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.
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Perry, V.H., J.A. Nicoll, and C. Holmes. 2010. Microglia in neurodegenerative disease. Nature Reviews Neurology 6: 193–201.
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.
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.
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.
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.
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.
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.
Block, M.L., L. Zecca, and J.S. Hong. 2007. Microglia-mediated neurotoxicity: uncovering the molecular mechanisms. Nat Rev Neurosci 8: 57–69.
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.
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.
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.
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.
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.
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.
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.
Taylor, P.L. 2011. Responsibility rewarded: ethics, engagement, and scientific autonomy in the labyrinth of the minotaur. Neuron 70: 577–581.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
Mullen, R.J., C.R. Buck, and A.M. Smith. 1992. NeuN, a neuronal specific nuclear protein in vertebrates. Development 116: 201–211.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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.
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).
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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
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DOI: https://doi.org/10.1007/s10753-012-9535-5