Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures
M. Penkowa et al., Interleukin-6 deficiency reduces the brain inflammatory response and increases oxidative stress and neurodegeneration after kainic acid-induced seizures, NEUROSCIENC, 102(4), 2001, pp. 805-818
The role of interleukin-6 in hippocampal tissue damage after injection with
kainic acid, a rigid glutamate analogue inducing epileptic seizures, has b
een studied by means of interleukin-6 null mice. Ar 35 mg/kg, kainic acid i
nduced convulsions in both control (75%) and interleukin-6 null (100%) mice
, and caused a significant mortality (62%) only in the latter mice, indicat
ing that interleukin-6 deficiency increased the susceptibility to kainic ac
id-induced brain damage. To compare the histopathological damage caused to
the brain, control and interleukin-6 null mice were administered 8.75 mg/kg
kainic acid and were killed six days later. Morphological damage to the hi
ppocampal field CA1-CA3 was seen after kainic acid treatment. Reactive astr
ogliosis and microgliosis were prominent in kainic acid-injected normal mic
e hippocampus, and clear signs of increased oxidative stress were evident.
Thus, the immunoreactivity for inducible nitric oxide synthase, peroxynitri
te-induced nitration of proteins and byproducts of fatty acid peroxidation
were dramatically increased, as was that for metallothiunein I + II. Mn-sup
eroxide dismutase and Cu/Zn-superoxide dismutase. In accordance, a signific
ant neuronal apoptosis was caused by kainic acid, as revealed by terminal d
eoxynucleotidyl transferase-mediated deoxyuridine triphosphare-biotin nick
end labeling and interieuliin-1 beta converting enzyme/Caspase-1 stainings.
In kainic acid-injected interleukin-6 null mice, reactive astrogliosis and
microgliosis were reduced, while morphological hippocampal damage, oxidati
ve stress and apoptotic neuronal death were increased. Since metallothionei
n-I + II levels were Lower, and those of inducible nitric oxide synthase hi
gher, these concomitant changes are likely to contribute to the observed in
creased oxidative stress and neuronal death in the interleukin-6 null mice.
The present results demonstrate that interleukin-6 deficiency increases neu
ronal injury and impairs the inflammatory response after kainic acid-induce
d seizures. (C) 2001 IBRO. Published by Elsevier Science Ltd. All rights re
served.