Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures.
The role of interleukin-6 in hippocampal tissue damage after injection with kainic acid, a rigid glutamate analogue inducing epileptic seizures, has been studied by means of interleukin-6 null mice. At 35mg/kg, kainic acid induced convulsions in both control (75%) and interleukin-6 null (100%) mice, and caused a significant mortality (62%) only in the latter mice, indicating that interleukin-6 deficiency increased the susceptibility to kainic acid-induced brain damage. To compare the histopathological damage caused to the brain, control and interleukin-6 null mice were administered 8.75mg/kg kainic acid and were killed six days later. Morphological damage to the hippocampal field CA1-CA3 was seen after kainic acid treatment. Reactive astrogliosis and microgliosis were prominent in kainic acid-injected normal mice hippocampus, and clear signs of increased oxidative stress were evident. Thus, the immunoreactivity for inducible nitric oxide synthase, peroxynitrite-induced nitration of proteins and byproducts of fatty acid peroxidation were dramatically increased, as was that for metallothionein I+II, Mn-superoxide dismutase and Cu/Zn-superoxide dismutase. In accordance, a significant neuronal apoptosis was caused by kainic acid, as revealed by terminal deoxynucleotidyl transferase-mediated deoxyuridine triphosphate-biotin nick end labeling and interleukin-1beta converting enzyme/Caspase-1 stainings. In kainic acid-injected interleukin-6 null mice, reactive astrogliosis and microgliosis were reduced, while morphological hippocampal damage, oxidative stress and apoptotic neuronal death were increased. Since metallothionein-I+II levels were lower, and those of inducible nitric oxide synthase higher, these concomitant changes are likely to contribute to the observed increased oxidative stress and neuronal death in the interleukin-6 null mice. The present results demonstrate that interleukin-6 deficiency increases neuronal injury and impairs the inflammatory response after kainic acid-induced seizures.
Penkowa
M
M
Department of Medical Anatomy, The Panum Institute, University of Copenhagen, Copenhagen, Denmark.
Molinero
A
A
Carrasco
J
J
Hidalgo
J
J
D000818:Animals; D017209:Apoptosis / Q000502:physiology; D001812:Blood-Brain Barrier / Q000502:physiology; D004660:Encephalitis / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D004827:Epilepsy / Q000276:immunology* / Q000378:metabolism* / Q000473:pathology; D018690:Excitatory Amino Acid Agonists; D015870:Gene Expression / Q000502:physiology; D005911:Gliosis / Q000378:metabolism / Q000473:pathology; D006624:Hippocampus / Q000378:metabolism / Q000473:pathology; D020287:In Situ Nick-End Labeling; D015850:Interleukin-6 / Q000235:genetics*; D007608:Kainic Acid; D008264:Macrophages / Q000473:pathology; D008668:Metallothionein / Q000378:metabolism; D051379:Mice; D018345:Mice, Knockout; D017628:Microglia / Q000473:pathology; D009410:Nerve Degeneration / Q000276:immunology / Q000378:metabolism / Q000473:pathology; D018384:Oxidative Stress / Q000502:physiology*; D012640:Seizures / Q000139:chemically induced / Q000378:metabolism / Q000473:pathology; D013482:Superoxide Dismutase / Q000378:metabolism
D018690:Excitatory Amino Acid Agonists; D015850:Interleukin-6; D008668:Metallothionein; D013482:Superoxide Dismutase; D007608:Kainic Acid