Kainic Acid-Induced Neurodegenerative Model: Potentials and Limitations

Excitotoxicity is considered to be an important mechanism involved in various neurodegenerative diseases in the central nervous system (CNS) such as Alzheimer's disease (AD). However, the mechanism by which excitotoxicity is implicated in neurodegenerative disorders remains unclear. Kainic acid (KA) is an epileptogenic and neuroexcitotoxic agent by acting on specific kainate receptors (KARs) in the CNS. KA has been extensively used as a specific agonist for ionotrophic glutamate receptors (iGluRs), for example, KARs, to mimic glutamate excitotoxicity in neurodegenerative models as well as to distinguish other iGluRs such as α-amino-3-hydroxy-5-methylisoxazole-4-propionate receptors and N-methyl-D-aspartate receptors. Given the current knowledge of excitotoxicity in neurodegeneration, interventions targeted at modulating excitotoxicity are promising in terms of dealing with neurodegenerative disorders. This paper summarizes the up-to-date knowledge of neurodegenerative studies based on KA-induced animal model, with emphasis on its potentials and limitations.

[1]  Sung-soo Kim,et al.  Neuroprotective effects of stanniocalcin 2 following kainic acid-induced hippocampal degeneration in ICR mice , 2010, Peptides.

[2]  Xi Liu,et al.  Structural insights into the assembly and activation of IL-1β with its receptors , 2010, Nature Immunology.

[3]  H. Neumann,et al.  Protective effects of microglia in multiple sclerosis , 2010, Experimental Neurology.

[4]  M. Pallàs,et al.  Differences in activation of ERK1/2 and p38 kinase in Jnk3 null mice following KA treatment , 2010, Journal of neurochemistry.

[5]  S. Jinap,et al.  Glutamate. Its applications in food and contribution to health , 2010, Appetite.

[6]  Dong Hyun Kim,et al.  Sinapic acid attenuates kainic acid-induced hippocampal neuronal damage in mice , 2010, Neuropharmacology.

[7]  P. Schauwecker Neuroprotection by glutamate receptor antagonists against seizure-induced excitotoxic cell death in the aging brain , 2010, Experimental Neurology.

[8]  Wei Wang,et al.  Excitotoxicity of TNFα derived from KA activated microglia on hippocampal neurons in vitro and in vivo , 2010, Journal of neurochemistry.

[9]  Michael T. Heneka,et al.  Neuroglia in neurodegeneration , 2010, Brain Research Reviews.

[10]  C. Colton,et al.  Assessing activation states in microglia. , 2010, CNS & neurological disorders drug targets.

[11]  H. Jia,et al.  Stabilization of mitochondrial function by tetramethylpyrazine protects against kainate-induced oxidative lesions in the rat hippocampus. , 2010, Free radical biology & medicine.

[12]  D. Baker,et al.  Inflammation in neurodegenerative diseases , 2010, Immunology.

[13]  D. Cleveland,et al.  Non–cell autonomous toxicity in neurodegenerative disorders: ALS and beyond , 2009, The Journal of cell biology.

[14]  S. Johann,et al.  Selective regulation of growth factor expression in cultured cortical astrocytes by neuro-pathological toxins , 2009, Neurochemistry International.

[15]  P Jeffrey Conn,et al.  Glutamate receptors as therapeutic targets for Parkinson's disease. , 2009, CNS & neurological disorders drug targets.

[16]  C. Beltramino,et al.  Differential role of gonadal hormones on kainic acid–induced neurodegeneration in medial amygdaloid nucleus of female and male rats , 2009, Neuroscience.

[17]  Wei Wang,et al.  Kainic Acid-Activated Microglia Mediate Increased Excitability of Rat Hippocampal Neurons in vitro and in vivo: Crucial Role of Interleukin-1beta , 2009, Neuroimmunomodulation.

[18]  M. Swamy,et al.  Nitric oxide (NO), citrulline–NO cycle enzymes, glutamine synthetase, and oxidative status in kainic acid–mediated excitotoxicity in rat brain , 2009, Drug and chemical toxicology.

[19]  D. Dexter,et al.  Relationship between microglial activation and dopaminergic neuronal loss in the substantia nigra: a time course study in a 6‐hydroxydopamine model of Parkinson’s disease , 2009, Journal of neurochemistry.

[20]  Myong-Jo Kim,et al.  Kainic Acid-induced Neuronal Death is Attenuated by Aminoguanidine but Aggravated by L-NAME in Mouse Hippocampus. , 2009, The Korean journal of physiology & pharmacology : official journal of the Korean Physiological Society and the Korean Society of Pharmacology.

[21]  S. Hino,et al.  Increased vulnerability of hippocampal pyramidal neurons to the toxicity of kainic acid in OASIS‐deficient mice , 2009, Journal of neurochemistry.

[22]  M. Knutson,et al.  Uptake of Materials from the Nasal Cavity into the Blood and Brain , 2009, Annals of the New York Academy of Sciences.

[23]  Jeffrey A. Johnson,et al.  The Nrf2–ARE cytoprotective pathway in astrocytes , 2009, Expert Reviews in Molecular Medicine.

[24]  C. Wiley,et al.  Imaging Microglial Activation During Neuroinflammation and Alzheimer’s Disease , 2009, Journal of Neuroimmune Pharmacology.

[25]  J. Bennett,et al.  Update on Inflammation, Neurodegeneration, and Immunoregulation in Multiple Sclerosis: Therapeutic Implications , 2009, Clinical neuropharmacology.

[26]  M. Sikorska,et al.  Astrocyte-secreted GDNF and glutathione antioxidant system protect neurons against 6OHDA cytotoxicity , 2009, Neurobiology of Disease.

[27]  R. Hohlfeld,et al.  Neuro-immune crosstalk in CNS diseases , 2009, Neuroscience.

[28]  Graham L. Collingridge,et al.  A nomenclature for ligand-gated ion channels , 2009, Neuropharmacology.

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

[30]  Qiang Wang,et al.  Therapeutic time window and mechanism of tetramethylpyrazine on transient focal cerebral ischemia/reperfusion injury in rats , 2009, Neuroscience Letters.

[31]  DelindaA . Johnson,et al.  Nrf2 Activation in Astrocytes Protects against Neurodegeneration in Mouse Models of Familial Amyotrophic Lateral Sclerosis , 2008, The Journal of Neuroscience.

[32]  G. Dakubo,et al.  Control of glial precursor cell development in the mouse optic nerve by sonic hedgehog from retinal ganglion cells , 2008, Brain Research.

[33]  W. Löscher,et al.  Behavioral alterations in a mouse model of temporal lobe epilepsy induced by intrahippocampal injection of kainate , 2008, Experimental Neurology.

[34]  T. Jin,et al.  TNF‐α receptor 1 deficiency enhances kainic acid–induced hippocampal injury in mice , 2008, Journal of neuroscience research.

[35]  H. Tamai,et al.  Edaravone prevents kainic acid-induced neuronal death , 2008, Brain Research.

[36]  B. Bahr,et al.  Calpain activation is involved in early caspase‐independent neurodegeneration in the hippocampus following status epilepticus , 2008, Journal of neurochemistry.

[37]  O. Pulido,et al.  Regional Susceptibility to Domoic Acid in Primary Astrocyte Cells Cultured from the Brain Stem and Hippocampus , 2008, Marine drugs.

[38]  N. Nishiyama,et al.  Ablation of p27 enhance kainate-induced seizure and hippocampal degeneration , 2007, Neuroreport.

[39]  J. Fessel,et al.  Seizure‐induced formation of isofurans: novel products of lipid peroxidation whose formation is positively modulated by oxygen tension , 2007, Journal of neurochemistry.

[40]  J. Hablitz,et al.  Pre- and postsynaptic effects of kainate on layer II/III pyramidal cells in rat neocortex , 2007, Neuropharmacology.

[41]  K. Yamagata,et al.  Roles of prostaglandin synthesis in excitotoxic brain diseases , 2007, Neurochemistry International.

[42]  A. Sano,et al.  Differences in two mice strains on kainic acid-induced amygdalar seizures. , 2007, Biochemical and biophysical research communications.

[43]  B. Winblad,et al.  IL-18 deficiency aggravates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice due to an overcompensation by IL-12 , 2007, Experimental Neurology.

[44]  S. Hino,et al.  A novel ER stress transducer, OASIS, expressed in astrocytes. , 2007, Antioxidants & redox signaling.

[45]  F. Kirchhoff,et al.  Glia: the fulcrum of brain diseases , 2007, Cell Death and Differentiation.

[46]  N. Belluardo,et al.  Endoplasmic Reticulum Stress Inhibition Protects against Excitotoxic Neuronal Injury in the Rat Brain , 2007, The Journal of Neuroscience.

[47]  N. Nishiyama,et al.  Calpain activation is required for glutamate‐induced p27 down‐regulation in cultured cortical neurons , 2006, Journal of neurochemistry.

[48]  O. Steward,et al.  Comparison of seizure phenotype and neurodegeneration induced by systemic kainic acid in inbred, outbred, and hybrid mouse strains , 2006, The European journal of neuroscience.

[49]  N. Nishiyama,et al.  p27 small interfering RNA induces cell death through elevating cell cycle activity in cultured cortical neurons: a proof-of-concept study , 2006, Cellular and Molecular Life Sciences CMLS.

[50]  K. Yamagata,et al.  Prostaglandin E2 produced by late induced COX-2 stimulates hippocampal neuron loss after seizure in the CA3 region , 2006, Neuroscience Research.

[51]  D. Pei,et al.  Neuroprotection of Tat-GluR6-9c against Neuronal Death Induced by Kainate in Rat Hippocampus via Nuclear and Non-nuclear Pathways* , 2006, Journal of Biological Chemistry.

[52]  Tian-Le Xu,et al.  Neuroprotection against ischaemic brain injury by a GluR6-9c peptide containing the TAT protein transduction sequence. , 2006, Brain : a journal of neurology.

[53]  G. Smith,et al.  Genetic background regulates semaphorin gene expression and epileptogenesis in mouse brain after kainic acid status epilepticus , 2005, Neuroscience.

[54]  Jun Chen,et al.  Cyclooxygenase-2 expression is induced in rat brain after kainate-induced seizures and promotes neuronal death in CA3 hippocampus , 2005, Brain Research.

[55]  J. Velíšková,et al.  Inflammatory Response and Glia Activation in Developing Rat Hippocampus after Status Epilepticus , 2005, Epilepsia.

[56]  A. Vezzani,et al.  Tumor necrosis factor‐α inhibits seizures in mice via p75 receptors , 2005 .

[57]  S. O’Mara,et al.  Exercise, but not environmental enrichment, improves learning after kainic acid-induced hippocampal neurodegeneration in association with an increase in brain-derived neurotrophic factor , 2005, Behavioural Brain Research.

[58]  J. Kemp,et al.  Ionotropic and metabotropic glutamate receptor structure and pharmacology , 2005, Psychopharmacology.

[59]  B. Winblad,et al.  Increased microglial activation and astrogliosis after intranasal administration of kainic acid in C57BL/6 mice. , 2005, Journal of neurobiology.

[60]  S. O’Mara,et al.  Post-treatment, but not pre-treatment, with the selective cyclooxygenase-2 inhibitor celecoxib markedly enhances functional recovery from kainic acid-induced neurodegeneration , 2004, Neuroscience.

[61]  T. Bártfai,et al.  Interleukin-18 null mice show diminished microglial activation and reduced dopaminergic neuron loss following acute 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment , 2004, Neuroscience.

[62]  M. Pallàs,et al.  p21WAF1/Cip1 is not involved in kainic acid-induced apoptosis in murine cerebellar granule cells , 2004, Brain Research.

[63]  B. Winblad,et al.  IL-12p35 deficiency alleviates kainic acid-induced hippocampal neurodegeneration in C57BL/6 mice , 2004, Neurobiology of Disease.

[64]  Jui-Wei Lin,et al.  Mitochondrial Dysfunction and Ultrastructural Damage in the Hippocampus during Kainic Acid–induced Status Epilepticus in the Rat , 2004, Epilepsia.

[65]  H. Okamura,et al.  Interleukin-18 stimulates synaptically released glutamate and enhances postsynaptic AMPA receptor responses in the CA1 region of mouse hippocampal slices , 2004, Brain Research.

[66]  A. Rodríguez-Moreno,et al.  Presynaptic kainate receptor facilitation of glutamate release involves protein kinase A in the rat hippocampus , 2004, The Journal of physiology.

[67]  M. Mattson,et al.  Kainic acid-induced naip expression in the hippocampus is blocked in mice lacking TNF receptors. , 2004, Brain research. Molecular brain research.

[68]  Giovambattista De Sarro,et al.  Seizure susceptibility to various convulsant stimuli of knockout interleukin-6 mice , 2004, Pharmacology Biochemistry and Behavior.

[69]  M. Randić,et al.  Modulation of excitatory synaptic transmission in the spinal substantia gelatinosa of mice deficient in the kainate receptor GluR5 and/or GluR6 subunit , 2004, The Journal of physiology.

[70]  A. Vezzani Brain Inflammation and Seizures , 2004, Epilepsy currents.

[71]  Stephen D Miller,et al.  Microglia are activated to become competent antigen presenting and effector cells in the inflammatory environment of the Theiler's virus model of multiple sclerosis , 2003, Journal of Neuroimmunology.

[72]  M. Tymianski,et al.  Novel treatment of excitotoxicity: targeted disruption of intracellular signalling from glutamate receptors. , 2003, Biochemical pharmacology.

[73]  M. Schultzberg,et al.  Inflammatory mechanisms associated with brain damage induced by kainic acid with special reference to the interleukin‐1 system , 2003, Journal of cellular and molecular medicine.

[74]  P. Werner,et al.  AMPA/kainate receptors in mouse spinal cord cell‐specific display of receptor subunits by oligodendrocytes and astrocytes and at the nodes of Ranvier , 2003, Glia.

[75]  Seol-Heui Han,et al.  Melatonin attenuates kainic acid‐induced hippocampal neurodegeneration and oxidative stress through microglial inhibition , 2003, Journal of pineal research.

[76]  S. Heinemann,et al.  Loss of Kainate Receptor-Mediated Heterosynaptic Facilitation of Mossy-Fiber Synapses in KA2−/− Mice , 2003, The Journal of Neuroscience.

[77]  Bin Liu,et al.  Role of Microglia in Inflammation-Mediated Neurodegenerative Diseases: Mechanisms and Strategies for Therapeutic Intervention , 2003, Journal of Pharmacology and Experimental Therapeutics.

[78]  K. Flanders,et al.  Kainate treatment alters TGF-beta3 gene expression in the rat hippocampus. , 2002, Brain research. Molecular brain research.

[79]  M. Rincón,et al.  The two faces of IL-6 on Th1/Th2 differentiation. , 2002, Molecular immunology.

[80]  U. Hanisch,et al.  Microglia as a source and target of cytokines , 2002, Glia.

[81]  Y. Mitsuyama,et al.  Glutamate excess and free radical formation during and following kainic acid-induced status epilepticus , 2002, Experimental Brain Research.

[82]  B. Winblad,et al.  Excitotoxic neurodegeneration induced by intranasal administration of kainic acid in C57BL/6 mice , 2002, Brain Research.

[83]  M. Pallàs,et al.  Kainic acid‐induced neuronal cell death in cerebellar granule cells is not prevented by caspase inhibitors , 2002, British journal of pharmacology.

[84]  David Lodge,et al.  A Critical Role of a Facilitatory Presynaptic Kainate Receptor in Mossy Fiber LTP , 2001, Neuron.

[85]  J. E. Lee,et al.  Differential roles of cyclooxygenase isoforms after kainic acid-induced prostaglandin E2 production and neurodegeneration in cortical and hippocampal cell cultures , 2001, Brain Research.

[86]  H. Wiesinger Arginine metabolism and the synthesis of nitric oxide in the nervous system , 2001, Progress in Neurobiology.

[87]  H. Prast,et al.  Nitric oxide as modulator of neuronal function , 2001, Progress in Neurobiology.

[88]  J. Hidalgo,et al.  Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures , 2001, Neuroscience.

[89]  E. Suzuki,et al.  Glufosinate ammonium stimulates nitric oxide production through N-methyl d-aspartate receptors in rat cerebellum , 2000, Neuroscience Letters.

[90]  L. Illum Transport of drugs from the nasal cavity to the central nervous system. , 2000, European journal of pharmaceutical sciences : official journal of the European Federation for Pharmaceutical Sciences.

[91]  E. Mackenzie,et al.  Ischemia-Induced Interleukin-6 as a Potential Endogenous Neuroprotective Cytokine against NMDA Receptor-Mediated Excitoxicity in the Brain , 2000, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[92]  T. Kishimoto,et al.  IL-6 Is Required for the Development of Th1 Cell-Mediated Murine Colitis1 , 2000, The Journal of Immunology.

[93]  J. Velazquez,et al.  Oxidative stress is involved in seizure-induced neurodegeneration in the kindling model of epilepsy , 2000, Neuroscience.

[94]  A. Hamberger,et al.  Quantitative immunochemistry on neuronal loss, reactive gliosis and BBB damage in cortex/striatum and hippocampus/amygdala after systemic kainic acid administration , 2000, Neurochemistry International.

[95]  C. Bendotti,et al.  Differential Expression of S100β and Glial Fibrillary Acidic Protein in the Hippocampus after Kainic Acid-Induced Lesions and Mossy Fiber Sprouting in Adult Rat , 2000, Experimental Neurology.

[96]  H. Kato,et al.  The Initiation of the Microglial Response , 2000, Brain pathology.

[97]  S. Sensi,et al.  AMPA Exposures Induce Mitochondrial Ca2+ Overload and ROS Generation in Spinal Motor Neurons In Vitro , 2000, The Journal of Neuroscience.

[98]  C. Greer,et al.  Differential distribution of ionotropic glutamate receptor subunits in the rat olfactory bulb , 1999, The Journal of comparative neurology.

[99]  Fred H. Gage,et al.  Altered synaptic physiology and reduced susceptibility to kainate-induced seizures in GluR6-deficient mice , 1998, Nature.

[100]  D. D. Hunter,et al.  Expression of non-N-methyl-d-aspartate glutamate receptor subunits in the olfactory epithelium , 1997, Neuroscience.

[101]  H. Hartung,et al.  Transforming growth factor-β1: A lesion-associated cytokine of the nervous system , 1995, International Journal of Developmental Neuroscience.

[102]  S. Yamashita,et al.  Direct Drug Transport from the Rat Nasal Cavity to the Cerebrospinal Fluid: the Relation to the Molecular Weight of Drugs , 1995, The Journal of pharmacy and pharmacology.

[103]  Richard J. Miller,et al.  Ca2+ entry via AMPA/KA receptors and excitotoxicity in cultured cerebellar Purkinje cells , 1994, The Journal of neuroscience : the official journal of the Society for Neuroscience.

[104]  T. Morgan,et al.  TGF-β1 mRNA Increases in Macrophage/Microglial Cells of the Hippocampus in Response to Deafferentation and Kainic Acid-Induced Neurodegeneration , 1993, Experimental Neurology.

[105]  C. Nathan,et al.  Purification and characterization of the cytokine-induced macrophage nitric oxide synthase: an FAD- and FMN-containing flavoprotein. , 1991, Proceedings of the National Academy of Sciences of the United States of America.

[106]  Y. Ben-Ari,et al.  Limbic seizure and brain damage produced by kainic acid: Mechanisms and relevance to human temporal lobe epilepsy , 1985, Neuroscience.

[107]  Erik B. Bloss,et al.  Hippocampal kainate receptors. , 2010, Vitamins and hormones.

[108]  G. Swanson Targeting AMPA and kainate receptors in neurological disease: therapies on the horizon? , 2009, Neuropsychopharmacology.

[109]  I. Cho,et al.  Expression of Adenomatous Polyposis Coli Protein in Reactive Astrocytes in Hippocampus of Kainic Acid-Induced Rat , 2009, Neurochemical Research.

[110]  Dong Woon Kim,et al.  Role of microglial IKK b in kainic acid-induced hippocampal neuronal cell death , 2008 .

[111]  R. Maccioni,et al.  Neuroinflammation: implications for the pathogenesis and molecular diagnosis of Alzheimer's disease. , 2008, Archives of medical research.

[112]  Á. Simonyi,et al.  Kainic acid-mediated excitotoxicity as a model for neurodegeneration , 2007, Molecular Neurobiology.

[113]  C. Chung,et al.  Glial Expression of Interleukin-18 and its Receptor After Excitotoxic Damage in the Mouse Hippocampus , 2007, Neurochemical Research.

[114]  A. Volterra,et al.  Glutamate release from astrocytes in physiological conditions and in neurodegenerative disorders characterized by neuroinflammation. , 2007, International review of neurobiology.

[115]  J. Lacaille,et al.  Selective degeneration and synaptic reorganization of hippocampal interneurons in a chronic model of temporal lobe epilepsy. , 2006, Advances in neurology.

[116]  V. Perry,et al.  Transforming growth factor-beta 1-mediated neuroprotection against excitotoxic injury in vivo. , 2003, Journal of cerebral blood flow and metabolism : official journal of the International Society of Cerebral Blood Flow and Metabolism.

[117]  L. Jarrard Use of excitotoxins to lesion the hippocampus: Update , 2002, Hippocampus.

[118]  G. Stoll,et al.  Cytokines in CNS disorders: neurotoxicity versus neuroprotection. , 2000, Journal of neural transmission. Supplementum.

[119]  U. Kompella,et al.  Nasal route for direct delivery of solutes to the central nervous system: fact or fiction? , 1998, Journal of drug targeting.