase-12 activation are involved in oxygen-glucose-serum deprivation/restoration-induced apoptosis of spinal cord astrocytes. Neurosci Lett 478:32–36

    Article  PubMed  CAS  Google Scholar 

  18. Ma X, Jiang Y, Wu A, Chen X, Pi R, Liu M, Liu Y (2010) Berberine attenuates experimental autoimmune encephalomyelitis in C57 BL/6 mice. PLoS One 5:e13489

    Article  PubMed  Google Scholar 

  19. Zhou XQ, Zeng XN, Kong H, Sun XL (2008) Neuroprotective effects of berberine on stroke models in vitro and in vivo. Neurosci Lett 447:31–36

    Article  PubMed  CAS  Google Scholar 

  20. Lee CK, Shin JI, Cho YS (2011) Protective effect of minocycline against cisplatin-induced ototoxicity. Clin Exp Otorhinolaryngol 4:77–82

    Article  PubMed  CAS  Google Scholar 

  21. Yrjänheikki J, Keinänen R, Pellikka M, Hökfelt T, Koistinaho J (1998) Tetracyclines inhibit microglial activation and are neuroprotective in global brain ischemia. Proc Natl Acad Sci USA 95:15769–15774

    Article  PubMed  Google Scholar 

  22. Morimoto N, Shimazawa M, Yamashima T, Nagai H, Hara H (2005) Minocycline inhibits oxidative stress and decreases in vitro and in vivo ischemic neuronal damage. Brain Res 1044:8–15

    Article  PubMed  CAS  Google Scholar 

  23. Song Y, Wei EQ, Zhang WP, Zhang L, Liu JR, Chen Z (2004) Minocycline protects PC12 cells from ischemic-like injury and inhibits 5-lipoxygenase activation. Neuroreport 15:2181–2184

    Article  PubMed  CAS  Google Scholar 

  24. Kikuchi K, Kawahara K, Biswas KK, Ito T, Tancharoen S, Morimoto Y, Matsuda F, Oyama Y, Takenouchi K, Miura N, Arimura N, Nawa Y, Meng X, Shrestha B, Arimura S, Iwata M, Mera K, Sameshima H, Ohno Y, Maenosono R, Yoshida Y, Tajima Y, Uchikado H, Kuramoto T, Nakayama K, Shigemori M, Hashiguchi T, Maruyama I (2009) Minocycline attenuates both OGD-induced HMGB1 release and HMGB1-induced cell death in ischemic neuronal injury in PC12 cells. Biochem Biophys Res Commun 385:132–136

    Article  PubMed  CAS  Google Scholar 

  25. Huang CL, Lee YC, Yang YC, Kuo TY, Huang NK (2012) Minocycline prevents paraquat-induced cell death through attenuating endoplasmic reticulum stress and mitochondrial dysfunction. Toxicol Lett 209:203–210

    Article  PubMed  CAS  Google Scholar 

  26. Hollborn M, Wiedemann P, Bringmann A, Kohen L (2010) Chemotactic and cytotoxic effects of minocycline on human retinal pigment epithelial cells. Invest Ophthalmol Vis Sci 51:2721–2729

    Article  PubMed  Google Scholar 

  27. Asahi M, Asahi K, Jung JC, del Zoppo GJ, Fini ME, Lo EH (2000) Role for matrix metalloproteinase 9 after focal cerebral ischemia: effects of gene knockout and enzyme inhibition with BB-94. J Cereb Blood Flow Metab 20:1681–1689

    Article  PubMed  CAS  Google Scholar 

  28. Gu Z, Kaul M, Yan B, Kridel SJ, Cui J, Strongin A, Smith JW, Liddington RC, Lipton SA (2002) S-nitrosylation of matrix metalloproteinases: signaling pathway to neuronal cell death. Science 297:1186–1190

    Article  PubMed  CAS  Google Scholar 

  29. Magnoni S, Baker A, George SJ, Duncan WC, Kerr LE, McCulloch J, Horsburgh K (2004) Differential alterations in the expression and activity of matrix metalloproteinases 2 and 9 after transient cerebral ischemia in mice. Neurobiol Dis 17:188–197

    Article  PubMed  CAS  Google Scholar 

  30. Machado LS, Anna Kozak, Ergul A, Hess DC, Borlongan CV, Fagan SC (2006) Delayed minocycline inhibits ischemia-activated matrix metalloproteinases 2 and 9 after experimental stroke. BMC Neurosci 7:1–7

    Article  Google Scholar 

  31. Bouchard V, Demers MJ, Thibodeau S, Laquerre V, Fujita N, Tsuruo T, Beaulieu JF, Gauthier R, Vezina A, Villeneuve L, Vachon PH (2007) Fak/Src signaling in human intestinal epithelial cell survival and anoikis: differentiation state-specific uncoupling with the PI3-K/Akt-1 and MEK/Erk pathways. J Cell Physiol 212:717–728

    Article  PubMed  CAS  Google Scholar 

  32. Pankov R, Cukierman E, Clark K, Matsumoto K, Hahn C, Poulin B, Yamada KM (2003) Specific beta1 integrin site selectively regulates Akt/protein kinase B signaling via local activation of protein phosphatase 2A. J Biol Chem 278:18671–18681

    Article  PubMed  CAS  Google Scholar 

  33. Burgering BM, Coffer PJ (1995) Protein kinase B (c-Akt) in phosphatidylinositol-3-OH kinase signal transduction. Nature 376:599–602

    Article  PubMed  CAS  Google Scholar 

  34. Kaya D, Gursoy-Ozdemir Y, Yemisci M, Tuncer N, Aktan S, Dalkara T (2005) VEGF protects brain against focal ischemia without increasing blood—brain permeability when administered intracerebroventricularly. J Cereb Blood Flow Metab 25:1111–1118

    Article  PubMed  CAS  Google Scholar 

  35. Zhao H, Sapolsky RM, Steinberg GK (2006) Phosphoinositide-3-kinase/Akt survival signal pathways are implicated in neuronal survival after stroke. Mol Neurobiol 34:249–269

    Article  PubMed  CAS  Google Scholar 

  36. Franke TF (2008) PI3k/Akt: getting it right matters. Oncogene 27:6473–6488

    Article  PubMed  CAS  Google Scholar 

Download references

Acknowledgments

This work was supported by grants (to X Chen) from the National Natural Science Foundation of China (81071068).

Author information

Authors and Affiliations

  1. Department of Neurology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, 510630, Guangdong, China

    Xiaohong Chen, Ying Jiang, Cansheng Zhu, Aimin Wu, Xiaomeng Ma, Fuhua Peng, Lili Ma, Dongliang Zhu & Qing Wang

  2. Department of Radiology, The Third Affiliated Hospital, Sun Yat-sen University, 600 Tianhe Road, Guangzhou, China

    Shaoqiong Chen

  3. Department of Pharmacology and Toxicology, School of Pharmaceutical Sciences Sun Yat-sen University, Guangzhou, China

    Rongbiao Pi

Authors
  1. Xiaohong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Shaoqiong Chen
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Ying Jiang
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Cansheng Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Aimin Wu
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Xiaomeng Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Fuhua Peng
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Lili Ma
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Dongliang Zhu
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Qing Wang
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Rongbiao Pi
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Xiaohong Chen.

Additional information

X. Chen and S. Chen contributed equally to this work.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Chen, X., Chen, S., Jiang, Y. et al. Minocycline reduces oxygen–glucose deprivation-induced PC12 cell cytotoxicity via matrix metalloproteinase-9, integrin β1 and phosphorylated Akt modulation. Neurol Sci 34, 1391–1396 (2013). https://doi.org/10.1007/s10072-012-1246-z

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10072-012-1246-z

Keywords

Search

Navigation