Empagliflozin Attenuates Global Cerebral Ischemic Injury After Cardiac Arrest Through Enhancing Ketone Body Oxidative Metabolism in Rats

BACKGROUND: Cardiac arrest (CA) causes severe neurologic deficits and cognitive impairments. Empagliflozin is a newly developed antidiabetic drug and has been shown to reduce ischemia-reperfusion injury. This study aims to elucidate the neuroprotective effects of empagliflozin on global cerebral ischemic injury induced by CA in rats. METHODS: A total of 206 adult male Sprague-Dawley rats were subjected to a CA model via ventricular fibrillation and subsequent cardiopulmonary resuscitation. Animals were randomized into groups receiving either empagliflozin, β-hydroxybutyrate (BHB), or vehicle post-CA. Assessments included neurologic deficit scoring, histopathological evaluation, Fluoro-Jade B staining, immunofluorescence staining, enzyme-linked immunosorbent assay, Western blot analysis, and mitochondrial complex I activity. RESULTS: Treatment with empagliflozin led to a significant improvement in neurologic outcomes, as indicated by enhanced survival rates, higher neurologic deficit scores, and reduced neuronal damage in the hippocampal CA1 region. Empagliflozin administration was also associated with an upregulation of serum and cerebral BHB levels post CA. Furthermore, both empagliflozin and BHB treatment attenuated microglial activation and suppressed the release of proinflammatory cytokines TNF-α (tumor necrosis factor alpha) and IL-1β (interleukin-1β) in both serum and brain tissue. Additionally, empagliflozin or BHB preserved the structural integrity of hippocampal synapses, as evidenced by an increased number of synapses, reduced postsynaptic density thickening, and a higher frequency of perforated synapses and multiple spine boutons. Empagliflozin or BHB also maintained mitochondrial structure and energy metabolism function. Importantly, inhibition of ketone body oxidative metabolism by pimozide diminished the neuroprotective effects of empagliflozin following CA in rats. CONCLUSIONS: Empagliflozin protects brain function after CA by enhancing oxidative metabolism of ketone body, and its underlying mechanism is associated with reducing neuroinflammation and improving mitochondrial energy metabolism. These findings suggest that empagliflozin may represent a novel therapeutic strategy for mitigating brain injury following CA.