Adjudin attenuates ischemic hippocampal damage in gerbils in association with increased SIRT3 immunoreactivity

Abstract Mitochondrial dysfunction and oxidative stress are major contributors to neuronal death following cerebral ischemia. Sirtuin 3 (SIRT3), a mitochondrial deacetylase, plays a critical role in regulating cellular metabolism and oxidative stress; however, its involvement in ischemia-induced neuronal injury remains incompletely understood. In the present study, we investigated temporal changes in SIRT3 immunoreactivity in the hippocampal CA1 region after transient forebrain ischemia and examined the neuroprotective effects of adjudin, a compound reported to upregulate SIRT3. In the sham-operated group, SIRT3 immunoreactivity was predominantly observed in hippocampal neurons, whereas its expression significantly decreased two days after ischemia. Adjudin treatment increased SIRT3 immunoreactivity in the CA1 region above vehicle levels following ischemia/reperfusion. Adjudin administration significantly attenuated ischemia-induced locomotor hyperactivity and reduced delayed neuronal death in the CA1 region. Furthermore, adjudin markedly suppressed ischemia-induced reactive oxygen species production and increased glutathione peroxidase immunoreactivity above the sham level. In parallel, adjudin treatment inhibited microglial activation and decreased the production of pro-inflammatory cytokines, including interleukin-1β and interleukin-6, in the hippocampus. Collectively, these findings show that the ischemia-induced reduction of SIRT3 immunoreactivity was accompanied by oxidative stress, neuroinflammation, and neuronal damage in the hippocampus, and that adjudin treatment increased SIRT3 immunoreactivity while attenuating these pathological changes. Because SIRT3 deacetylase activity and SIRT3 dependence were not directly assessed, the present data do not establish a SIRT3-dependent mechanism. These results nonetheless support further investigation of SIRT3 as a therapeutic target for ischemia-induced neuronal injury.