Skip to main content
Log in

Minocycline Treatment and Bone Marrow Mononuclear Cell Transplantation After Endothelin-1 Induced Striatal Ischemia

  • Published:
Inflammation Aims and scope Submit manuscript

Abstract

We explored whether the modulation of microglia activation with minocycline is beneficial to the therapeutic actions of bone marrow mononuclear cells (BMMCs) transplanted after experimental stroke. Male Wistar adult rats were divided in four experimental groups: ischemic control saline treated (G1, N = 6), ischemic minocycline treated (G2, N = 5), ischemic BMMC treated (G3, N = 5), and ischemic minocycline/BMMC treated (G4, N = 6). There was a significant reduction in the number of ED1+ cells in G3 animals (51.31 ± 2.41, P < 0.05), but this effect was more prominent following concomitant treatment with minocycline (G4 = 29.78 ± 1.56). There was conspicuous neuronal preservation in the brains of G4 animals (87.97 ± 4.27) compared with control group (G1 = 47.61 ± 2.25, P < 0.05). The behavioral tests showed better functional recovery in animals of G2, G3, and G4, compared with G1 and baseline (P < 0.05). The results suggest that a proper modulation of microglia activity may contribute to a more permissive ischemic environment contributing to increased neuroprotection and functional recovery following striatal ischemia.

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

Access this article

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

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3

Similar content being viewed by others

References

  1. Perry, V.H., J.A. Nicoll, and C. Holmes. 2010. Microglia in neurodegenerative disease. Nature Reviews Neurology 6: 193–201.

    Article  PubMed  Google Scholar 

  2. Lalancette-Hebert, M., G. Gowing, A. Simard, Y.C. Weng, and J. Kriz. 2007. Selective ablation of proliferating microglial cells exacerbates ischemic injury in the brain. Journal of Neuroscience 27: 2596–2605.

    Article  PubMed  CAS  Google Scholar 

  3. Neumann, J., S. Sauerzweig, R. Ronicke, F. Gunzer, K. Dinkel, O. Ullrich, et al. 2008. Microglia cells protect neurons by direct engulfment of invading neutrophil granulocytes: a new mechanism of CNS immune privilege. Journal of Neuroscience 28: 5965–5975.

    Article  PubMed  CAS  Google Scholar 

  4. Thored, P., U. Heldmann, W. Gomes-Leal, R. Gisler, V. Darsalia, J. Taneera, et al. 2009. Long-term accumulation of microglia with proneurogenic phenotype concomitant with persistent neurogenesis in adult subventricular zone after stroke. Glia 57: 835–849.

    Article  PubMed  Google Scholar 

  5. Yrjanheikki, J., T. Tikka, R. Keinanen, G. Goldsteins, P.H. Chan, and J. Koistinaho. 1999. A tetracycline derivative, minocycline, reduces inflammation and protects against focal cerebral ischemia with a wide therapeutic window. Proceedings of the National Academy of Sciences of the United States of America 96: 13496–13500.

    Article  PubMed  CAS  Google Scholar 

  6. Hamby, A.M., S.W. Suh, T.M. Kauppinen, and R.A. Swanson. 2007. Use of a poly(ADP-ribose) polymerase inhibitor to suppress inflammation and neuronal death after cerebral ischemia-reperfusion. Stroke 38: 632–636.

    Article  PubMed  CAS  Google Scholar 

  7. Burguillos, M.A., T. Deierborg, E. Kavanagh, A. Persson, N. Hajji, A. Garcia-Quintanilla, et al. 2011. Caspase signalling controls microglia activation and neurotoxicity. Nature 472: 319–324.

    Article  PubMed  CAS  Google Scholar 

  8. Block, M.L., L. Zecca, and J.S. Hong. 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8: 57–69.

    Article  PubMed  CAS  Google Scholar 

  9. Lampl, Y., M. Boaz, R. Gilad, M. Lorberboym, R. Dabby, A. Rapoport, et al. 2007. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 69: 1404–1410.

    Article  PubMed  CAS  Google Scholar 

  10. Schabitz, W.R., A. Schneider, and R. Laage. 2008. Minocycline treatment in acute stroke: an open-label, evaluator-blinded study. Neurology 71: 1461. author reply 1461.

    Article  PubMed  Google Scholar 

  11. Fagan, S.C., J.L. Waller, F.T. Nichols, D.J. Edwards, L.C. Pettigrew, W.M. Clark, et al. 2010. Minocycline to improve neurologic outcome in stroke (MINOS): a dose-finding study. Stroke 41: 2283–2287.

    Article  PubMed  CAS  Google Scholar 

  12. Weissman, I.L., D.J. Anderson, and F. Gage. 2001. Stem and progenitor cells: origins, phenotypes, lineage commitments, and transdifferentiations. Annual Review of Cell and Developmental Biology 17: 387–403.

    Article  PubMed  CAS  Google Scholar 

  13. de Vasconcelos Dos Santos, A., J. da Costa Reis, B. Diaz Paredes, L. Moraes, Jasmin, A. Giraldi-Guimaraes, et al. 2010. Therapeutic window for treatment of cortical ischemia with bone marrow-derived cells in rats. Brain Research 1306: 149–158.

    Article  PubMed  Google Scholar 

  14. Iihoshi, S., O. Honmou, K. Houkin, K. Hashi, and J.D. Kocsis. 2004. A therapeutic window for intravenous administration of autologous bone marrow after cerebral ischemia in adult rats. Brain Research 1007: 1–9.

    Article  PubMed  CAS  Google Scholar 

  15. Brenneman, M., S. Sharma, M. Harting, R. Strong, C.S. Cox Jr., J. Aronowski, et al. 2010. Autologous bone marrow mononuclear cells enhance recovery after acute ischemic stroke in young and middle-aged rats. Journal of Cerebral Blood Flow and Metabolism 30: 140–149.

    Article  PubMed  Google Scholar 

  16. Taylor, P.L. 2011. Responsibility rewarded: ethics, engagement, and scientific autonomy in the labyrinth of the minotaur. Neuron 70: 577–581.

    Article  PubMed  CAS  Google Scholar 

  17. Ideguchi, M., M. Shinoyama, M. Gomi, H. Hayashi, N. Hashimoto, and J. Takahashi. 2008. Immune or inflammatory response by the host brain suppresses neuronal differentiation of transplanted ES cell-derived neural precursor cells. Journal of Neuroscience Research 86: 1936–1943.

    Article  PubMed  CAS  Google Scholar 

  18. Buja, L.M., and D. Vela. 2010. Immunologic and inflammatory reactions to exogenous stem cells implications for experimental studies and clinical trials for myocardial repair. Journal of the American College of Cardiology 56: 1693–1700.

    Article  PubMed  CAS  Google Scholar 

  19. Rota Nodari, L., D. Ferrari, F. Giani, M. Bossi, V. Rodriguez-Menendez, G. Tredici, et al. 2010. Long-term survival of human neural stem cells in the ischemic rat brain upon transient immunosuppression. PLoS One 5. e14035.

  20. Keimpema, E., M.R. Fokkens, Z. Nagy, V. Agoston, P.G. Luiten, C. Nyakas, et al. 2009. Early transient presence of implanted bone marrow stem cells reduces lesion size after cerebral ischaemia in adult rats. Neuropathology and Applied Neurobiology 35: 89–102.

    Article  PubMed  CAS  Google Scholar 

  21. Michel-Monigadon, D., V. Nerriere-Daguin, X. Leveque, M. Plat, E. Venturi, P. Brachet, et al. 2010. Minocycline promotes long-term survival of neuronal transplant in the brain by inhibiting late microglial activation and T-cell recruitment. Transplantation 89: 816–823.

    Article  PubMed  CAS  Google Scholar 

  22. Morioka, T., A.N. Kalehua, and W.J. Streit. 1993. Characterization of microglial reaction after middle cerebral artery occlusion in rat brain. The Journal of Comparative Neurology 327: 123–132.

    Article  PubMed  CAS  Google Scholar 

  23. Souza-Rodrigues, R.D., R.R. Lima, J. Guimaraes-Silva, A.M. Costa, C.D. Dos Santos, C.W. Picanço-Diniz, et al. 2008. Inflammatory response and white matter damage after microinjections of endothelin-1 into the rat striatum. Brain Research 1200C: 78–88.

    Article  Google Scholar 

  24. Dos Santos, C.D., C.W. Picanço-Diniz, and W. Gomes-Leal. 2007. Differential patterns of inflammatory response, axonal damage and myelin impairment following excitotoxic or ischemic damage to the trigeminal spinal nucleus of adult rats. Brain Research 1172: 130–144.

    Article  PubMed  CAS  Google Scholar 

  25. Paxinos, G., C.R. Watson, and P.C. Emson. 1980. AChE-stained horizontal sections of the rat brain in stereotaxic coordinates. Journal of Neuroscience Methods 3: 129–149.

    Article  PubMed  CAS  Google Scholar 

  26. Stirling, D.P., K. Khodarahmi, J. Liu, L.T. McPhail, C.B. McBride, J.D. Steeves, et al. 2004. Minocycline treatment reduces delayed oligodendrocyte death, attenuates axonal dieback, and improves functional outcome after spinal cord injury. Journal of Neuroscience 24: 2182–2190.

    Article  PubMed  CAS  Google Scholar 

  27. Ekdahl, C.T., J.H. Claasen, S. Bonde, Z. Kokaia, and O. Lindvall. 2003. Inflammation is detrimental for neurogenesis in adult brain. Proceedings of the National Academy of Sciences of the United States of America 100: 13632–13637.

    Article  PubMed  CAS  Google Scholar 

  28. Giraldi-Guimaraes, A., M. Rezende-Lima, F.P. Bruno, and R. Mendez-Otero. 2009. Treatment with bone marrow mononuclear cells induces functional recovery and decreases neurodegeneration after sensorimotor cortical ischemia in rats. Brain Research 9: 108–120.

    Article  Google Scholar 

  29. Franco, E.C., M.M. Cardoso, A. Gouvêia, A. Pereira, and W. Gomes-Leal. 2012. Modulation of microglial activation enhances neuroprotection and functional recovery derived from bone marrow mononuclear cell transplantation after cortical ischemia. Neuroscience Research 73: 122–132.

    Article  PubMed  CAS  Google Scholar 

  30. Sughrue, M.E., J. Mocco, R.J. Komotar, A. Mehra, A.L. D’Ambrosio, B.T. Grobelny, et al. 2006. An improved test of neurological dysfunction following transient focal cerebral ischemia in rats. Journal of Neuroscience Methods 151: 83–89.

    Article  PubMed  Google Scholar 

  31. Mullen, R.J., C.R. Buck, and A.M. Smith. 1992. NeuN, a neuronal specific nuclear protein in vertebrates. Development 116: 201–211.

    PubMed  CAS  Google Scholar 

  32. Dijkstra, C.D., E.A. Dopp, P. Joling, and G. Kraal. 1985. The heterogeneity of mononuclear phagocytes in lymphoid organs: distinct macrophage subpopulations in rat recognized by monoclonal antibodies ED1, ED2 and ED3. Advances in Experimental Medicine and Biology 186: 409–419.

    PubMed  CAS  Google Scholar 

  33. Gomes-Leal, W., D.J. Corkill, M.A. Freire, C.W. Picanco-Diniz, and V.H. Perry. 2004. Astrocytosis, microglia activation, oligodendrocyte degeneration, and pyknosis following acute spinal cord injury. Experimental Neurology 190: 456–467.

    Article  PubMed  CAS  Google Scholar 

  34. Bao, X., J. Wei, M. Feng, S. Lu, G. Li, W. Dou, et al. 2011. Transplantation of human bone marrow-derived mesenchymal stem cells promotes behavioral recovery and endogenous neurogenesis after cerebral ischemia in rats. Brain Research 1367: 103–113.

    Article  PubMed  CAS  Google Scholar 

  35. Parr, A.M., I. Kulbatski, T. Zahir, X. Wang, C. Yue, A. Keating, et al. 2008. Transplanted adult spinal cord-derived neural stem/progenitor cells promote early functional recovery after rat spinal cord injury. Neuroscience 155: 760–770.

    Article  PubMed  CAS  Google Scholar 

  36. Zurita, M., and J. Vaquero. 2006. Bone marrow stromal cells can achieve cure of chronic paraplegic rats: functional and morphological outcome one year after transplantation. Neuroscience Letters 402: 51–56.

    Article  PubMed  CAS  Google Scholar 

  37. Chopp, M., Y. Li, and Z.G. Zhang. 2009. Mechanisms underlying improved recovery of neurological function after stroke in the rodent after treatment with neurorestorative cell-based therapies. Stroke 40: S143–S145.

    Article  PubMed  Google Scholar 

  38. Schwarting, S., S. Litwak, W. Hao, M. Bahr, J. Weise, and H. Neumann. 2008. Hematopoietic stem cells reduce postischemic inflammation and ameliorate ischemic brain injury. Stroke 39: 2867–2875.

    Article  PubMed  CAS  Google Scholar 

  39. Sarnowska, A., H. Braun, S. Sauerzweig, and K.G. Reymann. 2009. The neuroprotective effect of bone marrow stem cells is not dependent on direct cell contact with hypoxic injured tissue. Experimental Neurology 215: 317–327.

    Article  PubMed  CAS  Google Scholar 

  40. Hayakawa, K., K. Mishima, M. Nozako, M. Hazekawa, S. Mishima, M. Fujioka, et al. 2008. Delayed treatment with minocycline ameliorates neurologic impairment through activated microglia expressing a high-mobility group box1-inhibiting mechanism. Stroke 39: 951–958.

    Article  PubMed  CAS  Google Scholar 

  41. Vendrame, M., C. Gemma, D. de Mesquita, L. Collier, P.C. Bickford, C.D. Sanberg, et al. 2005. Anti-inflammatory effects of human cord blood cells in a rat model of stroke. Stem Cells and Development 14: 595–604.

    Article  PubMed  CAS  Google Scholar 

  42. Capone, C., S. Frigerio, S. Fumagalli, M. Gelati, M.C. Principato, C. Storini, et al. 2007. Neurosphere-derived cells exert a neuroprotective action by changing the ischemic microenvironment. PLoS One 4: 1–11.

    Google Scholar 

  43. Shechter, R., A. London, C. Varol, C. Raposo, M. Cusimano, G. Yovel, et al. 2009. Infiltrating blood-derived macrophages are vital cells playing an anti-inflammatory role in recovery from spinal cord injury in mice. PLoS Medicine 6: 1–13.

    Article  Google Scholar 

  44. Coyne, T.M., A.J. Marcus, D. Woodbury, and I.B. Black. 2006. Marrow stromal cells transplanted to the adult brain are rejected by an inflammatory response and transfer donor labels to host neurons and glia. Stem Cells 24: 2483–2492.

    Article  PubMed  Google Scholar 

  45. Molcanyi, M., P. Riess, K. Bentz, M. Maegele, J. Hescheler, B. Schafke, et al. 2007. Trauma-associated inflammatory response impairs embryonic stem cell survival and integration after implantation into injured rat brain. Journal of Neurotrauma 24: 625–637.

    Article  PubMed  Google Scholar 

Download references

Acknowledgments

This work was supported by the Brazilian National Council for Scientific and Technological Development (CNPq) and Fundação de Amparo A Pesquisa do Estado do Pará (FAPESPA). W Gomes-Leal is a principal investigator in grant number 573872/2008-2 from the Ministry of Science and Technology (MCT), Ministry of Health (MS), and CNPq (Edital CT-Biotecnologia/MCT/CNPq/MS/SCTIE/DECIT No. 17/2008) and FAPESPA (PRONEX-FAPESPA-CNPQ-Edital 012-2009).

Disclosures/Conflict of Interest

The authors declare no conflict of interest.

Author information

Authors and Affiliations

Authors

Corresponding author

Correspondence to Walace Gomes-Leal.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Cardoso, M.M., Franco, E.C.S., de Souza, C.C. et al. Minocycline Treatment and Bone Marrow Mononuclear Cell Transplantation After Endothelin-1 Induced Striatal Ischemia. Inflammation 36, 197–205 (2013). https://doi.org/10.1007/s10753-012-9535-5

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10753-012-9535-5

KEY WORDS

Navigation