Abstract TP126: The Ketones Acetoacetate And Beta-hydroxybutyrate Alleviate Ischemic Injury Following Occlusion Of The Middle Cerebral Artery
Acute ischemic stroke is treated with thrombolysis but therapeutic benefits are modest. One potential reason for the limited clinical improvement is the apoptotic, delayed cell death that occurs prominently in the periphery of the ischemic core, the penumbra, despite successful reperfusion. Apoptotic cell death has been attributed to glutamate excitotoxicity, a consequence of ischemic energy depletion as well as a cause of persistent mitochondrial dysfunction that perpetuates energetic failure. We have previously shown that glutamate excitotoxicity and mitochondrial dysfunction are alleviated by the ketones acetoacetate and beta-hydroxybutyrate, a combination of physiological compounds produced by liver during calorie restriction to sustain cellular energy requirements. Ketones enhance mitochondrial respiration driven by complex I of the electron transport chain, decrease oxidative stress and increase ATP synthesis. Here, we investigated the effects of ketones in 3 month-old mice subjected to middle cerebral artery (MCA) occlusion with a filament for 90 min. Ketones (50 mg/kg) were administered intraperitoneally 30 min after the onset of ischemia and significantly improved outcomes. MCA occlusion caused significant neuronal loss 24 hours later in the subcortical and cortical regions of the ipsilateral hemisphere. Damage was most severe in the subcortical region and was quite evident on a 7 Tesla MRI. The results were confirmed by non-invasive imaging of apoptosis with the fluorescent indicator Annexin Vivo 750 using a Xenogen IVIS Spectrum (Caliper). Treating mice with ketones significantly decreased neuronal damage based on histology, MRI and fluorescence imaging of apoptosis with Annexin Vivo 750. Furthermore, ketones improved motor activity on the Rotarod and Open Field tests. Untreated mice exhibited evident decreases in the times they remained on the rods whereas ketone-treated mice were almost back to baseline. Consistently, untreated animals were less active in the open field. In sum, our data show that a combination of physiological ketones previously shown to enhance mitochondrial activity and alleviate glutamate excitotoxicity decreases cellular loss and improves motor function in a mouse model of ischemic stroke.
- © 2012 by American Heart Association, Inc.