- Research article
- Open Access
Anticonvulsant activity of bone marrow cells in electroconvulsive seizures in mice
© Ferrazoli et al.; licensee BioMed Central Ltd. 2013
- Received: 16 October 2012
- Accepted: 3 September 2013
- Published: 6 September 2013
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.
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.
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.
Epilepsy represents a complex group of disorders in which the main characteristic is the manifestation of spontaneous convulsive seizures that develop from specific areas in the central nervous system. From a clinical perspective, treatment to control seizures is restricted to anti-epileptic drug therapy. A growing number of reports have shown the therapeutic potential of stem cells obtained from various sources, such as bone marrow, brain, cord blood and skin, in the treatment of diseases affecting the central nervous system . Bone marrow has been suggested as an accessible source of multipotent cells, and it has been used to treat patients with neurological diseases in a number of clinical trials [2–5]. It is believed that one of the major protective mechanisms of bone marrow stem cells is a paracrine effect by secreting substances with anti-inflammatory, anti-apoptotic, proliferative and pro-angiogenic actions [6–8]. However, bone marrow is also a source of inflammatory cells, which can infiltrate and proliferate into the brain parenchyma in response to alterations that may occur after epileptic seizures [9–13]. The continuous traffic of inflammatory cells into the cerebral tissue is accelerated after injury [14, 15] and is involved in cytokine response to seizures [16–18]. Thus, the inflammatory reaction induced by acute seizure in the presence of transplanted adult bone marrow cells is a critical point that was evaluated here.
Maximum electroconvulsive shock (MES) is a classic experimental model for the induction of single generalized tonic-clonic seizure activity in rodents. MES mimics seizures commonly found in drug-resistant epilepsy patients, and it is the elected model for the primary screening of new antiepileptic drugs [19, 20]. The MES screening test evaluates the effects of anticonvulsant drugs in preventing the spread of convulsive activity throughout the neural tissue, which is indicated by the abolishment of the hindlimb tonic extensor component of seizure [21, 22]. Interestingly, the induction of MES has been implicated in alterations of microglial expression patterns and blood levels of cytokines, which indicates a commitment of inflammatory responses to the convulsive stimulus [23, 24].
Based on these data, the focus of the current study was to investigate the effects of bone marrow cell transplantation on the behavioral and inflammatory responses to acute generalized tonic-clonic seizures induced by using the MES model. Because MES is the elected model to test anticonvulsive compounds, we proposed the use of MES to verify the ability of the transplanted bone marrow cells to inhibit seizure spread in the same paradigm as used in pharmacological screening tests.
Behavioral seizure analysis
The microglia expressing Iba1 was analyzed in naïve medium- and BM-injected animals (CTRL), MES-S, MES-BM groups in the neocortex (Cx), striatum (CPu), hippocampus (Hp), substantia nigra (SN), superior colliculus (SC), and periaqueductal gray area (PAG). Naïve bone marrow-injected animals composed, together with medium-injected animals, the control group for the Iba1 quantification (CTRL). Differences between the groups were detected for three main regions of interest, Cx, Hp and SN based on evidence that these areas are involved in motor activity  and electroconvulsive seizure susceptibility [26–28].
In contrast, for IL-10 blood levels, we detected a higher value for the MES-BM group compared to MES-S, MES-DC and naïve CTRL and BM groups (ANOVA one-way, followed by Tukey’s test p < 0.0001; t test MES-S versus MES-BM p = 0.0148; Figure 4-B). The levels of IL-1α, IL-1β and TNF-α did not differ significantly between the MES groups submitted to the different treatments (S, DC or BM) or CTRL (data are not shown for the IL-1α, IL-1β and TNF-α).
Correlation analyses were performed to assess the relation of the duration of tonic seizure with the number of Iba1 cells and the blood levels of IL-6 and IL-10. Significant positive correlations were noted between the tonic duration and the number of Iba1 in the cortex (r = 0.9998; p < 0.0001), and between tonic duration and IL-6 (r = 0.9167; p = 0.0165). The longer the tonic seizure the more Iba1 cells counted in the cortex, and the higher the IL-6 blood levels. The same was near to occur between the tonic duration and IL-10, with the difference coming close to the significance threshold for a negative correlation (r = − 0.7594; p = 0.0799). No other significant correlation was observed.
Discussion and conclusions
Our results indicate that bone marrow cells may alter the convulsive threshold and also show anticonvulsant effects by protecting transplanted animals from tonic seizures. Bone marrow cells were tested under the same paradigm as that employed in the pharmacologic screening of potential antiepileptic drugs , using MES as a model to evaluate the protective effect of the cells in vivo. As suggested by Stable and Kupferberg , the ability of the tested compound to inhibit MES-induced seizure spread is indicated by abolition of the hindlimb tonic extensor component of seizures. With this experimental design, primary screening showed that bone marrow cells were able not only to protect transplanted animals against the tonic component, but also to reduce the duration of the tonic phase of generalized seizures. These data are consistent with previous findings in which authors observed a protective effect of bone marrow cells transplanted in already-epileptic animals .
As has been outlined before, bone marrow-derived cells in the CNS contribute mainly for the generation of microglia [14, 35–40]. We reported previously that after status epilepticus, the number of microglia originated from bone marrow increases dramatically . However, here the temporal window between cell transplantation and the electroshock stimulus was too short to have allowed for migration of the cells into the brain parenchyma. Indeed, after the electroshock GFP+ cells were not present in the parenchyma of animals transplanted with bone marrow cells obtained from the transgenic EGFP donor mice (data not shown). We speculate that bone marrow transplanted cells might have a paracrine action that influences the microglial activity, in areas such as cortex, substantia nigra and hippocampus, and the release of modulatory substances that could switch off the tonic activity. As already described, microglia have been observed to show morphological alterations after electrical convulsive shock [23, 24]. Jansson and colleagues described a reduction of the density of processes of microglia following electroconvulsive shock. In a similar manner, we observed a clear reduction in the ramification of resident microglia after the electrical convulsive stimulation, regardless of the bone marrow cell administration, indicative of an intermediate stage between resting and reactive microglia [31, 32].
As suggested by Browning and colleagues, generalized seizures have distinct neuroanatomical substrates that start and sustain the seizure activity . After the electroconvulsive shock, the reactive response of microglia in the striatum and substantia nigra, areas strongly connected and related to motor activity, is probably due to the intense motor activity seen during the tonic seizure. Microglial expression was otherwise suppressed in transplanted animals (MES-BM compared with MES-DC) in SN (with a tendency in CPu) because the motor activity related to tonic seizure was protected by bone marrow cell transplantation. Although the tonic component of seizure was protected in MES-BM animals, the stimulated groups (MES-S, MES-DC and MES-BM) presented clonic seizures, which may explain the absence of differences in these areas and consequently suggest their responsiveness to the clonic seizure. In the hippocampus, a structure that is susceptible to convulsive seizures [42, 43], and that contains cells vulnerable to electroshock [26–28], transplantation of bone marrow cells in MES animals was able to raise the number of microglial cells. Concerning these data, we speculated whether the observed increase in Iba1 cells in the hippocampus was due to its role in generalized or focal seizures and/or by a direct participation on persisting clonic seizures. As proposed by Silverberg and co-authors, inflammatory cells are specifically recruited to damaged regions of brain associated with the focus of seizure . These authors suggested that in MES seizures, currents may spread throughout the brain and the intensity and/or duration of stimulus could alter cytokine and chemokine production. It has been also described that the number of Iba1cells was increased around the mesenchymal bone marrow transplanted cells in hippocampus of mice with Alzheimer’s disease . The transplantation per se accelerates the activation of microglia, regardless of pathological condition. In our case, the generalized seizures promoted by the MES stimulation, together with the injection of BM cells, may suggest that the higher numbers of hippocampal microglia found in transplanted animals function as part of an inflammatory response to seizure.
As suggested by Jankowsky and Patterson , the onset and duration of seizure are influenced by a variety of types and levels of cytokines that, at the time of induction, may compete to determine the behavioral outcome. Several studies have reported elevated concentrations of IL-6 immediately after seizure activity [46, 47]. In our hands, the trigger of MES convulsion induced an increase in IL-6 blood levels in both MES-S and MES-DC groups. However, these levels were decreased in animals transplanted with bone marrow cells. The low levels of IL-6 detected in MES-BM mice might be related the reduction of tonic seizure in these animals, as suggested by Pearson’s correlation. In concert with the decrease in IL-6 levels observed in BM transplanted animals, blood levels of IL-10 were higher in those animals, which may reduce susceptibility to seizures induced by pro-inflammatory cytokines, although it was not detected in correlation analysis. Our data corroborate other findings that showed a reduction in the pro-inflammatory cytokines and an increased in the IL-10 of chronic epileptic rats treated with mouse bone marrow cells . Accordingly, other authors proposed that IL-10 expression may be induced simultaneously with pro-inflammatory cytokines in the brain following an insult [49, 50]. The beneficial or detrimental roles of the innate immune response in the epileptic tissue, however, still needs to be clarified . To understand the relationship between cytokine signaling and bone marrow cell function in the epileptic brain, additional studies during the chronic period of spontaneous seizures are required.
Taken together, these results suggest that transplanted bone marrow cells exert protective effects by blocking the tonic component of generalized seizures induced by MES. Moreover, electroconvulsive seizures applied in transplanted mice triggered acute responses altering the pattern of microglia expression and blood levels of interleukins. Additionally, we suggest that the anticonvulsive potential of progenitor cells may be tested by the MES model, as a primary screen, in the same paradigm as that used for drug testing in pharmacological screening. In spite of these promising results, several considerations concerning the transplantation strategies, such as the number of cells and the timing and route of administration should be elucidated. Further studies on the inflammatory response to acute seizures in the presence of transplanted bone marrow cells could prove to be beneficial, and may open broad and productive discussions on mechanisms relevant to the pathophysiology of epilepsy.
All animals were housed in a pathogen-free facility and maintained in accordance with the Guide for the Care and Use of Laboratory Animals (National Research Council). All protocols were approved by the Ethics Committee of Universidade Federal de São Paulo (UNIFESP), process 0507/07, conformed to current guidelines and with approval by the Comissão Nacional de Ética em Pesquisa (CONEP).
Bone marrow cell extraction
Bone marrow cells were obtained from adult C57Bl/6-donor mice (20–25 g) (JAX® Mice and Services, Bar Harbor, Maine, USA) by flushing the femurs and tibiae with sterile medium. The mononuclear cell fraction was purified by centrifugation in a Ficoll-Paque gradient (Stemcell Technologies Inc, Vancouver, Canada). The cells were washed four times in Dulbecco’s Modified Eagle Medium (DMEM, Gibco, Grand Island, NY, EUA), counted and resuspended in sterile saline. Viability of cells was determined by trypan blue (Gibco, Grand Island, NY, EUA) dye exclusion test. Briefly, cells were incubated with trypan blue dye for 1 min. White cells was counted excluding blue positive cells in Neubauer chamber, and the percent of viable cells was calculated. Approximately 1 × 106 cells diluted in 200 μL or saline were delivered to each recipient animal by intravenous administration. Additionally to the saline (MES-S) and bone marrow (MES-BM) groups, age-matched groups were prepared by injecting similar volumes of bone marrow dead cells (MES-DC), obtained by repeated frost and thaw cycles, as a control for the inflammatory response, conditioned medium and cell toxicity; naïve bone marrow alive cells (BM), and medium-injected (CTRL) groups that were not seizure-induced by MES.
Maximum electroconvulsive shock (MES) induction
Thirty minutes after saline or cell administration, an electrical stimulus (65 mA; 60 Hz; 0.15 sec duration) was applied through a pair of corneal electrodes (AVS, Solução Integrada, São Paulo-SP) to induce acute generalized tonic-clonic seizure [19, 20]. The criterion for the occurrence of seizure activity was the tonic hindlimb extension response. The parameters used to estimate the anticonvulsant activity of transplanted cells were the protection against tonic hindlimb extension and the reduction in tonic seizure duration.
Two hours after the MES stimulus, mice were intraperitoneally anesthetized with thionembutal (200 mg/kg; Cristália, Brazil) and transcardially perfused with phosphate buffered saline (PBS; 100 mM, pH 7.2), followed by 4% paraformaldehyde (PFA) in PBS (w/v), 50–100 mL over 10 minutes per animal. The brains were removed and processed for immunohistochemistry on free-floating brain slices. Coronal brain sections (30 μm thick) were made between bregma 0.98 and bregma −3.28 mm, targeting the areas of interest in forebrain and midbrain; Cx, CPu, Hp, SC, SN, and PAG, according to the stereotaxic coordinates of the mouse brain atlas . The sections were selected (9 per animal) by targeting the areas of interest (neocortex, striatum and hippocampus), which were left free-floating in a multi-well plate. To stain microglia, sections were incubated in polyclonal rabbit anti-Iba1 primary antibody overnight (1:2000; Wako Chemicals, Richmond, VA, USA), followed by a biotinylated anti-rabbit secondary antibody for 2 h (1:600, Sigma-Aldrich Corporation, St. Louis, EUA). After using an ABC kit (Avidin/Biotinylated enzyme Complex Vectastain Elite, Vector, Burlingame, CA, EUA) followed by a DAB reaction (3,3’-Diaminobenzidine, Sigma-Aldrich Corporation, St. Louis, EUA), the sections were mounted on slides and sealed with coverslips. The slides were examined using a light microscope (Nikon 80i), and images were captured and digitized using the Nikon ACT-1 v.2 system. In each section, nuclear profiles of Iba1 cells were counted by an observer blinded to the experimental condition of each animal. Cells stained for Iba1 were counted under 20× magnification in 18 random, non-overlapping fields of 0.02 mm2 per structure of each animal.
With the animals deeply anesthetized, approximately 1 mL of blood was collected from abdominal aorta artery just before cardiac perfusion. Blood samples placed in 1.5 mL tubes were allowed to clot for 2 h at room temperature before centrifugation for 15 min at 1000 × g. The sera were collected, aliquoted and stored at −20°C. Analyte-specific antibodies against IL-1α, IL-1β, IL-6, IL-10 and TNF-α were pre-coated onto color-coded microparticles using the MAP Fluorokine kit (R & D Systems, Inc.). Microparticles, standards and samples were pipetted into wells and incubated with antibodies specific for the analytes of interest. After washing, streptavidin-phycoerythrin conjugate (Streptavidin-PE) was added to each well. The microparticles were resuspended in buffer and quantified using the Luminex analyzer (Luminex® 100/200 System, Austin, USA).
Statistical analyses were performed using Prism software (version 288 5.01, GraphPad Software, San Diego, CA, USA). Behavioral seizure, Iba1 cell and cytokine quantifications were analyzed with one-way analysis of variance (ANOVA) followed by Tukey’s multiple comparison test, and confirmed with Kruskall-Wallis followed by Dunn’s multiple comparison test. Student’s t test was used to compare two experimental groups. A significance level of 5% was assumed.
We are grateful to Maria Fernanda Valente and Simone Romariz for their technical support. This work was supported by Associação Beneficente de Coleta de Sangue da Fundação de Apoio à Pesquisa- UNIFESP (FAP-Colsan), Fundação de Amparo à Pesquisa do Estado de São Paulo (FAPESP), and National Counsel of Technological and Scientific Development (CNPq).
- Mello L, Longo B: Neurogenesis: a change of paradigms. Perspectives of Stem Cells. Edited by: Ulrich H. 2010, Netherlands: Springer, 11-33.View ArticleGoogle Scholar
- 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. 10.3727/096368912X633798.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.expneurol.2009.10.010.View ArticleGoogle Scholar
- 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.View ArticleGoogle Scholar
- Sanberg PR, Park DH, Kuzmin-Nichols N, Cruz E, Hossne NA, Buffolo E, Willing AE: Monocyte transplantation for neural and cardiovascular ischemia repair. J Cell Mol Med. 2010, 14 (3): 553-563.PubMed CentralPubMedGoogle Scholar
- Gnecchi M, Zhang Z, Ni A, Dzau VJ: Paracrine mechanisms in adult stem cell signaling and therapy. Circ Res. 2008, 103 (11): 1204-1219. 10.1161/CIRCRESAHA.108.176826.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1161/CIRCULATIONAHA.111.079699.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- Bhatt R, Rameshwar P, Goldstein K, Siegel A: Effects of kindled seizures upon hematopoiesis in rats. Epilepsy Res. 2003, 54 (2–3): 209-219.View ArticlePubMedGoogle Scholar
- 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. 10.1038/nm.1878.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1111/j.1528-1167.2010.02570.x.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.nbd.2008.05.007.View ArticlePubMedGoogle Scholar
- 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. 10.1016/S0014-4886(03)00082-7.View ArticlePubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- 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. 10.2174/1568007054546171.View ArticlePubMedGoogle Scholar
- Vezzani A: Inflammation and epilepsy. Epilepsy Curr. 2005, 5 (1): 1-6. 10.1111/j.1535-7597.2005.05101.x.PubMed CentralView ArticlePubMedGoogle Scholar
- 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. 10.1016/j.nbd.2004.07.023.View ArticlePubMedGoogle Scholar
- Swinyard EA, Brown WC, Goodman LS: Comparative assays of antiepileptic drugs in mice and rats. J Pharmacol Exp Ther. 1952, 106 (3): 319-330.PubMedGoogle Scholar
- 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. 10.1016/0024-3205(85)90573-9.View ArticlePubMedGoogle Scholar
- 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. 10.1016/0920-1211(91)90053-I.View ArticlePubMedGoogle Scholar
- 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. 10.1111/j.1528-1157.1987.tb04221.x.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.pnpbp.2009.06.007.View ArticlePubMedGoogle Scholar
- Jinno S, Kosaka T: Reduction of Iba1-expressing microglial process density in the hippocampus following electroconvulsive shock. Exp Neurol. 2008, 212 (2): 440-447. 10.1016/j.expneurol.2008.04.028.View ArticlePubMedGoogle Scholar
- 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. 10.1016/S0306-4522(99)00575-8.View ArticlePubMedGoogle Scholar
- 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. 10.1002/jnr.21474.View ArticlePubMedGoogle Scholar
- 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. 10.1007/s00221-003-1658-3.View ArticlePubMedGoogle Scholar
- 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. 10.1007/s11055-005-0115-0.View ArticlePubMedGoogle Scholar
- 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. 10.1002/glia.20552.View ArticlePubMedGoogle Scholar
- Davis EJ, Foster TD, Thomas WE: Cellular forms and functions of brain microglia. Brain Res Bull. 1994, 34 (1): 73-78. 10.1016/0361-9230(94)90189-9.View ArticlePubMedGoogle Scholar
- Streit WJ, Walter SA, Pennell NA: Reactive microgliosis. Prog Neurobiol. 1999, 57 (6): 563-581. 10.1016/S0301-0082(98)00069-0.View ArticlePubMedGoogle Scholar
- Jankowsky JL, Patterson PH: The role of cytokines and growth factors in seizures and their sequelae. Prog Neurobiol. 2001, 63 (2): 125-149. 10.1016/S0301-0082(00)00022-8.View ArticlePubMedGoogle Scholar
- Stables JP, Kupferberg HJ: The NIH Anticonvulsant Drug Development (ADD) Program: preclinical anticonvulsant screening project. Molecular and cellular targets for anti-epileptic drugs. Edited by: Avanzini G, Regesta G, Tanganelli P, Avoli M. 1997, London, England: Bethesda, MD: John Libbey & Company Ltd, 191-198.Google Scholar
- 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. 10.1016/j.seizure.2009.12.003.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.nbd.2005.01.023.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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. 10.1038/nm1201-1356.View ArticlePubMedGoogle Scholar
- Simard AR, Rivest S: Role of inflammation in the neurobiology of stem cells. Neuroreport. 2004, 15 (15): 2305-2310. 10.1097/00001756-200410250-00001.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.nbd.2004.01.002.View ArticlePubMedGoogle Scholar
- 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. 10.1006/exnr.1998.6981.View ArticlePubMedGoogle Scholar
- Loscher W, Ebert U: Basic mechanisms of seizure propagation: targets for rational drug design and rational polypharmacy. Epilepsy Res Suppl. 1996, 11: 17-43.PubMedGoogle Scholar
- Scharfman HE: Epileptogenesis in the parahippocampal region. Parallels with the dentate gyrus. Ann N Y Acad Sci. 2000, 911: 305-327.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.bbi.2009.10.006.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.neulet.2008.11.059.View ArticlePubMedGoogle Scholar
- 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. 10.1016/j.seizure.2010.12.005.View ArticlePubMedGoogle Scholar
- 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. 10.1016/S0920-1211(98)00024-2.View ArticlePubMedGoogle Scholar
- 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.View ArticlePubMedGoogle Scholar
- 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.PubMedGoogle Scholar
- 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. 10.1016/S0022-510X(97)00154-8.View ArticlePubMedGoogle Scholar
- Paxinos GFK: The Mouse Brain in Stereotaxic Coordinates. 2003, San Diego: Elsevier, Academic Press, 2Google Scholar
This article is published under license to BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated.