Ketone bodies are a promising area of neuroprotection research that may be ideally suited to the injured newborn. During normal development, the human infant is in significant ketosis for at least the first week of life. Ketone uptake and metabolism is upregulated in the both the fetus and neonate, with ketone bodies providing at least 10% of cerebral metabolic energy requirements, as well as being the preferred precursors for the synthesis of fatty acids and cholesterol. At the same time, ketone bodies have been shown to have multiple neuroprotective effects, including being anticonvulsant, decreasing oxidative stress and inflammation, and epigenetically upregulating the production of neurotrophic factors. While ketogenic diets and exogenous ketosis are largely being investigated in the setting of adult brain injury, the adaptation of the neonate to ketosis suggests that developmental brain injury may be the area most suited to the use of ketones for neuroprotection. Here, we describe the mechanisms by which ketone bodies exert their neuroprotective effects, and how these may translate to benefits within each of the phases of neonatal asphyxial brain injury.

1.
Kurinczuk
JJ
,
White-Koning
M
,
Badawi
N
.
Epidemiology of neonatal encephalopathy and hypoxic-ischaemic encephalopathy
.
Early Hum Dev
.
2010
Jun
;
86
(
6
):
329
38
.
[PubMed]
0378-3782
2.
Pauliah
SS
,
Shankaran
S
,
Wade
A
, et al.
Therapeutic hypothermia for neonatal encephalopathy in low- and middle-income countries: a systematic review and meta-analysis. PloS one.
2013
;8(3):e58834-e.
3.
Wassink
G
,
Gunn
E
,
Drury
P
, et al.
The mechanisms and treatment of asphyxial encephalopathy2014;8(40).
4.
Johnston
MV
,
Fatemi
A
,
Wilson
MA
,
Northington
F
.
Treatment advances in neonatal neuroprotection and neurointensive care
.
Lancet Neurol
.
2011
Apr
;
10
(
4
):
372
82
.
[PubMed]
1474-4422
5.
Hassell
KJ
,
Ezzati
M
,
Alonso-Alconada
D
,
Hausenloy
DJ
,
Robertson
NJ
.
New horizons for newborn brain protection: enhancing endogenous neuroprotection
.
Arch Dis Child Fetal Neonatal Ed
.
2015
Nov
;
100
(
6
):
F541
52
.
[PubMed]
1359-2998
6.
Jacobs
SE
,
Berg
M
,
Hunt
R
,
Tarnow-Mordi
WO
,
Inder
TE
,
Davis
PG
.
Cooling for newborns with hypoxic ischaemic encephalopathy
.
Cochrane Database Syst Rev
.
2013
Jan
;
1
(
1
):
CD003311
.
[PubMed]
1469-493X
7.
Edwards
AD
,
Brocklehurst
P
,
Gunn
AJ
,
Halliday
H
,
Juszczak
E
,
Levene
M
, et al.
Neurological outcomes at 18 months of age after moderate hypothermia for perinatal hypoxic ischaemic encephalopathy: synthesis and meta-analysis of trial data
.
BMJ
.
2010
Feb
;
340
feb09 3
:
c363
.
[PubMed]
0959-8138
8.
Smit
E
,
Liu
X
,
Jary
S
, et al.
Cooling neonates who do not fulfil the standard cooling criteria - short- and long-term outcomes. Acta paediatrica (Oslo, Norway : 1992).
2014
:1651-2227.
9.
Rangarajan
V
,
Juul
SE
.
Erythropoietin: emerging role of erythropoietin in neonatal neuroprotection
.
Pediatr Neurol
.
2014
Oct
;
51
(
4
):
481
8
.
[PubMed]
0887-8994
10.
Fleiss
B
,
Tann
CJ
,
Degos
V
,
Sigaut
S
,
Van Steenwinckel
J
,
Schang
AL
, et al.
Inflammation-induced sensitization of the brain in term infants
.
Dev Med Child Neurol
.
2015
Apr
;
57
Suppl 3
:
17
28
.
[PubMed]
0012-1622
11.
Hallberg
SJ
,
McKenzie
AL
,
Williams
PT
,
Bhanpuri
NH
,
Peters
AL
,
Campbell
WW
, et al.
Effectiveness and Safety of a Novel Care Model for the Management of Type 2 Diabetes at 1 Year: An Open-Label, Non-Randomized, Controlled Study
.
Diabetes Ther
.
2018
Apr
;
9
(
2
):
583
612
.
[PubMed]
1869-6953
12.
Cahill
GF
 Jr
.
Fuel metabolism in starvation
.
Annu Rev Nutr
.
2006
;
26
(
1
):
1
22
.
[PubMed]
0199-9885
13.
Melichar
V
,
Drahota
Z
,
Hahn
P
.
Ketone bodies in the blood of full term newborns, premature and dysmature infants and infants of diabetic mothers
.
Biol Neonat
.
1967
;
11
(
1
):
23
8
.
[PubMed]
0523-6525
14.
Bougneres
PF
,
Lemmel
C
,
Ferré
P
,
Bier
DM
.
Ketone body transport in the human neonate and infant
.
J Clin Invest
.
1986
Jan
;
77
(
1
):
42
8
.
[PubMed]
0021-9738
15.
Patel
MS
,
Johnson
CA
,
Rajan
R
,
Owen
OE
.
The metabolism of ketone bodies in developing human brain: development of ketone-body-utilizing enzymes and ketone bodies as precursors for lipid synthesis
.
J Neurochem
.
1975
Dec
;
25
(
6
):
905
8
.
[PubMed]
0022-3042
16.
Robinson
AM
,
Williamson
DH
.
Physiological roles of ketone bodies as substrates and signals in mammalian tissues
.
Physiol Rev
.
1980
Jan
;
60
(
1
):
143
87
.
[PubMed]
0031-9333
17.
Puchalska
P
,
Crawford
PA
.
Multi-dimensional Roles of Ketone Bodies in Fuel Metabolism, Signaling, and Therapeutics
.
Cell Metab
.
2017
Feb
;
25
(
2
):
262
84
.
[PubMed]
1550-4131
18.
Simeone
TA
,
Simeone
KA
,
Rho
JM
.
Ketone Bodies as Anti-Seizure Agents
.
Neurochem Res
.
2017
Jul
;
42
(
7
):
2011
8
.
[PubMed]
0364-3190
19.
Youm
YH
,
Nguyen
KY
,
Grant
RW
,
Goldberg
EL
,
Bodogai
M
,
Kim
D
, et al.
The ketone metabolite β-hydroxybutyrate blocks NLRP3 inflammasome-mediated inflammatory disease
.
Nat Med
.
2015
Mar
;
21
(
3
):
263
9
.
[PubMed]
1078-8956
20.
Simeone
TA
,
Simeone
KA
,
Stafstrom
CE
,
Rho
JM
.
Do ketone bodies mediate the anti-seizure effects of the ketogenic diet?
Neuropharmacology
.
2018
May
;
133
:
233
41
.
[PubMed]
0028-3908
21.
Kraus
H
,
Schlenker
S
,
Schwedesky
D
.
Developmental changes of cerebral ketone body utilization in human infants
.
Hoppe Seylers Z Physiol Chem
.
1974
Feb
;
355
(
2
):
164
70
.
[PubMed]
0018-4888
22.
Féry
F
,
Balasse
EO
.
Effect of exercise on the disposal of infused ketone bodies in humans
.
J Clin Endocrinol Metab
.
1988
Aug
;
67
(
2
):
245
50
.
[PubMed]
0021-972X
23.
Miles
JM
,
Haymond
MW
,
Gerich
JE
.
Suppression of glucose production and stimulation of insulin secretion by physiological concentrations of ketone bodies in man
.
J Clin Endocrinol Metab
.
1981
Jan
;
52
(
1
):
34
7
.
[PubMed]
0021-972X
24.
Gormsen
LC
,
Svart
M
,
Thomsen
HH
,
Søndergaard
E
,
Vendelbo
MH
,
Christensen
N
, et al.
Ketone Body Infusion With 3-Hydroxybutyrate Reduces Myocardial Glucose Uptake and Increases Blood Flow in Humans: A Positron Emission Tomography Study
.
J Am Heart Assoc
.
2017
Feb
;
6
(
3
):
e005066
.
[PubMed]
2047-9980
25.
Stubbs
BJ
,
Cox
PJ
,
Evans
RD
,
Santer
P
,
Miller
JJ
,
Faull
OK
, et al.
On the Metabolism of Exogenous Ketones in Humans
.
Front Physiol
.
2017
Oct
;
8
:
848
.
[PubMed]
1664-042X
26.
Krebs
HA
.
The regulation of the release of ketone bodies by the liver
.
Adv Enzyme Regul
.
1966
;
4
:
339
54
.
[PubMed]
0065-2571
27.
Cox
PJ
,
Clarke
K
.
Acute nutritional ketosis: implications for exercise performance and metabolism
.
Extrem Physiol Med
.
2014
Oct
;
3
(
1
):
17
.
[PubMed]
2046-7648
28.
Williamson
DH
,
Lund
P
,
Krebs
HA
.
The redox state of free nicotinamide-adenine dinucleotide in the cytoplasm and mitochondria of rat liver
.
Biochem J
.
1967
May
;
103
(
2
):
514
27
.
[PubMed]
0264-6021
29.
Page
KA
,
Williamson
A
,
Yu
N
,
McNay
EC
,
Dzuira
J
,
McCrimmon
RJ
, et al.
Medium-chain fatty acids improve cognitive function in intensively treated type 1 diabetic patients and support in vitro synaptic transmission during acute hypoglycemia
.
Diabetes
.
2009
May
;
58
(
5
):
1237
44
.
[PubMed]
0012-1797
30.
Henderson
ST
,
Vogel
JL
,
Barr
LJ
,
Garvin
F
,
Jones
JJ
,
Costantini
LC
.
Study of the ketogenic agent AC-1202 in mild to moderate Alzheimer’s disease: a randomized, double-blind, placebo-controlled, multicenter trial
.
Nutr Metab (Lond)
.
2009
Aug
;
6
(
1
):
31
.
[PubMed]
1743-7075
31.
Mikkelsen
KH
,
Seifert
T
,
Secher
NH
,
Grøndal
T
,
van Hall
G
.
Systemic, cerebral and skeletal muscle ketone body and energy metabolism during acute hyper-D-β-hydroxybutyratemia in post-absorptive healthy males
.
J Clin Endocrinol Metab
.
2015
Feb
;
100
(
2
):
636
43
.
[PubMed]
0021-972X
32.
Thomsen
HH
,
Rittig
N
,
Johannsen
M
,
Møller
AB
,
Jørgensen
JO
,
Jessen
N
, et al.
Effects of 3-hydroxybutyrate and free fatty acids on muscle protein kinetics and signaling during LPS-induced inflammation in humans: anticatabolic impact of ketone bodies
.
Am J Clin Nutr
.
2018
Oct
;
108
(
4
):
857
67
.
[PubMed]
0002-9165
33.
Müller
MJ
,
Paschen
U
,
Seitz
HJ
.
Effect of ketone bodies on glucose production and utilization in the miniature pig
.
J Clin Invest
.
1984
Jul
;
74
(
1
):
249
61
.
[PubMed]
0021-9738
34.
Evans
M
,
Patchett
E
,
Nally
R
,
Kearns
R
,
Larney
M
,
Egan
B
.
Effect of acute ingestion of β-hydroxybutyrate salts on the response to graded exercise in trained cyclists
.
Eur J Sport Sci
.
2018
Apr
;
18
(
3
):
376
86
.
[PubMed]
1746-1391
35.
Plecko
B
,
Stoeckler-Ipsiroglu
S
,
Schober
E
,
Harrer
G
,
Mlynarik
V
,
Gruber
S
, et al.
Oral beta-hydroxybutyrate supplementation in two patients with hyperinsulinemic hypoglycemia: monitoring of beta-hydroxybutyrate levels in blood and cerebrospinal fluid, and in the brain by in vivo magnetic resonance spectroscopy
.
Pediatr Res
.
2002
Aug
;
52
(
2
):
301
6
.
[PubMed]
0031-3998
36.
Clarke
K
,
Tchabanenko
K
,
Pawlosky
R
, et al.
Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects. Regulatory toxicology and pharmacology : RTP.
2012
;63(3).
37.
Leckey
JJ
,
Ross
ML
,
Quod
M
,
Hawley
JA
,
Burke
LM
.
Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists
.
Front Physiol
.
2017
Oct
;
8
:
806
.
[PubMed]
1664-042X
38.
Courchesne-Loyer
A
,
Fortier
M
,
Tremblay-Mercier
J
,
Chouinard-Watkins
R
,
Roy
M
,
Nugent
S
, et al.
Stimulation of mild, sustained ketonemia by medium-chain triacylglycerols in healthy humans: estimated potential contribution to brain energy metabolism
.
Nutrition
.
2013
Apr
;
29
(
4
):
635
40
.
[PubMed]
0899-9007
39.
Bach
AC
,
Babayan
VK
.
Medium-chain triglycerides: an update
.
Am J Clin Nutr
.
1982
Nov
;
36
(
5
):
950
62
.
[PubMed]
0002-9165
40.
Evans
M
,
Cogan
KE
,
Egan
B
.
Metabolism of ketone bodies during exercise and training: physiological basis for exogenous supplementation
.
J Physiol
.
2016
.
[PubMed]
0022-3751
41.
Fischer
T
,
Och
U
,
Klawon
I
,
Och
T
,
Grüneberg
M
,
Fobker
M
, et al.
Effect of a Sodium and Calcium DL-β-Hydroxybutyrate Salt in Healthy Adults
.
J Nutr Metab
.
2018
Apr
;
2018
:
9812806
.
[PubMed]
2090-0724
42.
Stubbs
BJ
,
Koutnik
AP
,
Poff
AM
, et al.
Commentary: Ketone Diester Ingestion Impairs Time-Trial Performance in Professional Cyclists2018;9(279).
43.
Clarke
K
,
Tchabanenko
K
,
Pawlosky
R
,
Carter
E
,
Todd King
M
,
Musa-Veloso
K
, et al.
Kinetics, safety and tolerability of (R)-3-hydroxybutyl (R)-3-hydroxybutyrate in healthy adult subjects
.
Regul Toxicol Pharmacol
.
2012
Aug
;
63
(
3
):
401
8
.
[PubMed]
0273-2300
44.
Shivva
V
,
Cox
PJ
,
Clarke
K
,
Veech
RL
,
Tucker
IG
,
Duffull
SB
.
The Population Pharmacokinetics of D-β-hydroxybutyrate Following Administration of (R)-3-Hydroxybutyl (R)-3-Hydroxybutyrate
.
AAPS J
.
2016
May
;
18
(
3
):
678
88
.
[PubMed]
1550-7416
45.
Cox
PJ
,
Kirk
T
,
Ashmore
T
,
Willerton
K
,
Evans
R
,
Smith
A
, et al.
Nutritional Ketosis Alters Fuel Preference and Thereby Endurance Performance in Athletes
.
Cell Metab
.
2016
Aug
;
24
(
2
):
256
68
.
[PubMed]
1550-4131
46.
Halestrap
AP
,
Price
NT
. The proton-linked monocarboxylate transporter (MCT) family: structure, function and regulation. The Biochemical journal.
1999
;343 Pt 2(Pt 2):281-99.
47.
Cremer
JE
.
Substrate utilization and brain development
.
J Cereb Blood Flow Metab
.
1982
Dec
;
2
(
4
):
394
407
.
[PubMed]
0271-678X
48.
Vannucci
SJ
,
Simpson
IA
.
Developmental switch in brain nutrient transporter expression in the rat
.
Am J Physiol Endocrinol Metab
.
2003
Nov
;
285
(
5
):
E1127
34
.
[PubMed]
0193-1849
49.
Cahill
GF
 Jr
,
Owen
OE
.
Starvation and survival
.
Trans Am Clin Climatol Assoc
.
1968
;
79
:
13
20
.
[PubMed]
0065-7778
50.
Tracey
TJ
,
Steyn
FJ
,
Wolvetang
EJ
,
Ngo
ST
.
Neuronal Lipid Metabolism: Multiple Pathways Driving Functional Outcomes in Health and Disease
.
Front Mol Neurosci
.
2018
Jan
;
11
:
10
.
[PubMed]
1662-5099
51.
Cunnane
SC
,
Crawford
MA
.
Survival of the fattest: fat babies were the key to evolution of the large human brain
.
Comp Biochem Physiol A Mol Integr Physiol
.
2003
Sep
;
136
(
1
):
17
26
.
[PubMed]
1095-6433
52.
Thompson
BJ
,
Smith
S
.
Biosynthesis of fatty acids by lactating human breast epithelial cells: an evaluation of the contribution to the overall composition of human milk fat
.
Pediatr Res
.
1985
Jan
;
19
(
1
):
139
43
.
[PubMed]
0031-3998
53.
Adam
PA
.
RÄIhÄ N, RÄHialÄ E-L, KekomÄKi M. OXIDATION OF GLUCOSE and D-B-OH-BUTYRATE BY THE EARLY HUMAN FETAL BRAIN
.
Acta Paediatr
.
1975
;
64
(
1
):
17
24
.
[PubMed]
0803-5253
54.
Nehlig
A
.
Brain uptake and metabolism of ketone bodies in animal models
.
Prostaglandins Leukot Essent Fatty Acids
.
2004
Mar
;
70
(
3
):
265
75
.
[PubMed]
0952-3278
55.
Hawkins
RA
,
Williamson
DH
,
Krebs
HA
.
Ketone-body utilization by adult and suckling rat brain in vivo
.
Biochem J
.
1971
Mar
;
122
(
1
):
13
8
.
[PubMed]
0264-6021
56.
Lockwood
EA
,
Bailey
E
.
The course of ketosis and the activity of key enzymes of ketogenesis and ketone-body utilization during development of the postnatal rat
.
Biochem J
.
1971
Aug
;
124
(
1
):
249
54
.
[PubMed]
0264-6021
57.
Brandorff
NP
.
The effect of dietary fat on the fatty acid composition of lipids secreted in rats’ milk
.
Lipids
.
1980
Apr
;
15
(
4
):
276
8
.
[PubMed]
0024-4201
58.
Moore
TJ
,
Lione
AP
,
Sugden
MC
,
Regen
DM
.
Beta-hydroxybutyrate transport in rat brain: developmental and dietary modulations
.
Am J Physiol
.
1976
Mar
;
230
(
3
):
619
30
.
[PubMed]
0002-9513
59.
Edmond
J
.
Ketone bodies as precursors of sterols and fatty acids in the developing rat
.
J Biol Chem
.
1974
Jan
;
249
(
1
):
72
80
.
[PubMed]
0021-9258
60.
Cremer
JE
,
Heath
DF
.
The estimation of rates of utilization of glucose and ketone bodies in the brain of the suckling rat using compartmental analysis of isotopic data
.
Biochem J
.
1974
Sep
;
142
(
3
):
527
44
.
[PubMed]
0264-6021
61.
Newman
JC
,
Verdin
E
.
β-Hydroxybutyrate: A Signaling Metabolite
.
Annu Rev Nutr
.
2017
Aug
;
37
(
1
):
51
76
.
[PubMed]
0199-9885
62.
Ystgaard
MB
,
Sejersted
Y
,
Løberg
EM
,
Lien
E
,
Yndestad
A
,
Saugstad
OD
.
Early Upregulation of NLRP3 in the Brain of Neonatal Mice Exposed to Hypoxia-Ischemia: No Early Neuroprotective Effects of NLRP3 Deficiency
.
Neonatology
.
2015
;
108
(
3
):
211
9
.
[PubMed]
1661-7800
63.
Kong
G
,
Huang
Z
,
Ji
W
,
Wang
X
,
Liu
J
,
Wu
X
, et al.
The Ketone Metabolite β-Hydroxybutyrate Attenuates Oxidative Stress in Spinal Cord Injury by Suppression of Class I Histone Deacetylases
.
J Neurotrauma
.
2017
Sep
;
34
(
18
):
2645
55
.
[PubMed]
0897-7151
64.
Zhao
M
,
Huang
X
,
Cheng
X
,
Lin
X
,
Zhao
T
,
Wu
L
, et al.
Ketogenic diet improves the spatial memory impairment caused by exposure to hypobaric hypoxia through increased acetylation of histones in rats
.
PLoS One
.
2017
Mar
;
12
(
3
):
e0174477
.
[PubMed]
1932-6203
65.
Massaro
AN
,
Wu
YW
,
Bammler
TK
,
Comstock
B
,
Mathur
A
,
McKinstry
RC
, et al.
Plasma Biomarkers of Brain Injury in Neonatal Hypoxic-Ischemic Encephalopathy
.
J Pediatr
.
2018
Mar
;
194
:
67
75.e1
.
[PubMed]
0022-3476
66.
Martin
K
,
Jackson
CF
,
Levy
RG
,
Cooper
PN
.
Ketogenic diet and other dietary treatments for epilepsy
.
Cochrane Database Syst Rev
.
2016
Feb
;
2
:
CD001903
.
[PubMed]
1469-493X
67.
McNally
MA
,
Hartman
AL
.
Ketone bodies in epilepsy
.
J Neurochem
.
2012
Apr
;
121
(
1
):
28
35
.
[PubMed]
0022-3042
68.
Juge
N
,
Gray
JA
,
Omote
H
,
Miyaji
T
,
Inoue
T
,
Hara
C
, et al.
Metabolic control of vesicular glutamate transport and release
.
Neuron
.
2010
Oct
;
68
(
1
):
99
112
.
[PubMed]
0896-6273
69.
Yum
MS
,
Lee
M
,
Woo
DC
,
Kim
DW
,
Ko
TS
,
Velíšek
L
.
β-Hydroxybutyrate attenuates NMDA-induced spasms in rats with evidence of neuronal stabilization on MR spectroscopy
.
Epilepsy Res
.
2015
Nov
;
117
:
125
32
.
[PubMed]
0920-1211
70.
Minlebaev
M
,
Khazipov
R
.
Antiepileptic effects of endogenous beta-hydroxybutyrate in suckling infant rats
.
Epilepsy Res
.
2011
Jun
;
95
(
1-2
):
100
9
.
[PubMed]
0920-1211
71.
Silverstein
FS
.
Do seizures contribute to neonatal hypoxic-ischemic brain injury?
J Pediatr
.
2009
Sep
;
155
(
3
):
305
6
.
[PubMed]
0022-3476
72.
Kim
DY
,
Simeone
KA
,
Simeone
TA
,
Pandya
JD
,
Wilke
JC
,
Ahn
Y
, et al.
Ketone bodies mediate antiseizure effects through mitochondrial permeability transition
.
Ann Neurol
.
2015
Jul
;
78
(
1
):
77
87
.
[PubMed]
0364-5134
73.
Kim
M
,
Stepanova
A
,
Niatsetskaya
Z
,
Sosunov
S
,
Arndt
S
,
Murphy
MP
, et al.
Attenuation of oxidative damage by targeting mitochondrial complex I in neonatal hypoxic-ischemic brain injury
.
Free Radic Biol Med
.
2018
Aug
;
124
:
517
24
.
[PubMed]
0891-5849
74.
Yager
JY
,
Brucklacher
RM
,
Vannucci
RC
.
Cerebral oxidative metabolism and redox state during hypoxia-ischemia and early recovery in immature rats
.
Am J Physiol
.
1991
Oct
;
261
(
4 Pt 2
):
H1102
8
.
[PubMed]
0002-9513
75.
Demarest
TG
,
Schuh
RA
,
Waite
EL
,
Waddell
J
,
McKenna
MC
,
Fiskum
G
.
Sex dependent alterations in mitochondrial electron transport chain proteins following neonatal rat cerebral hypoxic-ischemia
.
J Bioenerg Biomembr
.
2016
Dec
;
48
(
6
):
591
8
.
[PubMed]
0145-479X
76.
Tieu
K
,
Perier
C
,
Caspersen
C
,
Teismann
P
,
Wu
DC
,
Yan
SD
, et al.
D-β-hydroxybutyrate rescues mitochondrial respiration and mitigates features of Parkinson disease
.
J Clin Invest
.
2003
Sep
;
112
(
6
):
892
901
.
[PubMed]
0021-9738
77.
Elamin
M
,
Ruskin
DN
,
Masino
SA
,
Sacchetti
P
.
Ketone-Based Metabolic Therapy: Is Increased NAD+ a Primary Mechanism?
Front Mol Neurosci
.
2017
Nov
;
10
:
377
.
[PubMed]
1662-5099
78.
Houtkooper
RH
,
Pirinen
E
,
Auwerx
J
.
Sirtuins as regulators of metabolism and healthspan
.
Nat Rev Mol Cell Biol
.
2012
Mar
;
13
(
4
):
225
38
.
[PubMed]
1471-0072
79.
Fatokun
AA
,
Dawson
VL
,
Dawson
TM
.
Parthanatos: mitochondrial-linked mechanisms and therapeutic opportunities
.
Br J Pharmacol
.
2014
Apr
;
171
(
8
):
2000
16
.
[PubMed]
0007-1188
80.
Hagberg
H
,
Wilson
MA
,
Matsushita
H
,
Zhu
C
,
Lange
M
,
Gustavsson
M
, et al.
PARP-1 gene disruption in mice preferentially protects males from perinatal brain injury
.
J Neurochem
.
2004
Sep
;
90
(
5
):
1068
75
.
[PubMed]
0022-3042
81.
González Esquivel
D
,
Ramírez-Ortega
D
,
Pineda
B
,
Castro
N
,
Ríos
C
,
Pérez de la Cruz
V
.
Kynurenine pathway metabolites and enzymes involved in redox reactions
.
Neuropharmacology
.
2017
Jan
;
112
Pt B
:
331
45
.
[PubMed]
0028-3908
82.
Haces
ML
,
Hernández-Fonseca
K
,
Medina-Campos
ON
,
Montiel
T
,
Pedraza-Chaverri
J
,
Massieu
L
.
Antioxidant capacity contributes to protection of ketone bodies against oxidative damage induced during hypoglycemic conditions
.
Exp Neurol
.
2008
May
;
211
(
1
):
85
96
.
[PubMed]
0014-4886
83.
Kim
DY
,
Davis
LM
,
Sullivan
PG
,
Maalouf
M
,
Simeone
TA
,
van Brederode
J
, et al.
Ketone bodies are protective against oxidative stress in neocortical neurons
.
J Neurochem
.
2007
Jun
;
101
(
5
):
1316
26
.
[PubMed]
0022-3042
84.
Yin
J
,
Han
P
,
Tang
Z
,
Liu
Q
,
Shi
J
.
Sirtuin 3 mediates neuroprotection of ketones against ischemic stroke
.
J Cereb Blood Flow Metab
.
2015
Nov
;
35
(
11
):
1783
9
.
[PubMed]
0271-678X
85.
Sato
K
,
Kashiwaya
Y
,
Keon
CA
,
Tsuchiya
N
,
King
MT
,
Radda
GK
, et al.
Insulin, ketone bodies, and mitochondrial energy transduction
.
FASEB J
.
1995
May
;
9
(
8
):
651
8
.
[PubMed]
0892-6638
86.
Veech
RL
,
Chance
B
,
Kashiwaya
Y
,
Lardy
HA
,
Cahill
GF
 Jr
.
Ketone bodies, potential therapeutic uses
.
IUBMB Life
.
2001
Apr
;
51
(
4
):
241
7
.
[PubMed]
1521-6543
87.
Veech
RL
,
Bradshaw
PC
,
Clarke
K
,
Curtis
W
,
Pawlosky
R
,
King
MT
.
Ketone bodies mimic the life span extending properties of caloric restriction
.
IUBMB Life
.
2017
May
;
69
(
5
):
305
14
.
[PubMed]
1521-6543
88.
Nie
X
,
Lowe
DW
,
Rollins
LG
,
Bentzley
J
,
Fraser
JL
,
Martin
R
, et al.
Sex-specific effects of N-acetylcysteine in neonatal rats treated with hypothermia after severe hypoxia-ischemia
.
Neurosci Res
.
2016
Jul
;
108
:
24
33
.
[PubMed]
0168-0102
89.
Kannan
S
,
Dai
H
,
Navath
RS
, et al.
Dendrimer-Based Postnatal Therapy for Neuroinflammation and Cerebral Palsy in a Rabbit Model.
Science translational medicine.
2012
;4(130):130ra46-ra46.
90.
Lewerenz
J
,
Ates
G
,
Methner
A
,
Conrad
M
,
Maher
P
.
Oxytosis/Ferroptosis-(Re-) Emerging Roles for Oxidative Stress-Dependent Non-apoptotic Cell Death in Diseases of the Central Nervous System
.
Front Neurosci
.
2018
Apr
;
12
(
214
):
214
.
[PubMed]
1662-4548
91.
Brekke
EM
,
Morken
TS
,
Widerøe
M
,
Håberg
AK
,
Brubakk
AM
,
Sonnewald
U
.
The pentose phosphate pathway and pyruvate carboxylation after neonatal hypoxic-ischemic brain injury
.
J Cereb Blood Flow Metab
.
2014
Apr
;
34
(
4
):
724
34
.
[PubMed]
0271-678X
92.
Lee
BS
,
Woo
DC
,
Woo
CW
,
Kim
KS
.
Exogenous β-Hydroxybutyrate Treatment and Neuroprotection in a Suckling Rat Model of Hypoxic-Ischemic Encephalopathy
.
Dev Neurosci
.
2018
;
40
(
1
):
73
83
.
[PubMed]
0378-5866
93.
Kashiwaya
Y
,
Takeshima
T
,
Mori
N
,
Nakashima
K
,
Clarke
K
,
Veech
RL
.
D-beta-hydroxybutyrate protects neurons in models of Alzheimer’s and Parkinson’s disease
.
Proc Natl Acad Sci USA
.
2000
May
;
97
(
10
):
5440
4
.
[PubMed]
0027-8424
94.
Pawlosky
RJ
,
Kemper
MF
,
Kashiwaya
Y
,
King
MT
,
Mattson
MP
,
Veech
RL
.
Effects of a dietary ketone ester on hippocampal glycolytic and tricarboxylic acid cycle intermediates and amino acids in a 3xTgAD mouse model of Alzheimer’s disease
.
J Neurochem
.
2017
Apr
;
141
(
2
):
195
207
.
[PubMed]
0022-3042
95.
Prins
ML
,
Lee
SM
,
Fujima
LS
,
Hovda
DA
.
Increased cerebral uptake and oxidation of exogenous betaHB improves ATP following traumatic brain injury in adult rats
.
J Neurochem
.
2004
Aug
;
90
(
3
):
666
72
.
[PubMed]
0022-3042
96.
Kashiwaya
Y
,
Bergman
C
,
Lee
JH
,
Wan
R
,
King
MT
,
Mughal
MR
, et al.
A ketone ester diet exhibits anxiolytic and cognition-sparing properties, and lessens amyloid and tau pathologies in a mouse model of Alzheimer’s disease
.
Neurobiol Aging
.
2013
Jun
;
34
(
6
):
1530
9
.
[PubMed]
0197-4580
97.
Cunnane
SC
,
Courchesne-Loyer
A
,
Vandenberghe
C
,
St-Pierre
V
,
Fortier
M
,
Hennebelle
M
, et al.
Can Ketones Help Rescue Brain Fuel Supply in Later Life? Implications for Cognitive Health during Aging and the Treatment of Alzheimer’s Disease
.
Front Mol Neurosci
.
2016
Jul
;
9
:
53
.
[PubMed]
1662-5099
98.
Yager
JY
,
Heitjan
DF
,
Towfighi
J
,
Vannucci
RC
.
Effect of insulin-induced and fasting hypoglycemia on perinatal hypoxic-ischemic brain damage
.
Pediatr Res
.
1992
Feb
;
31
(
2
):
138
42
.
[PubMed]
0031-3998
99.
Gilbert
DL
,
Pyzik
PL
,
Freeman
JM
.
The ketogenic diet: seizure control correlates better with serum β-hydroxybutyrate than with urine ketones
.
J Child Neurol
.
2000
Dec
;
15
(
12
):
787
90
.
[PubMed]
0883-0738
100.
Reinke
SN
,
Walsh
BH
,
Boylan
GB
,
Sykes
BD
,
Kenny
LC
,
Murray
DM
, et al.
1H NMR derived metabolomic profile of neonatal asphyxia in umbilical cord serum: implications for hypoxic ischemic encephalopathy
.
J Proteome Res
.
2013
Sep
;
12
(
9
):
4230
9
.
[PubMed]
1535-3893
101.
Ahearne
CE
,
Denihan
NM
,
Walsh
BH
,
Reinke
SN
,
Kenny
LC
,
Boylan
GB
, et al.
Early Cord Metabolite Index and Outcome in Perinatal Asphyxia and Hypoxic-Ischaemic Encephalopathy
.
Neonatology
.
2016
;
110
(
4
):
296
302
.
[PubMed]
1661-7800
102.
D’Agostino
DP
,
Pilla
R
,
Held
HE
,
Landon
CS
,
Puchowicz
M
,
Brunengraber
H
, et al.
Therapeutic ketosis with ketone ester delays central nervous system oxygen toxicity seizures in rats
.
Am J Physiol Regul Integr Comp Physiol
.
2013
May
;
304
(
10
):
R829
36
.
[PubMed]
0363-6119
103.
Bronisz
A
,
Ozorowski
M
,
Hagner-Derengowska
M
.
Pregnancy Ketonemia and Development of the Fetal Central Nervous System
.
Int J Endocrinol
.
2018
Jun
;
2018
:
1242901
.
[PubMed]
1687-8337
104.
Harris
DL
,
Weston
PJ
,
Harding
JE
.
Point-of-care measurements of blood ketones in newborns
.
Arch Dis Child Fetal Neonatal Ed
.
2018
Nov
;
fetalneonatal-2018-316293
.
[PubMed]
1359-2998
Copyright / Drug Dosage / Disclaimer
Copyright: All rights reserved. No part of this publication may be translated into other languages, reproduced or utilized in any form or by any means, electronic or mechanical, including photocopying, recording, microcopying, or by any information storage and retrieval system, without permission in writing from the publisher.
Drug Dosage: The authors and the publisher have exerted every effort to ensure that drug selection and dosage set forth in this text are in accord with current recommendations and practice at the time of publication. However, in view of ongoing research, changes in government regulations, and the constant flow of information relating to drug therapy and drug reactions, the reader is urged to check the package insert for each drug for any changes in indications and dosage and for added warnings and precautions. This is particularly important when the recommended agent is a new and/or infrequently employed drug.
Disclaimer: The statements, opinions and data contained in this publication are solely those of the individual authors and contributors and not of the publishers and the editor(s). The appearance of advertisements or/and product references in the publication is not a warranty, endorsement, or approval of the products or services advertised or of their effectiveness, quality or safety. The publisher and the editor(s) disclaim responsibility for any injury to persons or property resulting from any ideas, methods, instructions or products referred to in the content or advertisements.
You do not currently have access to this content.