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<p>Abstract</p> <p>Background</p> <p>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.</p> <p>Methods</p> <p>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.</p> <p>Results</p> <p>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)-α, IL-6 and IL-10 was higher in KA-treated IL-18 KO mice.</p> <p>Conclusion</p> <p>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-α, IL-6 and IL-10.</p>