Enhanced seizures and hippocampal neurodegeneration following kainic acid-induced seizures in metallothionein-I + II-deficient mice.
Metallothioneins (MTs) are major zinc binding proteins in the CNS that could be involved in the control of zinc metabolism as well as in protection against oxidative stress. Mice lacking MT-I and MT-II (MT-I + II deficient) because of targeted gene inactivation were injected with kainic acid (KA), a potent convulsive agent, to examine the neurobiological importance of these MT isoforms. At 35 mg/kg KA, MT-I + II deficient male mice showed a higher number of convulsions and a longer convulsion time than control mice. Three days later, KA-injected mice showed gliosis and neuronal injury in the hippocampus. MT-I + II deficiency decreased both astrogliosis and microgliosis and potentiated neuronal injury and apoptosis as shown by terminal deoxynucleotidyl transferase-mediated in situ end labelling (TUNEL), detection of single stranded DNA (ssDNA) and by increased interleukin-1beta-converting enzyme (ICE) and caspase-3 levels. Histochemically reactive zinc in the hippocampus was increased by KA to a greater extent in MT-I + II-deficient compared with control mice. KA-induced seizures also caused increased oxidative stress, as suggested by the malondialdehyde (MDA) and protein tyrosine nitration (NITT) levels and by the expression of MT-I + II, nuclear factor-kappaB (NF-kappaB), and Cu/Zn-superoxide dismutase (Cu/Zn-SOD). MT-I + II deficiency potentiated the oxidative stress caused by KA. Both KA and MT-I + II deficiency significantly affected the expression of MT-III, granulocyte-macrophage colony stimulating factor (GM-CSF) and its receptor (GM-CSFr). The present results indicate MT-I + II as important for neuron survival during KA-induced seizures, and suggest that both impaired zinc regulation and compromised antioxidant activity contribute to the observed neuropathology of the MT-I + II-deficient mice.
Carrasco
J
J
Departamento de Biología Celular, de Fisiología y de Inmunología, Unidad de Fisiología Animal, Facultad de Ciencias, Universidad Autónoma de Barcelona, Bellaterra, Spain.
Penkowa
M
M
Hadberg
H
H
Molinero
A
A
Hidalgo
J
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001253:Astrocytes / Q000737:chemistry / Q000378:metabolism; D020170:Caspase 1 / Q000378:metabolism; D053148:Caspase 3; D020169:Caspases / Q000378:metabolism; D004277:DNA, Single-Stranded / Q000032:analysis; D004827:Epilepsy / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology*; D018690:Excitatory Amino Acid Agonists; D005260:Female; D015971:Gene Expression Regulation, Enzymologic; D005904:Glial Fibrillary Acidic Protein / Q000032:analysis; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D006624:Hippocampus / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D020287:In Situ Nick-End Labeling; D007608:Kainic Acid; D008297:Male; D008315:Malondialdehyde / Q000032:analysis / Q000378:metabolism; D008668:Metallothionein / Q000235:genetics* / Q000378:metabolism; D000090023:Metallothionein 3; D051379:Mice; D008815:Mice, Inbred Strains; D018345:Mice, Knockout; D017628:Microglia / Q000378:metabolism; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism; D009410:Nerve Degeneration / Q000201:enzymology / Q000473:pathology / Q000503:physiopathology*; D009419:Nerve Tissue Proteins / Q000378:metabolism; D009584:Nitrogen / Q000378:metabolism; D018384:Oxidative Stress / Q000235:genetics; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor / Q000235:genetics; D012640:Seizures / Q000139:chemically induced / Q000201:enzymology / Q000503:physiopathology; D013482:Superoxide Dismutase / Q000032:analysis / Q000378:metabolism; D014443:Tyrosine / Q000378:metabolism; D015032:Zinc / Q000032:analysis
D004277:DNA, Single-Stranded; D018690:Excitatory Amino Acid Agonists; D005904:Glial Fibrillary Acidic Protein; D000090023:Metallothionein 3; D016328:NF-kappa B; D009419:Nerve Tissue Proteins; D016187:Receptors, Granulocyte-Macrophage Colony-Stimulating Factor; D014443:Tyrosine; D008315:Malondialdehyde; D016178:Granulocyte-Macrophage Colony-Stimulating Factor; D008668:Metallothionein; D013482:Superoxide Dismutase; C505409:Casp3 protein, mouse; D053148:Caspase 3; D020169:Caspases; D020170:Caspase 1; D015032:Zinc; D009584:Nitrogen; D007608:Kainic Acid