Tracer injection as a bolus is the standard procedure in (preclinical) PET (Carson, 2000). Our results suggest that radiotracer infusion may be beneficial for detecting BBB leakage during epileptogenesis not only in MRI but in nuclear medicine techniques, too. Furthermore, a slower but longer lasting application as in infusion vs.
bolus provides a lesser impact on the brains endothelium. It may be taken into consideration that a quickly administration of a volume which is high in relation to the
bodyweight may per se influence BBB integrity (Nagaraja et al., 2007) in epilepsy models.
Even though all imaging techniques reveal changes in BBB integrity, MRI detects BBB leakage that is missed by PET and SPECT. Thus, MRI is superior to PET and SPECT in the used study design. However, every imaging modality has its specific limitations (James & Gambhir, 2012). A combinational use of PET, SPECT and MRI could therefore benefit from the strength of each imaging technique.
The results of the present studies are important as they provide further insights into the dynamics of BBB leakage and cerebral edema formation during epileptogenesis.
Moreover, they offer suitable imaging protocols to further evaluate the role of BBB impairment as potential biomarker for epileptogenesis. A combination of MRI and nuclear imaging may be beneficial for further investigating BBB during epileptogenesis in the future.
5.8 Conclusion
The study has offered an evaluative perspective on multimodal molecular imaging of changes in BBB integrity during epileptogenesis.
In the current studies, we present evidence that pre-clinical nuclear imaging is a valuable tool for the evaluation of BBB integrity. While contrast-enhanced MRI is a generally accepted and widely used tool for detecting BBB impairment, our observations that [68Ga]-DTPA PET and [99mTc]-DTPA SPECT can contribute to evaluation of BBB integrity during epileptogenesis are novel.
Our results show for the first time a successful reduction of BBB leakage by a dosing regimen of dexamethasone in mice during epileptogenesis which may contribute to epileptogenesis-modifying pharmacotherapies. The use of in vivo MR imaging enables the evaluation of pharmacotherapeutic effects on BBB integrity. Thus, assessment of patients responding to BBB-protective therapy may be feasible in the future.
6 References
ABBOTT,N.J. (2002). Astrocyte–endothelial interactions and blood–brain barrier permeability. Journal of Anatomy 200, 629-638.
ABBOTT,N.J. & FRIEDMAN,A. (2012). Overview and introduction: The blood–brain barrier in health and disease. Epilepsia 53, 1-6.
ABBOTT,N.J., PATABENDIGE, A.A.K., DOLMAN, D.E.M., YUSOF, S.R. & BEGLEY, D.J. (2010). Structure and function of the blood–brain barrier. Neurobiology of Disease 37, 13-25.
ABBOTT, N.J., RONNBACK, L. & HANSSON, E. (2006). Astrocyte-endothelial interactions at the blood-brain barrier. Nature Reviews Neuroscience 7, 41-53.
AL-SHORBAGY, M.Y., EL SAYEH, B.M. & ABDALLAH, D.M. (2012). Diverse effects of variant doses of dexamethasone in lithium-pilocarpine induced seizures in rats. Canadian Journal of Physiology and Pharmacology 90, 13-21.
ALLAN, S.M., TYRRELL, P.J. & ROTHWELL, N.J. (2005). Interleukin-1 and neuronal injury. Nature Reviews Immunology 5, 629-640.
ALLEN JR,H.C., LIBBY,R.L. & CASSEN,B. (1951). The scintillation counter in clinical studies of human thyroid physiology using I131. The Journal of Clinical Endocrinology & Metabolism 11, 492-511.
AUPHAN,N., DIDONATO,J.A., ROSETTE,C., HELMBERG,A. & KARIN,M. (1995). Immunosuppression by glucocorticoids: inhibition of NF-kappaB activity through induction of IkappaB synthesis. Science 270, 286.
BANKSTAHL,J.P. & BANKSTAHL,M. (2012). Präklinische Positronen-Emissions-Tomographie-Studien in Epilepsiemodellen. Zeitschrift für Epileptologie 25, 200-207.
BANKSTAHL,J.P., BANKSTAHL,M., KUNTNER,C., STANEK,J., WANEK,T., MEIER,M., DING,X.-Q., MÜLLER, M., LANGER,O. & LÖSCHER,W. (2011). A Novel Positron Emission Tomography Imaging Protocol Identifies Seizure-Induced Regional Overactivity of P-Glycoprotein at the Blood–Brain Barrier.
The Journal of Neuroscience 31, 8803-8811.
BANKSTAHL,J.P., KUNTNER,C., ABRAHIM,A., KARCH,R., STANEK,J., WANEK,T., WADSAK,W., KLETTER, K., MÜLLER, M. & LÖSCHER, W. (2008). Tariquidar-induced P-glycoprotein inhibition at the rat blood–brain barrier studied with (R)-11C-verapamil and PET. Journal of Nuclear Medicine 49, 1328-1335.
BAR‐KLEIN,G., CACHEAUX, L.P., KAMINTSKY,L., PRAGER,O., WEISSBERG,I., SCHOKNECHT,K., CHENG, P., KIM,S.Y., WOOD,L. & HEINEMANN,U. (2014). Losartan prevents acquired epilepsy via TGF‐β signaling suppression. Annals of Neurology 75, 864-875.
BARNES,P.J. (2006). Corticosteroid effects on cell signalling. European Respiratory Journal 27, 413-426.
BAiKAYA, M.K., MURALIKRISHNA RAO, A., DOĞAN, A., DONALDSON, D. & DEMPSEY, R.J. (1997). The biphasic opening of the blood–brain barrier in the cortex and hippocampus after traumatic brain injury in rats. Neuroscience Letters 226, 33-36.
BAUER, B., HARTZ, A.M., FRICKER, G. & MILLER, D.S. (2005). Modulation of p-glycoprotein transport function at the blood-brain barrier. Experimental Biology and Medicine 230, 118-127.
BAUER,B., SCHLICHTIGER,J., PEKCEC,A. & HARTZ,A.M. (2011). The Blood-Brain Barrier in Epilepsy. In Clinical and Genetic Aspects of Epilepsy, pp. 23-54: Intech.
BEN-ARI, Y., LAGOWSKA, J., TREMBLAY, E. & LA SALLE, G.L.G. (1979). A new model of focal status epilepticus: intra-amygdaloid application of kainic acid elicits repetitive secondarily generalized convulsive seizures. Brain Research 163, 176-179.
BERG,A.T., BERKOVIC,S.F., BRODIE,M.J., BUCHHALTER,J., CROSS,J.H., VAN EMDE BOAS,W., ENGEL, J., FRENCH,J., GLAUSER,T.A. & MATHERN,G.W. (2010). Revised terminology and concepts for organization of seizures and epilepsies: report of the ILAE Commission on Classification and Terminology, 2005–2009. Epilepsia 51, 676-685.
BERKOVIC,S.F., ANDERMANN,F., OLIVIER,A., ETHIER,R., MELANSON,D., ROBITAILLE,Y., KUZNIECKY,R., PETERS,T. & FEINDEL,W. (1991). Hippocampal sclerosis in temporal lobe epilepsy demonstrated by magnetic resonance imaging. Annals of Neurology 29, 175-182.
BERTORELLI,R., ADAMI,M., DI SANTO,E. & GHEZZI,P. (1998). MK 801 and dexamethasone reduce both tumor necrosis factor levels and infarct volume after focal cerebral ischemia in the rat brain.
Neuroscience Letters 246, 41-44.
BERTRAM, E.H. (2009). Temporal lobe epilepsy: Where do the seizures really begin? Epilepsy &
Behavior 14, 32-37.
BETZ, A.L., FIRTH, J.A. & GOLDSTEIN, G.W. (1980). Polarity of the blood-brain barrier: distribution of enzymes between the luminal and antiluminal membranes of brain capillary endothelial cells.
Brain Research 192, 17-28.
BIALER,M. & WHITE,H.S. (2010). Key factors in the discovery and development of new antiepileptic drugs. Nature Reviews Drug Discovery 9, 68-82.
BLAMIRE,A. (2014). The technology of MRI—the next 10 years? The British Journal of Radiology 81, 601-617.
BOUILLERET,V., NEHLIG,A., MARESCAUX,C. & NAMER,I.J. (2000). Magnetic resonance imaging follow-up of progressive hippocampal changes in a mouse model of mesial temporal lobe epilepsy.
Epilepsia 41, 642-650.
BOUILLERET, V., RIDOUX, V., DEPAULIS, A., MARESCAUX, C., NEHLIG, A. & LA SALLE, G.L. (1999).
Recurrent seizures and hippocampal sclerosis following intrahippocampal kainate injection in adult mice: Electroencephalography, histopathology and synaptic reorganization similar to mesial temporal lobe epilepsy. Neuroscience 89, 717-729.
BRADBURY,M.W.B. & LIGHTMAN,S.L. (1990). The blood-brain interface. Eye 4, 249-254.
BRAGIN,A., ENGEL,J., WILSON,C.L., VIZENTIN,E. & MATHERN,G.W. (1999). Electrophysiologic analysis of a chronic seizure model after unilateral hippocampal KA injection. Epilepsia 40, 1210-1221.
BROWN, R.C., MARK, K.S., EGLETON, R.D., HUBER, J.D., BURROUGHS, A.R. & DAVIS, T.P. (2003).
Protection against hypoxia-induced increase in blood-brain barrier permeability: role of tight junction proteins and NFκB. Journal of Cell Science 116, 693-700.
CACHEAUX, L.P., IVENS, S., DAVID, Y., LAKHTER, A.J., BAR-KLEIN, G., SHAPIRA, M., HEINEMANN, U., FRIEDMAN,A. & KAUFER,D. (2009). Transcriptome profiling reveals TGF-β signaling involvement in epileptogenesis. The Journal of Neuroscience 29, 8927-8935.
CAMPOLO,M., AHMAD, A., CRUPI, R., IMPELLIZZERI,D., MORABITO, R., ESPOSITO, E. & CUZZOCREA, S.
(2013). Combination therapy with melatonin and dexamethasone in a mouse model of traumatic brain injury. Journal of Endocrinology 217, 291-301.
CANDELARIO‐JALIL,E., GONZÁLEZ‐FALCÓN,A., GARCÍA‐CABRERA,M., LEÓN,O.S. & FIEBICH,B.L. (2007).
Post‐ischaemic treatment with the cyclooxygenase‐2 inhibitor nimesulide reduces blood–brain barrier disruption and leukocyte infiltration following transient focal cerebral ischaemia in rats.
Journal of Neurochemistry 100, 1108-1120.
CARSON,R.E. (2000). PET physiological measurements using constant infusion. Nuclear Medicine and Biology 27, 657-660.
CHABARDÈS,S., KAHANE,P., MINOTTI,L., TASSI,L., GRAND,S., HOFFMANN,D. & BENABID,A.L. (2005).
The temporopolar cortex plays a pivotal role in temporal lobe seizures. Brain 128, 1818-1831.
CHANG,B.S. & LOWENSTEIN,D.H. (2003). Mechanisms of disease - Epilepsy. New England Journal of Medicine 349, 1257-1266.
CHASSIDIM, Y., VAZANA,U., PRAGER, O., VEKSLER, R., BAR-KLEIN,G., SCHOKNECHT,K., FASSLER,M., LUBLINSKY, S. & SHELEF, I. (2015). Analyzing the blood–brain barrier: The benefits of medical imaging in research and clinical practice. Seminars in Cell & Developmental Biology 38, 43-52.
CHERRY,S.R. & DAHLBOM,M. (2004). PET: Physics, instrumentation, and scanners. In PET, pp. 1-124:
Springer.
CHERRY, S.R. & GAMBHIR, S.S. (2001). Use of Positron Emission Tomography in Animal Research.
ILAR Journal 42, 219-232.
CHOY, M., CHEUNG, K.K., THOMAS, D.L., GADIAN, D.G., LYTHGOE, M.F. & SCOTT, R.C. (2010).
Quantitative MRI predicts status epilepticus-induced hippocampal injury in the lithium–pilocarpine rat model. Epilepsy Research 88, 221-230.
CORNFORD, E.M. & OLDENDORF, W.H. (1986). Epilepsy and the blood-brain barrier. Advances in Neurology 44, 787-812.
CUCULLO,L., HALLENE,K., DINI,G., DAL TOSO,R. & JANIGRO,D. (2004). Glycerophosphoinositol and dexamethasone improve transendothelial electrical resistance in an in vitro study of the blood–
brain barrier. Brain Research 997, 147-151.
CURIA,G., LONGO,D., BIAGINI,G., JONES,R.S. & AVOLI,M. (2008). The pilocarpine model of temporal lobe epilepsy. Journal of Neuroscience Methods 172, 143-157.
DAVID,Y., CACHEAUX,L.P., IVENS,S., LAPILOVER,E., HEINEMANN,U., KAUFER,D. & FRIEDMAN,A. (2009).
Astrocytic dysfunction in epileptogenesis: consequence of altered potassium and glutamate homeostasis? The Journal of Neuroscience 29, 10588-10599.
DEDEURWAERDERE, S., JUPP, B. & O'BRIEN, T.J. (2007). Positron emission tomography in basic epilepsy research: a view of the epileptic brain. Epilepsia 48, 56-64.
DIJKHUIZEN, R.M. (2011). Advances in MRI-based detection of cerebrovascular changes after experimental traumatic brain injury. Translational Stroke Research 2, 524-532.
DUDEK,F.E., CLARK,S., WILLIAMS,P.A. & GRABENSTATTER,H.L. (2006). Chapter 34 - Kainate-Induced Status Epilepticus: A Chronic Model of Accuired Epilepsy. In Models of Seizures and Epilepsy.
ed. MOSHÉ,S.L., PITKÄNEN,A. & SCHWARTZKROIN,P.A., pp. 415-432. Burlington: Academic Press.
DUFFY,B.A., CHUN,K.P., MA,D., LYTHGOE,M.F. & SCOTT,R.C. (2014). Dexamethasone exacerbates cerebral edema and brain injury following lithium-pilocarpine induced status epilepticus.
Neurobiology of Disease 63, 229-236.
ENGEL,J. (1996). Introduction to temporal lobe epilepsy. Epilepsy Research 26, 141-150.
ENGEL,J. (2006). Report of the ILAE classification core group. Epilepsia 47, 1558-1568.
ENGELHARDT, B. & COISNE,C. (2011). Fluids and barriers of the CNS establish immune privilege by confining immune surveillance to a two-walled castle moat surrounding the CNS castle. Fluids and Barriers of the CNS 8, 4.
ENGLANDER, J., BUSHNIK, T., DUONG, T.T., CIFU, D.X., ZAFONTE, R., WRIGHT, J., HUGHES, R. &
BERGMAN, W. (2003). Analyzing risk factors for late posttraumatic seizures: a prospective, multicenter investigation. Archives of Physical Medicine and Rehabilitation 84, 365-373.
FABENE,P.F., MORA,G.N., MARTINELLO,M., ROSSI,B., MERIGO,F., OTTOBONI,L., BACH,S., ANGIARI,S., BENATI, D., CHAKIR, A., ZANETTI, L., SCHIO, F., OSCULATI, A., MARZOLA, P., NICOLATO, E., HOMEISTER,J.W., XIA,L., LOWE,J.B., MCEVER,R.P., OSCULATI,F., SBARBATI,A., BUTCHER,E.C. &
CONSTANTIN,G. (2008). A role for leukocyte-endothelial adhesion mechanisms in epilepsy. Nature Medicine 14, 1377-1383.
FISHER,R.S., BOAS,W.V.E., BLUME,W., ELGER,C., GENTON,P., LEE,P. & ENGEL,J. (2005). Epileptic seizures and epilepsy: definitions proposed by the International League Against Epilepsy (ILAE) and the International Bureau for Epilepsy (IBE). Epilepsia 46, 470-472.
FRIEDMAN, A. (2011). Blood–brain barrier dysfunction, status epilepticus, seizures, and epilepsy: A puzzle of a chicken and egg? Epilepsia 52, 19-20.
FRIEDMAN,A. & HEINEMANN,U. (2010). Role of blood–brain barrier injury in epileptogenesis. Epilepsia 51, 34-34.
FRIEDMAN,A., KAUFER,D. & HEINEMANN,U. (2009). Blood–brain barrier breakdown-inducing astrocytic transformation: Novel targets for the prevention of epilepsy. Epilepsy Research 85, 142-149.
FUJIKAWA,D.G. (1996). The temporal evolution of neuronal damage from pilocarpine-induced status epilepticus. Brain Research 725, 11-22.
GALANOPOULOU, A.S., BUCKMASTER, P.S., STALEY, K.J., MOSHE, S.L., PERUCCA, E., ENGEL, J., JR., LÖSCHER,W., NOEBELS,J.L., PITKÄNEN,A., STABLES,J., WHITE,H.S., O'BRIEN,T.J. & SIMONATO, M. (2012). Identification of new epilepsy treatments: issues in preclinical methodology. Epilepsia 53, 571-582.
GILAD, R., LAMPL, Y., EILAM, A., BOAZ, M. & LOYBERBOIM, M. (2012). SPECT-DTPA as a tool for evaluating the blood–brain barrier in post-stroke seizures. Journal of Neurology 259, 2041-2044.
GLIEN,M., BRANDT,C., POTSCHKA,H., VOIGT,H., EBERT,U. & LÖSCHER,W. (2001). Repeated low-dose treatment of rats with pilocarpine: low mortality but high proportion of rats developing epilepsy.
Epilepsy Research 46, 111-119.
GOFFIN, K., DEDEURWAERDERE, S., VAN LAERE, K. & VAN PAESSCHEN, W. (2008). Neuronuclear assessment of patients with epilepsy. Seminars in Nuclear Medicine 38, 227-239.
GOFFIN,K., VAN PAESSCHEN,W., DUPONT,P. & VAN LAERE,K. (2009). Longitudinal microPET imaging of brain glucose metabolism in rat lithium-pilocarpine model of epilepsy. Experimental Neurology 217, 205-209.
GORTER,J.A., VAN VLIET,E.A. & ARONICA,E. (2015). Status epilepticus, blood–brain barrier disruption, inflammation, and epileptogenesis. Epilepsy & Behavior 49, 13-16.
GREINER,W. & MÜLLER,B. (1994). Quantum Mechanics, vol. 2: Springer Science & Business Media, 233.
GRÖHN, O. & PITKÄNEN, A. (2007). Magnetic resonance imaging in animal models of epilepsy—
noninvasive detection of structural alterations. Epilepsia 48, 3-10.
GRÖHN, O., SIERRA, A., IMMONEN, R., LAITINEN, T., LEHTIMÄKI, K., AIRAKSINEN, A., HAYWARD, N., NAIRISMAGI, J., LEHTO, L. & PITKÄNEN, A. (2011). Multimodal MRI assessment of damage and plasticity caused by status epilepticus in the rat brain. Epilepsia 52, 57-60.
GRÖTICKE, I., HOFFMANN, K. & LÖSCHER, W. (2008). Behavioral alterations in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainate. Experimental Neurology 213, 71-83.
GUO,Y., GAO,F., WANG,S., DING,Y., ZHANG,H., WANG,J. & DING,M.P. (2009). In vivo mapping of temporospatial changes in glucose utilization in rat brain during epileptogenesis: An F-18-fluorodeoxyglucose-small animal positron emission tomography study. Neuroscience 162, 972-979.
GUPTA,S.C., PATCHVA,S. & AGGARWAL,B.B. (2013). Therapeutic roles of curcumin: lessons learned from clinical trials. The AAPS journal 15, 195-218.
HAMILTON, S.E., LOOSE, M.D., QI, M., LEVEY, A.I., HILLE, B., MCKNIGHT, G.S., IDZERDA, R.L. &
NATHANSON, N.M. (1997). Disruption of the m1 receptor gene ablates muscarinic receptor-dependent M current regulation and seizure activity in mice. Proceedings of the National Academy of Sciences of the United States of America 94, 13311-13316.
HÄRTIG, W., BRUCKNER, G., HOLZER, M., BRAUER, K. & BIGL, V. (1995). Digoxigenylated primary antibodies for sensitive dual-peroxidase labelling of neural markers. Histochemistry and Cell Biology 104, 467-472.
HAUSER, W., ATKINS, H., NELSON, K. & RICHARDS, P. (1970). Technetium-99m DTPA: A New Radiopharmaceutical for Brain and Kidney Scanning 1. Radiology 94, 679-684.
HEDLEY‐WHYTE, E.T. & HSU, D.W. (1986). Effect of dexamethasone on blood‐brain barrier in the normal mouse. Annals of Neurology 19, 373-377.
HEINEMANN,U., GABRIEL,S., JAUCH,R., SCHULZE,K., KIVI,A., EILERS,A., KOVACS,R. & LEHMANN,T.N.
(2000). Alterations of glial cell function in temporal lobe epilepsy. Epilepsia 41, 185-189.
HERMAN,S.T. (2002). Epilepsy after brain insult Targeting epileptogenesis. Neurology 59, 21-26.
HERSCHMAN,H.R. (2003). Micro-PET imaging and small animal models of disease. Current Opinion in Immunology 15, 378-384.
HOLTMAN,L., VAN VLIET,E.A., APPELDOORN,C., GAILLARD,P.J., DE BOER, M., DORLAND,R., WADMAN, W.J. & GORTER,J.A. (2014). Glutathione pegylated liposomal methylprednisolone administration after the early phase of status epilepticus did not modify epileptogenesis in the rat. Epilepsy Research 108, 396-404.
HONCHAR,M.P., OLNEY,J.W. & SHERMAN,W.R. (1983). Systemic cholinergic agents induce seizures and brain damage in lithium-treated rats. Science 220, 323-325.
HSU, Y.H., LEE, W.T. & CHANG, C. (2007). Multiparametric MRI evaluation of kainic acid-induced neuronal activation in rat hippocampus. Brain 130, 3124-3134.
HUE, C.D., CHO, F.S., CAO, S., RDALER BASS, C.R., MEANEY, D.F. & MORRISON III, B. (2015).
Dexamethasone potentiates in vitro blood-brain barrier recovery after primary blast injury by glucocorticoid receptor-mediated upregulation of ZO-1 tight junction protein. Journal of Cerebral Blood Flow & Metabolism 35, 1191-1198.
IVANOVA, N., PECHLIVANOVA, D., TCHEKALAROVA, J., POPOV, D., MARKOVA, P. & STOYNEV, A. (2013).
Beneficial effects of chronic treatment with losartan on behavioural disturbances in kainate model of temporal lobe epilepsy. Comptes rendus de l'Académie bulgare des Sciences 66, 1761-1768.
IVENS, S., KAUFER, D., FLORES, L.P., BECHMANN, I., ZUMSTEG, D., TOMKINS, O., SEIFFERT, E., HEINEMANN,U. & FRIEDMAN,A. (2007). TGF-β receptor-mediated albumin uptake into astrocytes is involved in neocortical epileptogenesis. Brain 130, 535-547.
JAMES, M.L. & GAMBHIR, S.S. (2012). A molecular imaging primer: modalities, imaging agents, and applications. Physiological Reviews 92, 897-965.
JANIGRO,D. (1999). Blood–brain barrier, ion homeostasis and epilepsy: possible implications towards the understanding of ketogenic diet mechanisms. Epilepsy Research 37, 223-232.
JANIGRO,D., GASPARINI,S., D’AMBROSIO,R., MCKHANN II, G. & DIFRANCESCO,D. (1997). Reduction of K+ uptake in glia prevents long-term depression maintenance and causes epileptiform activity.
The Journal of Neuroscience 17, 2813-2824.
JIANG,J., WANG,W., SUN,Y.J., HU,M., LI,F. & ZHU,D.Y. (2007). Neuroprotective effect of curcumin on focal cerebral ischemic rats by preventing blood–brain barrier damage. European Journal of Pharmacology 561, 54-62.
JUPP,B., WILLIAMS,J., BINNS,D. & HICKS,R. (2007). Imaging small animal models of epileptogenesis.
Neurology Asia 12, 51-54.
JUPP, B., WILLIAMS, J., BINNS,D., HICKS, R.J., CARDAMONE, L., JONES, N., REES, S. & O'BRIEN, T.J.
(2012). Hypometabolism precedes limbic atrophy and spontaneous recurrent seizures in a rat model of TLE. Epilepsia 53, 1233-1244.
KAAL,E.C. & VECHT,C.J. (2004). The management of brain edema in brain tumors. Current Opinion in Oncology 16, 593-600.
KARLIK,S., STAVRAKY,R., TAYLOR,A., FOX,A. & MCLACHLAN,R. (1991). Magnetic resonance imaging and 31P spectroscopy of an interictal cortical spike focus in the rat. Epilepsia 32, 446-453.
KASSNER,A. & THORNHILL,R. (2011). Measuring the integrity of the human blood–brain barrier using magnetic resonance imaging. In The Blood-Brain and Other Neural Barriers, pp. 229-245:
Springer.
KAYA,M., KALAYCI,R., KÜÇÜK, M., ARICAN, N., ELMAS,I., KUDAT, H. & KORKUT, F. (2003). Effect of losartan on the blood–brain barrier permeability in diabetic hypertensive rats. Life Sciences 73, 3235-3244.
KEITH L. BLACK, TIM CLOUGHESY, SUNG-CHENG HUANG, Y. PIERRE GOBIN, YUN ZHOU, JOHN GROUS, GILLIAN NELSON, KEYVAN FARAHANI, CARL K.HOH & MICHAEL PHELPS. (1997). Intracarotid infusion of RMP-7, a bradykinin analog, and transport of gallium-68 ethylenediamine tetraacetic acid into human gliomas. Journal of Neurosurgery 86, 603-609.
KING, M., BRUGGEN, N.V., AHIER, R., CREMER, J., HAJNAL, J., WILLIAMS, S. & DORAN, M. (1991). blood-brain barrier can be reversed by inhibition of the proteasome. Stroke 42, 1081-1089.
KNAKE, S., HAMER, H.M. & ROSENOW, F. (2009). Status epilepticus: A critical review. Epilepsy &
Behavior 15, 10-14.
KNIGHT,R.A., KARKI,K., EWING,J.R., DIVINE,G.W., FENSTERMACHER,J.D., PATLAK,C.S. & NAGARAJA, T.N. (2009). Estimating blood and brain concentrations and blood-to-brain influx by magnetic resonance imaging with step-down infusion of Gd-DTPA in focal transient cerebral ischemia and confirmation by quantitative autoradiography with Gd-[(14)C]DTPA. Journal of Cerebral Blood Flow and Metabolism 29, 1048-1058.
KNIGHT,R.A., NAGARAJA,T.N., EWING,J.R., NAGESH,V., WHITTON,P.A., BERSHAD,E., FAGAN,S.C. &
FENSTERMACHER, J.D. (2005). Quantitation and localization of blood-to-brain influx by magnetic resonance imaging and quantitative autoradiography in a model of transient focal ischemia.
Magnetic Resonance in Medicine 54, 813-821.
KOEPPE,R.A. (2002). Data Analysis and Imaging Processing. In Principles and Practice of Positron Emission Tomography. ed. WAHL,R.L., pp. 65-99: Lippincott Williams & Wilkins.
KORNBLUM,H.I., ARAUJO,D.M., ANNALA,A.J., TATSUKAWA,K.J., PHELPS,M.E. & CHERRY,S.R. (2000).
In vivo imaging of neuronal activation and plasticity in the rat brain by high resolution positron emission tomography (microPET). Nature Biotechnology 18, 655-660.
LAMPL, Y., SHMUILOVICH, O., LOCKMAN, J., SADEH, M. & LORBERBOYM, M. (2005). Prognostic Significance of Blood Brain Barrier Permeability in Acute Hemorrhagic Stroke. Cerebrovascular Diseases 20, 433-437.
LAURILA, J.P., LAATIKAINEN, L.E., CASTELLONE, M.D. & LAUKKANEN, M.O. (2009). SOD3 Reduces Inflammatory Cell Migration by Regulating Adhesion Molecule and Cytokine Expression. PLoS ONE 4, e5786.
LECCHI, M., OTTOBRINI, L., MARTELLI, C., DEL SOLE,A. & LUCIGNANI,G. (2007). Instrumentation and probes for molecular and cellular imaging. The Quarterly Journal of Nuclear Medicine and Molecular Imaging 51, 111-126.
LEE,E.M., PARK,G.Y., IM,K.C., KIM,S.T., WOO,C.-W., CHUNG,J.H., KIM,K.S., KIM,J.S., SHON,Y.-M., KIM, Y.I. & KANG, J.K. (2012). Changes in glucose metabolism and metabolites during the epileptogenic process in the lithium-pilocarpine model of epilepsy. Epilepsia 53, 860-869.
LEITE,J., GARCIA-CAIRASCO,N. & CAVALHEIRO,E. (2002). New insights from the use of pilocarpine and kainate models. Epilepsy Research 50, 93-103.
LIBRIZZI, L., REGONDI, M.C., PASTORI, C., FRIGERIO, S., FRASSONI, C. & DE CURTIS, M. (2007).
Expression of adhesion factors induced by epileptiform activity in the endothelium of the isolated guinea pig brain in vitro. Epilepsia 48, 743-751.
LIN,K.-J., LIU,H.-L., HSU,P.-H., CHUNG, Y.-H., HUANG,W.-C., CHEN,J.-C., WEY,S.-P., YEN,T.-C. &
HSIAO, I.-T. (2009). Quantitative micro-SPECT/CT for detecting focused ultrasound-induced blood–brain barrier opening in the rat. Nuclear Medicine and Biology 36, 853-861.
LÖSCHER,W. (2002). Animal models of epilepsy for the development of antiepileptogenic and disease-modifying drugs. A comparison of the pharmacology of kindling and post-status epilepticus models of temporal lobe epilepsy. Epilepsy Research 50, 105-123.
LÖSCHER, W. (2003). Pharmakologische Grundlagen zur Behandlung der Epilepsie bei Hund und Katze. Praktischer Tierarzt 14, 574-587.
LÖSCHER,W. & BRANDT,C. (2010). Prevention or Modification of Epileptogenesis after Brain Insults:
Experimental Approaches and Translational Research. Pharmacological Reviews 62, 668-700.
LÖSCHER,W. & POTSCHKA,H. (2005). Drug resistance in brain diseases and the role of drug efflux transporters. Nature Reviews Neuroscience 6, 591-602.
LÖSCHER,W. & SCHMIDT,D. (2002). New horizons in the development of antiepileptic drugs. Epilepsy Research 50, 3-16.
LOTHMAN,E. (1990). The biochemical basis and pathophysiology of status epilepticus. Neurology 40, 13-23.
LOWENSTEIN,D.H. (2009). Epilepsy after head injury: an overview. Epilepsia 2, 4-9.
MARCHI,N., ANGELOV,L., MASARYK,T., FAZIO,V., GRANATA,T., HERNANDEZ,N., HALLENE,K., DIGLAW, T., FRANIC, L., NAJM,I. & JANIGRO,D. (2007a). Seizure-Promoting Effect of Blood–Brain Barrier Disruption. Epilepsia 48, 732-742.
MARCHI,N., FAN,Q., GHOSH,C., FAZIO,V., BERTOLINI,F., BETTO,G., BATRA,A., CARLTON,E., NAJM,I. &
GRANATA, T. (2009). Antagonism of peripheral inflammation reduces the severity of status epilepticus. Neurobiology of Disease 33, 171-181.
MARCHI,N., GRANATA,T., FRERI,E., CIUSANI,E., RAGONA,F., PUVENNA,V., TENG,Q., ALEXOPOLOUS,A.
& JANIGRO,D. (2011a). Efficacy of Anti-Inflammatory Therapy in a Model of Acute Seizures and in a Population of Pediatric Drug Resistant Epileptics. PLoS ONE 6, e18200.
MARCHI, N., GRANATA, T., GHOSH, C. & JANIGRO, D. (2012). Blood–brain barrier dysfunction and epilepsy: Pathophysiologic role and therapeutic approaches. Epilepsia 53, 1877-1886.
MARCHI,N., OBY,E., BATRA,A., UVA,L., DE CURTIS,M., HERNANDEZ,N., BOXEL‐DEZAIRE,V., NAJM,I. &
JANIGRO,D. (2007b). In vivo and in vitro effects of pilocarpine: relevance to ictogenesis. Epilepsia 48, 1934-1946.
MARCHI,N., TIERNEY,W., ALEXOPOULOS,A.V., PUVENNA,V., GRANATA,T. & JANIGRO,D. (2011b). The etiological role of blood-brain barrier dysfunction in seizure disorders. Cardiovascular Psychiatry and Neurology 482415, 30.
MAROSO, M., BALOSSO, S., RAVIZZA, T., IORI, V., WRIGHT, C.I., FRENCH, J. & VEZZANI, A. (2011).
Interleukin-1 beta Biosynthesis Inhibition Reduces Acute Seizures and Drug Resistant Chronic Epileptic Activity in Mice. Neurotherapeutics 8, 304-315.
MATTSON,R.H., CRAMER,J.A. & COLLINS,J.F. (1992). A comparison of valproate with carbamazepine for the treatment of complex partial seizures and secondarily generalized tonic–clonic seizures in adults. New England Journal of Medicine 327, 765-771.
MCMASTER,A. & RAY,D.W. (2007). Modelling the glucocorticoid receptor and producing therapeutic agents with anti‐inflammatory effects but reduced side‐effects. Experimental Physiology 92, 299-309.
MCNAMARA,J.O. (1994). Cellular and molecular basis of epilepsy. The Journal of Neuroscience 14, 3413-3425.
MICHALSKI,D., GROSCHE,J., PELZ,J., SCHNEIDER,D., WEISE,C., BAUER,U., KACZA,J., GÄRTNER,U., HOBOHM, C. & HÄRTIG, W. (2010). A novel quantification of blood–brain barrier damage and histochemical typing after embolic stroke in rats. Brain Research 1359, 186-200.
MIRRIONE, M.M., SCHIFFER, W.K., SIDDIQ, M., DEWEY, S.L. & TSIRKA, S.E. (2006). PET imaging of glucose metabolism in a mouse model of temporal lobe epilepsy. Synapse 59, 119-121.
NACER, A., MOVILA, A., BAER, K., MIKOLAJCZAK, S.A., KAPPE, S.H. & FREVERT, U. (2012).
NACER, A., MOVILA, A., BAER, K., MIKOLAJCZAK, S.A., KAPPE, S.H. & FREVERT, U. (2012).