Ketogenic diet and β-Hydroxybutyrate alleviate ischemic brain injury in mice via an IRAKM-dependent pathway.

Ketogenic diet (KD) is a classical nonpharmacological therapy that has recently been shown to benefit cerebral ischemia, but the mechanism remains unclear. This study investigated the neuroprotective effects of KD pretreatment and β-hydroxybutyrate (BHB, bioactive product of KD) post-treatment in a mouse model of temporary middle cerebral artery occlusion (tMCAO). Neurological function, infarct volume, as well as inflammatory reactions are evaluated 24 hours after ischemia. Results showed that both KD pretreatment or BHB post-treatment improved the Bederson score and Grip test score, reduced infarct volume and the extravasation of IgG, suppressed the over-activation of microglia, and modulated the expression of cytokines. Mechanically, we found that both KD pretreatment or BHB post-treatment significantly stimulated the expression of interleukin-1 receptor-associated kinase M (IRAKM) and then inhibited the nuclear translocation of NF-κB. IRAKM deletion (Irakm) exacerbated tMCAO-induced neurovascular injuries, and aggravated neuroinflammatory response. Moreover, KD pretreatment or BHB post-treatment lost their neuroprotection in the tMCAO-treated Irakm mice. Our results support that KD pretreatment and BHB post-treatment alleviate ischemic brain injury in mice, possibly via an IRAKM-dependent way.