The Role of Ketone Bodies in Stroke
Michelle Puchowicz, PhD
University of Tennessee
Puchowicz M. Role of ketone bodies in stroke [published online May 8, 2019]. Neurology Consultant.
Over the past decade, the research of my colleagues and me has consistently shown that ketosis is neuroprotective against global and focal ischemic insults in the young adult and aged rats.1-3 The focus has been on discerning the mechanistic link(s) of ketosis on neuroprotection. We propose that ketosis plays a major role in neuroprotection through metabolic modulations that favor balanced energetics, such as with stabilization of glucose metabolism, as ketones (β-hydroxybutyrate [BHB] and acetoacetate [AcAc]; ketone bodies [KBs]) are alternative energy substrates to glucose. This is especially critical during metabolic derangements of glucose metabolism (glucose sparing), such as with ischemia/reperfusion injury–induced oxidative stress and injury. In support that KBs are alternative energy substrates to glucose, we have shown a decrease glucose consumption (CMRglucose), as measured by positron emission tomography (PET) imaging and stable isotope analysis, in young adult ketotic rats following preconditioning with ketogenic diet.4,5
However, the mechanistic link(s) between ketosis and neuroprotection remains unclear and is viewed as multifaceted. The role of KBs in stroke is currently exploratory, both clinically and in basic scientific research. The mechanisms appear to be related to the change in the regulation of neuronal cells’ stress responses as a result of the changes in glucose oxidative metabolism. Moreover, neuroprotection by ketosis is most likely linked through metabolic regulation involving reduction in glutamate neurotoxicity via promotion of the synthesis of γ-aminobutyric acid and/or reduction of mitochondrial oxidative stress through reduction in circulating levels of reactive oxygen species.5 We also maintain that KBs (independent of alternative energy substrates to glucose) act as signaling molecules that target cellular defenses against oxidative stress and energy regulatory systems, such as with Akt and HIF1α-related mechanisms.1 Potential mechanisms include Akt-dependent actions through Nrf2-related antioxidant and cellular growth pathways and/or HIF1α-mediated downregulation of proinflammatory cytokines. Regulation of these cellular responses most likely requires metabolic adaptation, as with chronic ketosis induced by ketogenic diet.
Induction of ketosis via supplementation or administration of exogenous ketones or precursors to KB synthesis has been explored for decades but remains challenging for the following reasons: As previously published, induction of monocarboxylate transporters at the blood-brain barrier and neurovascular unit require a stable chronic ketotic state, such as with ketogenic diet.1 KB compounds (BHB, AcAc) are commercially available and are either in the form of sodium salts or acids. To administer these exogenous compounds in large enough doses to achieve 1 mM (or higher) blood ketones would result in sodium overload or acid (pH) imbalance. Thus, ketone esters such as 1,3-butanediol monoesters/diesters of BHB and AcAc have been proposed as alternative neutral compounds with minimal to no deleterious side effects. However, dosing to maintain stable ketosis over time is challenging, since the half-life of KB utilization is about 20 minutes in rodents and dogs and is similar in humans.6 Medium-chain triglyceride diets have also been explored, but the efficacy and tolerance are often less than with long-chain (unsaturated/saturated) high-fat diets.
Common questions regarding applications of the use of KBs or induction of ketosis as therapeutic strategies against pathologies associated with oxidative injury, such as with stroke recovery, include:
- Can intermittent fasting be neuroprotective?
- What blood levels of KBs are necessary for neuroprotection?
- What are the best dietary fats for induction of ketosis, and what are the health concerns with long-term feeding of ketogenic diets?
The takeaway messages are that KBs or ketosis induced by diet are neuroprotective in animals and humans. It is well known that ketogenic diets provide neuroprotection in humans with epilepsy, but there is less information on and fewer reports of the efficacy of ketosis on other neuropathophysiological deficits, such as with stroke.
Thus, the use of ketosis for treatment of other neurological diseases such as stroke remains to be determined, because induction by diet or exogenous administration is complicated and difficult. The therapeutic levels of ketosis (as measured by blood KB levels) required for neuroprotection are unknown and only speculative. Thus, studying the neuroprotective mechanisms of therapeutic ketosis is critical to discovery of alternative drug-based therapies for improving stroke outcomes.
Michelle Puchowicz, PhD, is an associate professor of Pediatrics-Obesity at the University of Tennessee Health Science Center in Memphis, Tennessee.
- Puchowicz MA, Zechel JL, Valerio J, et al. Neuroprotection in diet-induced ketotic rat brain after focal ischemia. J Cereb Blood Flow Metab. 2008;28(12):1907-1916. https://doi.org/10.1038/jcbfm.2008.79.
- Xu K, LaManna JC, Puchowicz MA. Neuroprotective properties of ketone bodies. Adv Exp Med Biol. 2012;737:97-102. https://doi.org/10.1007/978-1-4614-1566-4_15.
- Xu K, Sun X, Eroku BO, Tsipis CP, Puchowicz MA, LaManna JC. Diet-induced ketosis improves cognitive performance in aged rats. Adv Exp Med Biol. 2010;662:71-75. https://doi.org/10.1007/978-1-4419-1241-1_9.
- Zhang Y, Kuang Y, Xu K, et al. Ketosis proportionately spares glucose utilization in brain. J Cereb Blood Flow Metab. 2013;33(8):1307-1311. https://doi.org/10.1038/jcbfm.2013.87.
- Zhang Y, Zhang S, Marin-Valencia I, Puchowicz MA. Decreased carbon shunting from glucose toward oxidative metabolism in diet-induced ketotic rat brain. J Neurochem. 2015;132(3):301-312. https://doi.org/10.1111/jnc.12965.
- Puchowicz MA, Smith CL, Bomont C, Koshy J, David F, Brunengraber H. Dog model of therapeutic ketosis induced by oral administration of R,S-1,3-butanediol diacetoacetate. J Nutr Biochem. 2000;11(5):281-287. https://doi.org/10.1016/S0955-2863(00)00079-6.