Anticonvulsant activity of bone marrow cells in electroconvulsive seizures in mice

BMC Neuroscience

Beatriz Monteiro Longo⁴  Luiz Eugênio Mello⁴  Ricardo Ribeiro-dos-Santos¹  Milena Botelho Pereira Soares¹  Luciana Bahia²  André Luis Lacerda Bachi³  Simone Bittencourt⁴  Miriam Marcela Blanco⁴  Enéas Galdini Ferrazoli⁴ 

[1] Centro de Biotecnologia e Terapia Celular, Hospital São Rafael, Salvador, BA, Brazil;Centro de Pesquisas Gonçalo Moniz, Fundação Oswaldo Cruz, Salvador, BA, Brazil;Disciplina de Imunologia, Departamento de Micro-Imuno-Parasitologia, UNIFESP, São Paulo, Brazil;Laboratório de Neurofisiologia, Departamento de Fisiologia, Federal University of São Paulo - UNIFESP, R. Botucatu, 862 5 andar, V. Clementino – CEP, 04023-066, São Paulo, Brazil

关键词: Hippocampus;    Microglia;    Tonic seizure;    Electroconvulsive shock;    Cell transplantation;    Bone marrow;   

Others  :  1140088
DOI  :  10.1186/1471-2202-14-97

 received in 2012-10-16, accepted in 2013-09-03,  发布年份 2013

【 摘 要 】

Background

Bone marrow is an accessible source of progenitor cells, which have been investigated as treatment for neurological diseases in a number of clinical trials. Here we evaluated the potential benefit of bone marrow cells in protecting against convulsive seizures induced by maximum electroconvulsive shock (MES), a widely used model for screening of anti-epileptic drugs. Behavioral and inflammatory responses were measured after MES induction in order to verify the effects promoted by transplantation of bone marrow cells. To assess the anticonvulsant effects of bone marrow cell transplantation, we measured the frequency and duration of tonic seizure, the mortality rate, the microglial expression and the blood levels of cytokine IL-1, IL-6, IL-10 and TNF-α after MES induction. We hypothesized that these behavioral and inflammatory responses to a strong stimulus such as a convulsive seizure could be modified by the transplantation of bone marrow cells.

Results

Bone marrow transplanted cells altered the convulsive threshold and showed anticonvulsant effect by protecting from tonic seizures. Bone marrow cells modified the microglial expression in the analyzed brain areas, increased the IL-10 and attenuate IL-6 levels.

Conclusions

Bone marrow cells exert protective effects by blocking the course of electroconvulsive seizures. Additionally, electroconvulsive seizures induced acute inflammatory responses by altering the pattern of microglia expression, as well as in IL-6 and IL-10 levels. Our findings also indicated that the anticonvulsant effects of these cells can be tested with the MES model following the same paradigm used for drug testing in pharmacological screening. Studies on the inflammatory reaction in response to acute seizures in the presence of transplanted bone marrow cells might open a wide range of discussions on the mechanisms relevant to the pathophysiology of epilepsies.

【 授权许可】

   
2013 Ferrazoli et al.; licensee BioMed Central Ltd.

【 图 表 】

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【 参考文献 】

• [1]Mello L, Longo B: Neurogenesis: a change of paradigms. In Perspectives of Stem Cells. Edited by Ulrich H. Netherlands: Springer; 2010:11-33.
• [2]Sharma A, Gokulchandran N, Chopra G, Kulkarni P, Lohia M, Badhe P, Jacob VC: Administration of autologous bone marrow derived mononuclear cells in children with incurable neurological disorders and injury is safe and improves their quality of life. Cell Transplant 2012, 21:S79-90.
• [3]Yamout B, Hourani R, Salti H, Barada W, El-Hajj T, Al-Kutoubi A, Herlopian A, Baz EK, Mahfouz R, Khalil-Hamdan R, et al.: Bone marrow mesenchymal stem cell transplantation in patients with multiple sclerosis: a pilot study. J Neuroimmunol 2010, 227(1–2):185-189.
• [4]da Fonseca LM B, Gutfilen B, de Castro PH R, Battistella V, Goldenberg RC, Kasai-Brunswick T, Chagas CL, Wajnberg E, Maiolino A, Salles Xavier S, et al.: Migration and homing of bone-marrow mononuclear cells in chronic ischemic stroke after intra-arterial injection. Exp Neurol 2010, 221(1):122-128.
• [5]Battistella V, de Freitas GR, da Fonseca LM, Mercante D, Gutfilen B, Goldenberg RC, Dias JV, Kasai-Brunswick TH, Wajnberg E, Rosado-de-Castro PH, et al.: Safety of autologous bone marrow mononuclear cell transplantation in patients with nonacute ischemic stroke. Regen Med 2010, 6(1):45-52.
• [6]Sanberg PR, Park DH, Kuzmin-Nichols N, Cruz E, Hossne NA Jr, Buffolo E, Willing AE: Monocyte transplantation for neural and cardiovascular ischemia repair. J Cell Mol Med 2010, 14(3):553-563.
• [7]Gnecchi M, Zhang Z, Ni A, Dzau VJ: Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res 2008, 103(11):1204-1219.
• [8]Iekushi K, Seeger F, Assmus B, Zeiher AM, Dimmeler S: Regulation of cardiac MicroRNAs by bone marrow mononuclear cell therapy in myocardial infarction. Circulation 2012, 125(14):1765-1773.
• [9]Cook LL, Persinger MA: Infiltration of lymphocytes in the limbic brain following stimulation of subclinical cellular immunity and low dosages of lithium and a cholinergic agent. Toxicol Lett 1999, 109(1–2):77-85.
• [10]Bhatt R, Rameshwar P, Goldstein K, Siegel A: Effects of kindled seizures upon hematopoiesis in rats. Epilepsy Res 2003, 54(2–3):209-219.
• [11]Fabene PF, Navarro Mora G, Martinello M, Rossi B, Merigo F, Ottoboni L, Bach S, Angiari S, Benati D, Chakir A, et al.: A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nat Med 2008, 14(12):1377-1383.
• [12]Longo B, Romariz S, Blanco MM, Vasconcelos JF, Bahia L, Soares MB, Mello LE, Ribeiro-Dos-Santos R: Distribution and proliferation of bone marrow cells in the brain after pilocarpine-induced status epilepticus in mice. Epilepsia 2010, 51(8):1628-1632.
• [13]Ravizza T, Noe F, Zardoni D, Vaghi V, Sifringer M, Vezzani A: Interleukin converting enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1beta production. Neurobiol Dis 2008, 31(3):327-333.
• [14]Schilling M, Besselmann M, Leonhard C, Mueller M, Ringelstein EB, Kiefer R: Microglial activation precedes and predominates over macrophage infiltration in transient focal cerebral ischemia: a study in green fluorescent protein transgenic bone marrow chimeric mice. Exp Neurol 2003, 183(1):25-33.
• [15]Vallieres L, Sawchenko PE: Bone marrow-derived cells that populate the adult mouse brain preserve their hematopoietic identity. J Neurosci 2003, 23(12):5197-5207.
• [16]Bernardino L, Ferreira R, Cristovao AJ, Sales F, Malva JO: Inflammation and neurogenesis in temporal lobe epilepsy. Curr Drug Targets CNS Neurol Disord 2005, 4(4):349-360.
• [17]Vezzani A: Inflammation and epilepsy. Epilepsy Curr 2005, 5(1):1-6.
• [18]Voutsinos-Porche B, Koning E, Kaplan H, Ferrandon A, Guenounou M, Nehlig A, Motte J: Temporal patterns of the cerebral inflammatory response in the rat lithium-pilocarpine model of temporal lobe epilepsy. Neurobiol Dis 2004, 17(3):385-402.
• [19]Swinyard EA, Brown WC, Goodman LS: Comparative assays of antiepileptic drugs in mice and rats. J Pharmacol Exp Ther 1952, 106(3):319-330.
• [20]Browning RA, Nelson DK: Variation in threshold and pattern of electroshock-induced seizures in rats depending on site of stimulation. Life Sci 1985, 37(23):2205-2211.
• [21]Loscher W, Honack D, Nolting B, Fassbender CP: Trans-2-en-valproate: reevaluation of its anticonvulsant efficacy in standardized seizure models in mice, rats and dogs. Epilepsy Res 1991, 9(3):195-210.
• [22]Swinyard EA, Woodhead JH, Franklin MR, Sofia RD, Kupferberg HJ: The effect of chronic felbamate administration on anticonvulsant activity and hepatic drug-metabolizing enzymes in mice and rats. Epilepsia 1987, 28(3):295-300.
• [23]Jansson L, Wennstrom M, Johanson A, Tingstrom A: Glial cell activation in response to electroconvulsive seizures. Prog Neuropsychopharmacol Biol Psychiatry 2009, 33(7):1119-1128.
• [24]Jinno S, Kosaka T: Reduction of Iba1-expressing microglial process density in the hippocampus following electroconvulsive shock. Exp Neurol 2008, 212(2):440-447.
• [25]Joel D, Weiner I: The connections of the dopaminergic system with the striatum in rats and primates: an analysis with respect to the functional and compartmental organization of the striatum. Neuroscience 2000, 96(3):451-474.
• [26]Cardoso A, Assuncao M, Andrade JP, Pereira PA, Madeira MD, Paula-Barbosa MM, Lukoyanov NV: Loss of synapses in the entorhinal-dentate gyrus pathway following repeated induction of electroshock seizures in the rat. J Neurosci Res 2008, 86(1):71-83.
• [27]Lukoyanov NV, Sa MJ, Madeira MD, Paula-Barbosa MM: Selective loss of hilar neurons and impairment of initial learning in rats after repeated administration of electroconvulsive shock seizures. Exp Brain Res 2004, 154(2):192-200.
• [28]Zarubenko II, Yakovlev AA, Stepanichev MY, Gulyaeva NV: Electroconvulsive shock induces neuron death in the mouse hippocampus: correlation of neurodegeneration with convulsive activity. Neurosci Behav Physiol 2005, 35(7):715-721.
• [29]Jinno S, Fleischer F, Eckel S, Schmidt V, Kosaka T: Spatial arrangement of microglia in the mouse hippocampus: a stereological study in comparison with astrocytes. Glia 2007, 55(13):1334-1347.
• [30]Davis EJ, Foster TD, Thomas WE: Cellular forms and functions of brain microglia. Brain Res Bull 1994, 34(1):73-78.
• [31]Streit WJ, Walter SA, Pennell NA: Reactive microgliosis. Prog Neurobiol 1999, 57(6):563-581.
• [32]Jankowsky JL, Patterson PH: The role of cytokines and growth factors in seizures and their sequelae. Prog Neurobiol 2001, 63(2):125-149.
• [33]Stables JP, Kupferberg HJ: The NIH Anticonvulsant Drug Development (ADD) Program: preclinical anticonvulsant screening project. In Molecular and cellular targets for anti-epileptic drugs. Edited by Avanzini G, Regesta G, Tanganelli P, Avoli M. London, England: Bethesda, MD: John Libbey & Company Ltd; 1997:191-198.
• [34]Costa-Ferro ZS, Vitola AS, Pedroso MF, Cunha FB, Xavier LL, Machado DC, Soares MB, Ribeiro-dos-Santos R, DaCosta JC: Prevention of seizures and reorganization of hippocampal functions by transplantation of bone marrow cells in the acute phase of experimental epilepsy. Seizure 2010, 19(2):84-92.
• [35]Corti S, Locatelli F, Donadoni C, Guglieri M, Papadimitriou D, Strazzer S, Del Bo R, Comi GP: Wild-type bone marrow cells ameliorate the phenotype of SOD1-G93A ALS mice and contribute to CNS, heart and skeletal muscle tissues. Brain 2004, 127(Pt 11):2518-2532.
• [36]Kokovay E, Cunningham LA: Bone marrow-derived microglia contribute to the neuroinflammatory response and express iNOS in the MPTP mouse model of Parkinson’s disease. Neurobiol Dis 2005, 19(3):471-478.
• [37]McMahon EJ, Suzuki K, Matsushima GK: Peripheral macrophage recruitment in cuprizone-induced CNS demyelination despite an intact blood–brain barrier. J Neuroimmunol 2002, 130(1–2):32-45.
• [38]Priller J, Flugel A, Wehner T, Boentert M, Haas CA, Prinz M, Fernandez-Klett F, Prass K, Bechmann I, de Boer BA, et al.: Targeting gene-modified hematopoietic cells to the central nervous system: use of green fluorescent protein uncovers microglial engraftment. Nat Med 2001, 7(12):1356-1361.
• [39]Simard AR, Rivest S: Role of inflammation in the neurobiology of stem cells. Neuroreport 2004, 15(15):2305-2310.
• [40]Yagi T, McMahon EJ, Takikita S, Mohri I, Matsushima GK, Suzuki K: Fate of donor hematopoietic cells in demyelinating mutant mouse, twitcher, following transplantation of GFP + bone marrow cells. Neurobiol Dis 2004, 16(1):98-109.
• [41]Browning RA, Wang C, Nelson DK, Jobe PC: Effect of precollicular transection on audiogenic seizures in genetically epilepsy-prone rats. Exp Neurol 1999, 155(2):295-301.
• [42]Loscher W, Ebert U: Basic mechanisms of seizure propagation: targets for rational drug design and rational polypharmacy. Epilepsy Res Suppl 1996, 11:17-43.
• [43]Scharfman HE: Epileptogenesis in the parahippocampal region. Parallels with the dentate gyrus. Ann N Y Acad Sci 2000, 911:305-327.
• [44]Silverberg J, Ginsburg D, Orman R, Amassian V, Durkin HG, Stewart M: Lymphocyte infiltration of neocortex and hippocampus after a single brief seizure in mice. Brain Behav Immun 2010, 24:263-272.
• [45]Lee JK, Jin HK, Bae JS: Bone marrow-derived mesenchymal stem cells reduce brain amyloid-beta deposition and accelerate the activation of microglia in an acutely induced Alzheimer’s disease mouse model. Neurosci Lett 2009, 450(2):136-141.
• [46]Li G, Bauer S, Nowak M, Norwood B, Tackenberg B, Rosenow F, Knake S, Oertel WH, Hamer HM: Cytokines and epilepsy. Seizure 2011, 20(3):249-256.
• [47]Peltola J, Hurme M, Miettinen A, Keranen T: Elevated levels of interleukin-6 may occur in cerebrospinal fluid from patients with recent epileptic seizures. Epilepsy Res 1998, 31(2):129-133.
• [48]Costa-Ferro ZS, Souza BS, Leal MM, Kaneto CM, Azevedo CM, da Silva IC, Soares MB, Ribeiro-Dos-Santos R, Dacosta JC: Transplantation of bone marrow mononuclear cells decreases seizure incidence, mitigates neuronal loss and modulates pro-inflammatory cytokine production in epileptic rats. Neurobiol Dis 2011, 46(2):302-313.
• [49]Kubera M, Budziszewska B, Basta-Kaiml A, Zajicova A, Holan V, Lason W: Immunoreactivity in kainate model of epilepsy. Pol J Pharmacol 2001, 53(5):541-545.
• [50]Zhai QH, Futrell N, Chen FJ: Gene expression of IL-10 in relationship to TNF-alpha, IL-1beta and IL-2 in the rat brain following middle cerebral artery occlusion. J Neurol Sci 1997, 152(2):119-124.
• [51]Paxinos GFK: The Mouse Brain in Stereotaxic Coordinates. 2nd edition. San Diego: Elsevier, Academic Press; 2003.