Kainic acid-induced microglial activation is attenuated in aged interleukin-18 deficient mice.
BACKGROUND
Previously, we found that interleukin (IL)-18 deficiency aggravates kainic acid (KA)-induced hippocampal neurodegeneration in young C57BL/6 mice due to an over-compensation by IL-12. Additionally, IL-18 participates in fundamental inflammatory processes that increase during aging. In the present study, we were interested in the role of IL-18 in KA-induced neurodegeneration in aged female C57BL/6 mice.


METHODS
Fifteen aged female IL-18 knockout (KO) and 15 age-matched wild-type (WT) mice (18 to 19 months old) were treated with KA at a dose of 25 mg/kg body weight intranasally. Seizure activities and behavioral changes were rated using a 6-point scoring system and open-field test, respectively. Seven days after KA treatment, degenerating neurons were detected by Nissl's method and Fluoro-Jade B staining; and microglial activation was analyzed by immunohistochemistry and flow cytometry.


RESULTS
Aged female IL-18 KO and WT mice showed similar responses to treatment with KA as demonstrated by comparable seizure activities, behavioral changes and neuronal cell death. However, aged female IL-18 KO mice failed to exhibit the strong microglial activation shown in WT mice. Interestingly, even though the number of activated microglia was less in KA-treated IL-18 KO mice than in KA-treated WT mice, the proportion of microglia that expressed the cytokines tumor necrosis factor (TNF)-alpha, IL-6 and IL-10 was higher in KA-treated IL-18 KO mice.


CONCLUSIONS
Deficiency of IL-18 attenuates microglial activation after KA-induced excitotoxicity in aged brain, while the net effects of IL-18 deficiency are balanced by the enhancement of other cytokines, such as TNF-alpha, IL-6 and IL-10.
Zhang
Xing-Mei
XM
Department of Neurobiology, Care Sciences and Society, Karolinska Institute, Stockholm, Sweden. xingmei.zhang@ki.se
Jin
Tao
T
Quezada
Hernan Concha
HC
Mix
Eilhard
E
Winblad
Bengt
B
Zhu
Jie
J
D000375:Aging / Q000502:physiology*; D000818:Animals; D001921:Brain / Q000473:pathology; D018690:Excitatory Amino Acid Agonists / Q000494:pharmacology*; D005260:Female; D005434:Flow Cytometry; D007150:Immunohistochemistry; D016753:Interleukin-10 / Q000096:biosynthesis; D020382:Interleukin-18 / Q000235:genetics* / Q000502:physiology*; D015850:Interleukin-6 / Q000096:biosynthesis; D007608:Kainic Acid / Q000494:pharmacology*; D008262:Macrophage Activation / Q000187:drug effects; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D017628:Microglia / Q000187:drug effects*; D009043:Motor Activity / Q000502:physiology; D019636:Neurodegenerative Diseases / Q000235:genetics / Q000473:pathology; D012640:Seizures / Q000473:pathology; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis
D018690:Excitatory Amino Acid Agonists; D020382:Interleukin-18; D015850:Interleukin-6; D014409:Tumor Necrosis Factor-alpha; D016753:Interleukin-10; D007608:Kainic Acid
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