Chronic ketosis provides neuroprotection through HIF-1α-mediated control of the TXNIP/NLRP3 axis by regulating the inflammatory and apoptotic response

We and others have previously demonstrated that hypoxia-inducible factor alpha (HIF-1α) stabilization through diet-induced ketosis plays a vital role during brain ischemic injury. We have recently reported that ketosis-stabilized HIF-1α regulates the inflammatory response and contributes to neuroprotection in a rat stroke model. In the current investigation, we examined the downstream mechanism by which the ketogenic (KG) diet protects against brain damage after stroke in mice. Six-seven-week-old male mice were fed the standard diet (SD) or the KG diet to mimic the metabolic state of chronic ketosis. After four weeks, mice were subjected to photothrombotic ischemic stroke. Behavior analysis was recorded at 24 h, 48h, and 72h post-stroke. After 72h, mice were euthanized for infarction, brain edema, hemorrhage, and molecular analysis. Our results showed that the KG diet significantly alleviated infarction, brain edema, and hemorrhage, improved the neurobehavioral outcomes, and attenuated ischemic stroke-induced oxidative/nitrative stress and apoptotic markers at 72h post-stroke. Further, the KG diet upregulated the HIF-1α and interleukin (IL)-10 expression and inhibited thioredoxin-interacting protein (TXNIP), NOD-like receptor family pyrin domain-containing 3 (NLRP3) inflammasome activation and pro-inflammatory cytokines expression compared to SD-fed mice after stroke. We further showed that the genetic deletion of NLRP3 mediates KG-induced neuroprotection after stroke. Our current study demonstrates that the KG diet exerts neuroprotective effects by inhibiting TXNIP-NLRP3 inflammasome, mainly dependent on heightening the upregulation of IL-10 via HIF-1α stabilization. Thus, the KG diet might be considered a new therapeutic strategy for ischemic patients.