Sirtuin 3 Mediates Neuroprotection of Ketones against Ischemic Stroke

Abstract

Stroke is one of the leading causes of death. Growing evidence indicates that ketone bodies have beneficial effects in treating stroke, but their underlying mechanism remains unclear. Our previous study showed ketone bodies reduced reactive oxygen species by using NADH as an electron donor, thus increasing the NAD + /NADH ratio. In this study, we investigated whether mitochondrial NAD + -dependent Sirtuin 3 (SIRT3) could mediate the neuroprotective effects of ketone bodies after ischemic stroke. We injected mice with either normal saline or ketones (beta-hydroxybutyrate and acetoacetate) at 30 minutes after ischemia induced by transient middle cerebral artery (MCA) occlusion. We found that ketone treatment enhanced mitochondria function, reduced oxidative stress, and therefore reduced infarct volume. This led to improved neurologic function after ischemia, including the neurologic score and the performance in Rotarod and open field tests. We further showed that ketones' effects were achieved by upregulating NAD + -dependent SIRT3 and its downstream substrates forkhead box O3a (FoxO3a) and superoxide dismutase 2 (SOD2) in the penumbra region since knocking down SIRT3 in vitro diminished ketones' beneficial effects. These results provide us a foundation to develop novel therapeutics targeting this SIRT3-FoxO3a-SOD2 pathway.

Intermittent metabolic switching, neuroplasticity and brain health

“…The contribution of ketosis to the excitoprotective effects of IMS has not been established but could be tested in animal models in which ketone production or transport into neurons is genetically or pharmacologically disabled. Ketones may also mediate neuronal resistance to ischaemic and traumatic insults, as demonstrated in animal models in which BHB treatment lessened brain damage by mechanisms involving enhanced mitochondrial bioenergetics and stress resistance as well as suppression of neuroinflammation 124–126 . Indeed, BHB exerts anti-inflammatory actions by activating hydroxy-carboxylic acid receptor 2 and inhibiting the NRLP3 (NACHT, LRR and PYD domains-containing protein 3) inflammasome 127 .…”

Pertussis toxin reduces calcium influx to protect ischemic stroke in a middle cerebral artery occlusion model

“…It was then advanced 10-11 mm past the carotid bifurcation until a slight resistance was felt. At this point, the intraluminal filament blocked the origin of the middle cerebral artery (Yin et al 2015). After the permanent middle cerebral artery occlusion (pMCAO) procedure, mice were monitored carefully to assure temperature regulation while recovering from anesthesia.…”

3‐Hydroxybutyrate regulates energy metabolism and induces BDNF expression in cerebral cortical neurons

“…; Yin et al . ). Clinical data also suggest that ketone bodies can have a therapeutic benefit in neurodegenerative diseases such as AD and PD (Reger et al .…”

“…Ketogenic diets (McNally and Hartman 2012) and fasting (Bruce-Keller et al, 1999) can protect hippocampal neurons against seizure-induced damage. Fasting and 3OHB can also counteract disease processes and improve functional outcome in animal models of Alzheimer's and Parkinson's diseases, stroke, and traumatic brain injury (Duan and Mattson 1999;Anson et al 2003;Arumugam et al 2010;Kashiwaya et al 2013;Prins and Matsumoto 2014;Greco et al 2015;Yin et al 2015). Clinical data also suggest that ketone bodies can have a therapeutic benefit in neurodegenerative diseases such as AD and PD (Reger et al 2004;Vanitallie et al 2005).…”