Table 1.

Animal and basic science studies on effects of ketone administration on brain injury

Mechanism of injury	Reference	Ketone source	Study	Outcome
Glutamate-induced injury	Massieu and colleagues [55]	i.v.	AcAc infusion for 14 days in adult rodent model prior to and during glutamate-induced injury	Decreased neuronal damage, decreased lesion volume and increased cellular ATP levels
	Noh and colleagues [57,58]	p.o.	21-day-old mice fed ketogenic diet prior to kianic-induced neuronal damage	Preservation of neurons in hippocampus by inhibiting caspase-3-mediated apoptosis
	Mejia-Toiber and colleagues [56]	In vivo	BHB applied before glutamate-induced neurotoxicity	BHB reduces injury and lipoperoxidation
	Maalouf and colleagues [54]	In vivo	Addition of BHB to in vitro model of glutamate neurotoxicity	Reduction in free radical formation and enhanced mitochondrial respiration
Cerebral hypoxia	Puchowicz and colleagues [60]	p.o.	Rats fed ketogenic diet 3 weeks prior to hypoxic injury	Decreased cerebral lactate and increased tolerance of hypoxia
	Masuda and colleagues [59]	In vivo	Rat neurons exposed to hypoxia following treatment with BHB	Decreased cell death and number of apoptotic cells with maintenance of mitochondrial membrane
Cerebral ischemia	Suzuki and colleagues [70]	i.v.	Rats infused with BHB 3 to 6 hours after bilateral carotid artery occlusion	Decreased cerebral edema and sodium content and increased ATP levels
	Suzuki and colleagues [63]	i.v.	BHB infusions following occlusion of the middle cerebral artery	50% reduction in cerebral infarct volume
	Marie and colleagues [69]	Fasted	Adult rats fasted for 24 hours before four-vessel occlusion	Decreased mortality, post-traumatic seizures and brain lactate
	Go and colleagues [68]	Fasted	Starvation-induced ketosis followed by carotid occlusion	Fasting protected rats from brain infarction
Traumatic brain injury	Prins and colleagues [65]	i.v.	BHB infusion following TBI in adult rats	Increase in serum BHB and cerebral BHB and improved cortical ATP levels
	Prins and colleagues [64]	p.o.	Rats with TBI fed ketogenic diet	50% reduction in cortical contusion volume
	Biros and Nordness [67]	p.o.	Rats of differing ages fed ketogenic diet following TBI	Younger rats demonstrated larger reduction in contusion volume
	Hu and colleagues [61,62]	p.o.	Rats fed ketogenic diet prior to TBI	Reduced brain edema and cellular apoptosis in rats fed ketone diet

AcAc, acetoacetate; BHB, β-hydroxybutyrate; In vivo, in vivo experiment; i.v., intravenous; p.o., per orally; TBI, traumatic brain injury.