Neuromodulatory role of endogenous interleukin-1β in acute seizures: Possible contribution of cyclooxygenase-2

The function of endogenous interleukin-1β (IL-1β) signaling in acute seizure activity was examined using transgenic mice harboring targeted deletions in the genes for either IL-1β (Il1b) or its signaling receptor (Il1r1). Acute epileptic seizure activity was modeled using two mechanistically distinct chemoconvulsants, kainic acid (KA) and pentylenetetrazole (PTZ). KA-induced seizure activity was more severe in homozygous null (-/-) Il1b mice compared to their wild-type (+/+) littermate controls, as indicated by an increase in the incidence of sustained generalized convulsive seizure activity. In the PTZ seizure model, the incidence of acute convulsive seizures was increased in both Il1b and Il1r1-/- mice compared to their respective +/+ littermate controls. Interestingly, the selective cyclooxygenase (COX)-2 inhibitor, rofecoxib, mimicked the effect of IL-1β deficiency on PTZ-induced convulsions in Il1r1+/+ but not -/- mice. Together, these results suggest that endogenous IL-1β possesses anticonvulsive properties that may be mediated by arachidonic acid metabolites derived from the catalytic action of COX-2.

[1]  B. Winblad,et al.  Impaired long term memory consolidation in transgenic mice overexpressing the human soluble form of IL-1ra in the brain , 2009, Journal of Neuroimmunology.

[2]  D. Smart,et al.  The interleukin-1 type I receptor is expressed in human hypothalamus. , 1999, Brain : a journal of neurology.

[3]  A. Vezzani,et al.  Interleukin Converting Enzyme inhibition impairs kindling epileptogenesis in rats by blocking astrocytic IL-1β production , 2008, Neurobiology of Disease.

[4]  C. Dinarello,et al.  Immunoreactive interleukin-1β localization in the rat forebrain , 1990, Brain Research.

[5]  Q. Pittman,et al.  Causal Links between Brain Cytokines and Experimental Febrile Convulsions in the Rat , 2005, Epilepsia.

[6]  M. Horne,et al.  Electroencephalographic characterisation of pentylenetetrazole-induced seizures in mice lacking the α4 subunit of the neuronal nicotinic receptor , 2003, Neuropharmacology.

[7]  D. Covey,et al.  Pentylenetetrazole-induced inhibition of recombinant gamma-aminobutyric acid type A (GABA(A)) receptors: mechanism and site of action. , 2001, The Journal of pharmacology and experimental therapeutics.

[8]  S. Garattini,et al.  Inflammatory cytokines and related genes are induced in the rat hippocampus by limbic status epilepticus , 2000, The European journal of neuroscience.

[9]  C. Wilson,et al.  Electrophysiologic Analysis of a Chronic Seizure Model After Unilateral Hippocampal KA Injection , 1999, Epilepsia.

[10]  A. Vezzani,et al.  Status epilepticus induces time-dependent neuronal and astrocytic expression of interleukin-1 receptor type I in the rat limbic system , 2006, Neuroscience.

[11]  C. Mancuso,et al.  Evidence for the neuronal origin of immunoreactive interleukin-1β released by rat hypothalamic explants , 1996, Neuroscience Letters.

[12]  A. Vezzani,et al.  Inactivation of Caspase‐1 in Rodent Brain: A Novel Anticonvulsive Strategy , 2006, Epilepsia.

[13]  S. Summerfield,et al.  The Cyclooxygenase-2 Inhibitor GW406381X [2-(4-Ethoxyphenyl)-3-[4-(methylsulfonyl)phenyl]-pyrazolo[1,5-b]pyridazine] Is Effective in Animal Models of Neuropathic Pain and Central Sensitization , 2005, Journal of Pharmacology and Experimental Therapeutics.

[14]  J. de Belleroche,et al.  Cyclooxygenase‐2 Induction in Cerebral Cortex: An Intracellular Response to Synaptic Excitation , 1996, Journal of neurochemistry.

[15]  R. Bonsall,et al.  Detection of interleukin-1 bioactivity in various brain regions of normal healthy rats. , 1996, Neuroimmunomodulation.

[16]  J. Watt,et al.  Interleukin‐1β immunoreactivity in identified neurons of the rat magnocellular neurosecretory system: Evidence for activity‐dependent release , 2000, Journal of neuroscience research.

[17]  A. Ferguson,et al.  Prostaglandin E2 Mediates Cellular Effects of Interleukin‐1β on Parvocellular Neurones in the Paraventricular Nucleus of the Hypothalamus , 2005, Journal of neuroendocrinology.

[18]  D. Swaab,et al.  IL-1β immunoreactive neurons in the human hypothalamus: reduced numbers in multiple sclerosis , 2000, Journal of Neuroimmunology.

[19]  Jinhyung Kim,et al.  A Genetic Switch for Epilepsy in Adult Mice , 2004, The Journal of Neuroscience.

[20]  C. Plata-salamán,et al.  Kindling modulates the IL-1β system, TNF-α, TGF-β1, and neuropeptide mRNAs in specific brain regions , 2000 .

[21]  M. Saito,et al.  Interleukin-1 Induces Slow-Wave Sleep at the Prostaglandin D2-Sensitive Sleep-Promoting Zone in the Rat Brain , 1998, The Journal of Neuroscience.

[22]  Takao Shimizu,et al.  Profiling of Eicosanoid Production in the Rat Hippocampus during Kainic Acid-induced Seizure , 2006, Journal of Biological Chemistry.

[23]  S. Deadwyler,et al.  Kainic acid produces depolarization of CA3 pyramidal cells in the in vitro hippocampal slice , 1981, Brain Research.

[24]  A. Vezzani,et al.  Functional Role of Inflammatory Cytokines and Antiinflammatory Molecules in Seizures and Epileptogenesis , 2002, Epilepsia.

[25]  N. Bazan,et al.  Postsynaptically Synthesized Prostaglandin E2 (PGE2) Modulates Hippocampal Synaptic Transmission via a Presynaptic PGE2 EP2 Receptor , 2005, The Journal of Neuroscience.

[26]  C. Pert,et al.  Visualization and characterization of interleukin 1 receptors in brain. , 1987, Journal of immunology.

[27]  C. Dinarello,et al.  The IL-1 family and inflammatory diseases. , 2002, Clinical and experimental rheumatology.

[28]  Klaas Kramer,et al.  Evaluation and applications of radiotelemetry in small laboratory animals. , 2003, Physiological genomics.

[29]  N. Schork,et al.  Mapping Loci for Pentylenetetrazol-Induced Seizure Susceptibility in Mice , 1999, The Journal of Neuroscience.

[30]  E. Lynd-Balta,et al.  Enhanced cyclooxygenase-2 expression in olfactory-limbic forebrain following kainate-induced seizures , 2006, Neuroscience.

[31]  G. Westbrook,et al.  Cellular and synaptic basis of kainic acid-induced hippocampal epileptiform activity , 1983, Brain Research.

[32]  G. Hertting,et al.  Regional distribution of arachidonic acid metabolites in rat brain following convulsive stimuli. , 1981, Prostaglandins.

[33]  C. Saper,et al.  Interleukin-1 immunoreactive innervation of the human hypothalamus. , 1988, Science.

[34]  S. Kulkarni,et al.  Rofecoxib, a selective cyclooxygenase-2 (COX-2) inhibitor increases pentylenetetrazol seizure threshold in mice: Possible involvement of adenosinergic mechanism , 2008, Epilepsy Research.

[35]  Carol A. Barnes,et al.  Expression of a mitogen-inducible cyclooxygenase in brain neurons: Regulation by synaptic activity and glucocorticoids , 1993, Neuron.

[36]  H Perrier,et al.  Rofecoxib [Vioxx, MK-0966; 4-(4'-methylsulfonylphenyl)-3-phenyl-2-(5H)-furanone]: a potent and orally active cyclooxygenase-2 inhibitor. Pharmacological and biochemical profiles. , 1999, The Journal of pharmacology and experimental therapeutics.

[37]  R. Racine,et al.  Modification of seizure activity by electrical stimulation. II. Motor seizure. , 1972, Electroencephalography and clinical neurophysiology.

[38]  S. Moshé,et al.  How do seizures stop? , 2008, Epilepsia.

[39]  M. Minami,et al.  In situ hybridization study of interleukin-1 beta mRNA induced by kainic acid in the rat brain. , 1993, Brain research. Molecular brain research.

[40]  M. Shokrgozar,et al.  Antiepileptogenic and anticonvulsant activity of interleukin-1β in amygdala-kindled rats , 2005, Experimental Neurology.

[41]  E. Oliw,et al.  Nimesulide aggravates kainic acid-induced seizures in the rat. , 2001, Pharmacology & toxicology.

[42]  M. Opp,et al.  How (and why) the immune system makes us sleep , 2009, Nature Reviews Neuroscience.

[43]  H. White,et al.  Clinical Significance of Animal Seizure Models and Mechanism of Action Studies of Potential Antiepileptic Drugs , 1997, Epilepsia.

[44]  R. Rosenkranz,et al.  Anticonvulsant effects of PGE2 on electrical, chemical and photomyoclonic animal models of epilepsy. , 1981, Progress in lipid research.

[45]  N. Morioka,et al.  Interleukin‐1β Induces Substance P Release from Primary Afferent Neurons Through the Cyclooxygenase‐2 System , 1999, Journal of neurochemistry.

[46]  M. Iyo,et al.  A decrease in interleukin-1 receptor antagonist expression in the prefrontal cortex of schizophrenic patients , 2003, Neuroscience Research.

[47]  V. Bolivar,et al.  Cautionary insights on knockout mouse studies: The gene or not the gene? , 2009, Brain, Behavior, and Immunity.

[48]  I. Goshen,et al.  A dual role for interleukin-1 in hippocampal-dependent memory processes , 2007, Psychoneuroendocrinology.

[49]  E. Cavalheiro,et al.  Cyclooxygenase-2/PGE2 pathway facilitates pentylenetetrazol-induced seizures , 2008, Epilepsy Research.

[50]  P. Jennum,et al.  Measurement of cortical and hippocampal epileptiform activity in freely moving rats by means of implantable radiotelemetry , 2004, Journal of Neuroscience Methods.

[51]  Peihua Lu,et al.  Interleukin-1β mediates proliferation and differentiation of multipotent neural precursor cells through the activation of SAPK/JNK pathway , 2007, Molecular and Cellular Neuroscience.

[52]  Detlef Balschun,et al.  A neuromodulatory role of interleukin-1β in the hippocampus , 1998 .

[53]  P. Greengard,et al.  Dopamine D1 vs D5 receptor-dependent induction of seizures in relation to DARPP-32, ERK1/2 and GluR1-AMPA signalling , 2008, Neuropharmacology.

[54]  W. Farrar,et al.  Participation of lymphocyte activating factor (Interleukin 1) in the induction of cytotoxic T cell responses. , 1980, Journal of immunology.

[55]  J. Krueger,et al.  The Role of Cytokines in Physiological Sleep Regulation , 2001, Annals of the New York Academy of Sciences.

[56]  Yi-Sook Jung,et al.  Involvement of endogenous prostaglandin F2α on kainic acid-induced seizure activity through FP receptor: The mechanism of proconvulsant effects of COX-2 inhibitors , 2008, Brain Research.

[57]  A. Comert,et al.  Inhibition of pentylenetetrazol-induced seizures in rats by prostaglandin D2 , 1998, Epilepsy Research.

[58]  A. Vezzani,et al.  Interleukin-1β Immunoreactivity and Microglia Are Enhanced in the Rat Hippocampus by Focal Kainate Application: Functional Evidence for Enhancement of Electrographic Seizures , 1999, The Journal of Neuroscience.

[59]  R. Dantzer,et al.  Expression and localization of p80 and p68 interleukin-1 receptor proteins in the brain of adult mice , 1999, Journal of Neuroimmunology.

[60]  G. Engelhardt,et al.  Meloxicam: influence on arachidonic acid metabolism. Part II. In vivo findings. , 1996, Biochemical pharmacology.

[61]  J. Hewett,et al.  Oral Treatment with Rofecoxib Reduces Hippocampal Excitotoxic Neurodegeneration , 2006, Journal of Pharmacology and Experimental Therapeutics.

[62]  E. D. De Souza,et al.  Interleukin-1 receptors in mouse brain: characterization and neuronal localization. , 1990, Endocrinology.

[63]  J. Krueger,et al.  Diurnal variations of interleukin-1β mRNA and β-actin mRNA in rat brain , 1997, Journal of Neuroimmunology.

[64]  D. Dewitt,et al.  Characterization of inducible cyclooxygenase in rat brain , 1995, The Journal of comparative neurology.

[65]  K. Rijkers,et al.  The role of interleukin-1 in seizures and epilepsy: A critical review , 2009, Experimental Neurology.

[66]  C. Dinarello,et al.  Interleukin-1 augments gamma-aminobutyric acidA receptor function in brain. , 1991, Molecular pharmacology.

[67]  I. Goshen,et al.  Impaired interleukin‐1 signaling is associated with deficits in hippocampal memory processes and neural plasticity , 2003, Hippocampus.

[68]  A. Depaulis,et al.  Evolution of hippocampal epileptic activity during the development of hippocampal sclerosis in a mouse model of temporal lobe epilepsy , 2002, Neuroscience.

[69]  W. H. Jordan,et al.  Mesial Temporal Lobe Epilepsy: Pathogenesis, Induced Rodent Models and Lesions , 2007, Toxicologic pathology.

[70]  M. Ticku,et al.  Differential interactions of GABA agonists, depressant and convulsant drugs with [35S]-t-butylbicyclophosphorothionate binding sites in cortex and cerebellum , 1984, Pharmacology Biochemistry and Behavior.

[71]  H. Baran,et al.  Increased prostaglandin formation in rat brain following systemic application of kainic acid , 1987, Brain Research.

[72]  G. Sperk,et al.  Powerful anticonvulsant action of IL-1 receptor antagonist on intracerebral injection and astrocytic overexpression in mice. , 2000, Proceedings of the National Academy of Sciences of the United States of America.

[73]  D. Riendeau,et al.  Characterization of rofecoxib as a cyclooxygenase‐2 isoform inhibitor and demonstration of analgesia in the dental pain model , 1999, Clinical pharmacology and therapeutics.

[74]  J. McHowat,et al.  Interleukin-1beta stimulates phospholipase A2 activity in adult rat ventricular myocytes. , 1997, The American journal of physiology.

[75]  Marco Weiergräber,et al.  Electrocorticographic and deep intracerebral EEG recording in mice using a telemetry system. , 2005, Brain research. Brain research protocols.

[76]  L. Marnett,et al.  NMDA-induced seizure intensity is enhanced in COX-2 deficient mice. , 2008, Neurotoxicology.

[77]  D. Giulian,et al.  Interleukin-1 is an astroglial growth factor in the developing brain , 1988, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[78]  Z. Emri,et al.  Epileptogenesis and chronic seizures in a mouse model of temporal lobe epilepsy are associated with distinct EEG patterns and selective neurochemical alterations in the contralateral hippocampus , 2005, Experimental Neurology.

[79]  C. Mancuso,et al.  The release of immunoreactive interleukin-1 beta from rat hypothalamic explants is modulated by neurotransmitters and corticotropin-releasing hormone. , 1997, Pharmacological research.

[80]  J. Calixto,et al.  Modulation of pentylenetetrazol-induced seizures by prostaglandin E2 receptors , 2008, Neuroscience.

[81]  U. Förstermann,et al.  Effects of intracerebroventricular administration of prostaglandin D2 on behaviour, blood pressure and body temperature as compared to prostaglandins E2 and F2α , 2004, Psychopharmacology.

[82]  E. Baik,et al.  Cyclooxygenase-2 selective inhibitors aggravate kainic acid induced seizure and neuronal cell death in the hippocampus , 1999, Brain Research.

[83]  J. Bockaert,et al.  “Inflammatory” Cytokines , 2000, Journal of neurochemistry.

[84]  C. Mulle,et al.  Kainate receptors in epilepsy and excitotoxicity , 2009, Neuroscience.

[85]  H. Korf,et al.  Interleukin‐1β exacerbates and interleukin‐1 receptor antagonist attenuates neuronal injury and microglial activation after excitotoxic damage in organotypic hippocampal slice cultures , 2005 .

[86]  F. Edward Dudek,et al.  Recurrent spontaneous motor seizures after repeated low-dose systemic treatment with kainate: assessment of a rat model of temporal lobe epilepsy , 1998, Epilepsy Research.

[87]  Fiona M. Ross,et al.  A dual role for interleukin-1 in LTP in mouse hippocampal slices , 2003, Journal of Neuroimmunology.

[88]  P. Morrissey,et al.  Phenotypic and functional characterization of mice that lack the type I receptor for IL-1. , 1997, Journal of immunology.

[89]  H. Lipp,et al.  Dissecting the Behaviour of Transgenic Mice: Is it the Mutation, the Genetic Background, or the Environment? , 2000, Experimental physiology.

[90]  M. Wong,et al.  Endogenous interleukin-1 receptor antagonist is neuroprotective. , 1997, Biochemical and biophysical research communications.

[91]  U. Förstermann,et al.  Potential anticonvulsive properties of endogenous prostaglandins formed in mouse brain , 1982, Brain Research.

[92]  Eleonora Aronica,et al.  Innate and adaptive immunity during epileptogenesis and spontaneous seizures: Evidence from experimental models and human temporal lobe epilepsy , 2008, Neurobiology of Disease.

[93]  T. Bártfai,et al.  IL-1/IL-1ra balance in the brain revisited – Evidence from transgenic mouse models , 2009, Brain, Behavior, and Immunity.

[94]  H. Moldofsky,et al.  Adenosine: a Mediator of Interleukin-1β-Induced Hippocampal Synaptic Inhibition , 1999, The Journal of Neuroscience.

[95]  E. Kharasch,et al.  Central Nervous System Concentrations of Cyclooxygenase-2 Inhibitors in Humans , 2005, Anesthesiology.

[96]  M. O’Banion,et al.  The role of interleukin-1 in neuroinflammation and Alzheimer disease: an evolving perspective , 2008, Journal of Neuroinflammation.

[97]  B. Winblad,et al.  Inhibition of kainic acid induced expression of interleukin-1 beta and interleukin-1 receptor antagonist mRNA in the rat brain by NMDA receptor antagonists. , 2000, Brain research. Molecular brain research.

[98]  S. Hewett,et al.  Interleukin‐1β: a bridge between inflammation and excitotoxicity? , 2008 .

[99]  Adam Sapirstein,et al.  Interleukin-1β-mediated induction of Cox-2 in the CNS contributes to inflammatory pain hypersensitivity , 2001, Nature.

[100]  A. Vezzani,et al.  Functional role of proinflammatory and anti-inflammatory cytokines in seizures. , 2004, Advances in experimental medicine and biology.

[101]  A. Shaw,et al.  Resistance to fever induction and impaired acute-phase response in interleukin-1 beta-deficient mice. , 1995, Immunity.

[102]  Wim E Crusio,et al.  Knockout mice: simple solutions to the problems of genetic background and flanking genes , 2002, Trends in Neurosciences.

[103]  T. Baram,et al.  Interleukin‐1β contributes to the generation of experimental febrile seizures , 2005, Annals of neurology.

[104]  L. Ballou,et al.  Cyclooxygenase-2 mediates the febrile response of mice to interleukin-1β , 2001, Brain Research.

[105]  J. R. Pick,et al.  EFFECT OF TYPE OF BEDDING MATERIAL ON THRESHOLDS OF PENTYLENETETRAZOL CONVULSIONS IN MICE. , 1965, Laboratory animal care.