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Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic Relationship Between Metabolism and Brain Activity

September 2009
Current Neuropharmacology 7(3):257-68

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For many years the neuromodulator adenosine has been recognized as an endogenous anticonvulsant molecule and termed a "retaliatory metabolite." As the core molecule of ATP, adenosine forms a unique link between cell energy and neuronal excitability. In parallel, a ketogenic (high-fat, low-carbohydrate) diet is a metabolic therapy that influences neuronal activity significantly, and ketogenic diets have been used successfully to treat medically-refractory epilepsy, particularly in children, for decades. To date the key neural mechanisms underlying the success of dietary therapy are unclear, hindering development of analogous pharmacological solutions. Similarly, adenosine receptor-based therapies for epilepsy and myriad other disorders remain elusive. In this review we explore the physiological regulation of adenosine as an anticonvulsant strategy and suggest a critical role for adenosine in the success of ketogenic diet therapy for epilepsy. While the current focus is on the regulation of adenosine, ketogenic metabolism and epilepsy, the therapeutic implications extend to acute and chronic neurological disorders as diverse as brain injury, inflammatory and neuropathic pain, autism and hyperdopaminergic disorders. Emerging evidence for broad clinical relevance of the metabolic regulation of adenosine will be discussed.

. Conditions that Increase Adenosine in the CNS

…

The metabolic relationship between ketones and adenosine. Compounds upregulated by a ketogenic diet or exogenous ketones are italicized. (1) During ketolytic metabolism, the ketone bodies β-hydroxybutyrate (and its breakdown products acetone and acetoacetate) are either generated locally or hepatically and transported via the blood to other tissues (such as brain). Ketones are converted intracellularly into acetyl-CoA which enters the tricarboxylic acid cycle. (2) This mitochondrial energy cycle generates, at multiple steps (----), protons and electrons that are channeled to the electron transport chain by NADH and FADH2 (β-hydroxybutyrate conversion to acetoacetate also contributes). Many steps of the tricarboxylic acid cycle are omitted for simplicity. (3) The electron transport chain drives an electrochemical gradient across the mitochondrial outer membrane and ultimately oxidative phosphorylation which forms ATP from ADP and phosphate (Pi) by ATP synthase. (4) Enhanced ATP can be converted to phosphocreatine for energy storage, or broken down to its core molecule, adenosine. Adenosine levels inside and outside of the cell membrane are influenced concurrently by an equilibrative transporter. Due to the very large ATP / adenosine ratio inside the cell, a small increase in intracellular ATP could translate into a large relative increase in intracellular, and thus extracellular, adenosine.

…

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Current Neuropharmacology, 2009, 7, 257-268 257

Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic

Relationship Between Metabolism and Brain Activity

S.A. Masino1,2,*, M. Kawamura Jr.1,2, C.D. Wasser2, L.T. Pomeroy2 and D.N. Ruskin1,2

1Psychology Department, 2Neuroscience Program, Trinity College, 300 Summit St., Hartford, CT, USA

Abstract: For many years the neuromodulator adenosine has been recognized as an endogenous anticonvulsant molecule

and termed a “retaliatory metabolite.” As the core molecule of ATP, adenosine forms a unique link between cell energy

and neuronal excitability. In parallel, a ketogenic (high-fat, low-carbohydrate) diet is a metabolic therapy that influences

neuronal activity significantly, and ketogenic diets have been used successfully to treat medically-refractory epilepsy, par-

ticularly in children, for d ecades. To date the key neural mechanisms underlying the success of dietary therapy are un-

clear, hindering development of analogous pharmacological solutions. Similarly, adenosine receptor–based therapies for

epilepsy and myriad other disorders remain elusive. In this review we explore the physiological regulation of adenosine as

an anticonvulsant strategy and suggest a critical role for adenosine in the success of ketogenic diet therapy for epilepsy.

While the current focus is on the regulation of adenosine, ketogenic metabolism and epilepsy, the therapeutic implications

extend to acute and chronic neurological disorders as diverse as brain injury, inflammatory and neuropathic pain, autism

and hyperdopaminergic disorders. Emerging evidence for broad clinical relevance of the metabolic regulation of adeno-

sine will be discussed.

Key Words: Metabolism, neuroprotection, neurodegeneration, sleep, pain, autism, addiction, dopamine.

INTRODUCTION

Adenosine is a potent neuromodulatory purine present

throughout the extracellular space of the central nervous sys-

tem. Adenosine acts at pre- and postsynaptic G protein-

coupled receptor subtypes (A1, A2A, A2B, and A3) [58], and

the influence of A1 and A2A receptor subtypes predominates

due to their higher affinity for adenosine (~100 nM) [100]

and their activation by ongoing levels of adenosine. In brain,

A1 receptors are distributed widely [73] and A2A receptors

are located preferentially in the basal ganglia and olfactory

tubercle [169]. Both the A1 and A2 receptor subtypes are

antagonized by caffeine, the most widely used psychoactive

substance worldwide, and caffeine’s actions at adenosine A1

and A2A receptors in the central nervous system underlie its

alerting, locomotor and cognitive effects [136].

Adenosine exerts a tonic inhibition of neuronal excitabil-

ity via A1 receptors in many brain regions, including hippo-

campus and cerebral cortex, and this baseline inhibition in-

fluences both baseline synaptic activity [132, 175] and neu-

ronal plasticity [36]. Adenosine’s inhibitory influence also

alters seizure threshold directly, and increased extracellular

adenosine during a seizure plays a key role in postictal de-

pression [193] and in keeping a seizure focus localized [140]

via adenosine A1 receptors [74]. Large additional amounts of

adenosine are mobilized during metabolically stressful cellu-

lar conditions such as low oxygen or glucose [57], and in-

creased extracellular adenosine acting at the adenosine A

receptor has been shown to be neuroprotective during condi-

tions of metabolic stress [45]. Overall, adenosine holds well

established and profound therapeutic potential for conditions

such as stroke, brain injury, pain and epilepsy, among others

[17, 79].

*Address correspondence to this author at Psychology Department, Neuro-

science Program, Trinity College, 300 Summit St., Hartford, CT, U SA; Tel:

860-297-2557; Fax: 860-297-2538; E-mail: susan.masino@trincoll.edu

Whereas adenosine’s role as an endogenous neuroprotec-

tive molecule during pathology such as stroke, hypoxia and

brain injury is of paramount clinical importance, and has

long been the focus on adenosine-based therapies, the ongo-

ing effects of adenosine are critical to baseline neuronal ex-

citability and sleep behaviors. In addition, adenosine influ-

ences the risk for an epileptic seizure, and can control sig-

nificantly the expression and progression of a broad range of

acute and chronic neurological conditions. With an unparal-

leled long-term epidemiological database based on manipu-

lating the influence of endogenous adenosine, i.e. the world-

wide consumption of caffeine [60, 85], a strategy focused on

regulating endogenous adenosine is likely to be well toler-

ated and non-toxic.

To date, receptor-based strategies to augment the inhibi-

tory influence of adenosine by targeting A

1 receptors have

been unable to harness its clinical potential, primarily due to

peripheral side effects [43, 51]. Accordingly, interest has

intensified in the regulation of adenosine directly by physio-

logical stimulation [42, 45, 76, 77], metabolism [125] and

adenosine kinase [75], an astrocytic intracellular enzyme

that, together with equilibrative adenosine transport, controls

extracellular adenosine levels. We now appreciate the active

role of astrocytes in regulating extracellular adenosine [156],

underscoring the multi-faceted and direct impact that glia

have on neuronal activity and signaling. Together, these re-

cent findings highlight the dynamic regulation of adenosine

by cellular and metabolic stimuli, and thus expose new clini-

cally-relevant strategies for augmenting adenosine.

ADENOSINE: A KEY LINK BETWEEN METABO-

LISM AND NEURONAL SIGNALING

As both the core of ATP and a prevalent neuromodulator,

adenosine is poised to link changes in cell metabolism with

changes in neuronal activity [109]. Indeed, adenosine levels

rise dramatically in the extracellular space during all types of

258 Current Neuropharmacology, 2009, Vol. 7, No. 3 Masino et al.

metabolic stress and earned adenosine the apt title of “re-

taliatory metabolite” [138] - its profound inhibitory influence

at both pre- and postsynaptic receptors serves to limit energy

demand and excitotoxicity when energy availability is com-

promised [59]. The direct release of adenosine via nucleoside

transporters can increase extracellular adenosine under

physiologically stressful conditions [114], and typically

adenosine’s role as a retaliatory metabolite is thought to be

mobilized when intracellular ATP dephosphorylation out-

strips ATP production [145, 170]. However, the regulation of

adenosine by ongoing physiological stimuli and under non-

pathological conditions of adequate or even high intracellular

ATP is becoming more appreciated [45, 96, 128]. In addi-

tion, degradation of extracellular ATP is a major source of

extracellular adenosine [29, 44, 82], so manipulations that

increase extracellular ATP have a net effect on neuromodu-

lation by adenosine [44].

Ketogenic strategies such as fasting or adhering to a ke-

togenic (high-fat, low-carbohydrate) diet increase ATP and

other energy molecules in brain [20, 37, 126, 134]. These

metabolic manipulations are known to reduce seizures sig-

nificantly [194], and have been shown to offer neuroprotec-

tion in animal models of brain injury [70, 125]. Emerging

evidence suggests that mimicking key cellular aspects of

ketogenic metabolism increases extracellular adenosine [96],

and furthermore, that an increased influence of adenosine at

the A1 subtype plays a key role in the anticonvulsant success

of ketogenic strategies [127] via its combined presynaptic

inhibition of glutamatergic terminals and its postsynaptic

hyperpolarization via K

+ channels. Due to the functional

coupling and inverse relationship between adenosine and

dopamine receptors (A2A/D2 and A1/D1) [66], a general in-

crease in extracellular adenosine could also decrease dopa-

minergic transmission. A diverse set of physiological and

pathological stimuli that modulate extracellular adenosine

are outlined in Table 1.

Table 1. Conditions that Increase Adenosine in the CNS

Manipulation

Reference

Hypoxia

Fowler 1989 [55]

Dale & Frenguelli 2000 [34]

Saransaari & Oja 2003 [172]

Martín, Fernández, Perea, Pascual, Haydon,

Araque & Ceña 2007 [123]

Ischemia

Fowler 1990 [56]

Latini, Corsi, Pedata & Pepeu 1995 [108]

Frenguelli, Llaudet & Dale 2003 [63]

Parkinson, Xiong & Zamzow 2005 [155]

Frenguelli, Wigmore, Llaudet & Dale 2007 [64]

NMDA receptor

activation

Manzoni, Manabe & Nicoll 1994 [119]

Semba & White 1997 [176]

Melani, Corsi, Giménez-Llort, Martínez, Ogren,

Pedata & Ferré 1999 [130]

Brambilla, Chapman & Greene 2005 [21]

(Table 1. Contd….)

Manipulation

Reference

H2O2

Masino, Mesches, Bickford & Dunwiddie

1999 [129]

Saransaari & Oja 2003 [172]

Hypoglycemia or

impaired glycolysis

Fowler 1993 [57]

Zhu & Krnjević 1993 [201]

Calabresi, Centonze, Pisani & Bernardi 1997

[22]

Zhao, Tekkök & Krnjević [200]

Minor, Rowe, Soames Job, Ferguson [131]

Increased tempera-

ture

Gabriel, Klussman & Igelmund 1998 [67]

Masino & Dunwiddie 1999 [124]

Hypercap-

nia/acidification

Dulla, Dobelis, Pearson, Frenguelli, Staley &

Masino 2005 [42]

Gourine, Llaudet, Dale & Spyer 2005 [77]

Otsuguro, Yamaji, Ban, Ohta & Ito 2006 [146]

Depolarization

Pedata, Pazzagli, Tilli & Pepeu 1990 [157]

Latini, Corsi, Pedata & Pepeu 1995 [108]

Metabolic poisons

Doolette1997 [40]

Zhu & Krnjević 1997 [202]

Saransaari & Oja 2003 [172]

Astrocyte activation

Zhang, Wang, Ye, Ge, Chen, Jiang, Wu, Poo &

Duan 2003 [199]

Parkinson & Xiong 2004 [154]

Pascual, Casper, Kubera, Zhang, Revilla-

Sanchez, Sul, Takano, Moss, McCarthy & Hay-

don

2005 [156]

Seizures

Whitcomb, Lupica, Rosen & Berman 1990 [193]

During & Spencer 1993 [46]

Berman, Fredholm, Aden & O’Connor 2000

[11]

Kaku, Jiang, Hada, Morimoto & Hayashi 2001

[93]

Etherington, Patterson, Meechan, Boison,

Irving, Dale & Frenguelli 2008 [52]

Intense exercise

Dworak, Diel, Voss, Hollman & Strüder 2007

[47]

Sleep deprivation

Porkka-Heiskanen, Strecker, Thakkar, Bjorkum,

Greene & McCarley 1997 [162]

Porkka-Heiskanen, Strecker & McCarley

2000 [161]

Kalinchuk, McCarley, Stenberg, Porkka-

Heiskanen & Basheer 2008 [94]

Murillo-Rodriguez, Liu, Blanco-Centurion &

Shiromani, 2008 [133]

An overview of both physiological and p athological conditions of altered metabolism

and cellular activity that can increase extracellular adenosine. Due to the rapid

dephosphorylation of extracellular ATP to adenosine, increased extracellular ATP

yields a net increase in adenosine. This table is not meant to be exhaustive of th e litera-

ture, but to highlight the u biquitous and rapid nature of the adenosine response and thus

its broad and dynamic influence in the nervous system.

Adenosine, Ketogenic Diet and Epilepsy Current Neuropharmacology, 2009, Vol. 7, No. 3 259

ADENOSINE, METABOLISM AND EPILEPSY

The inhibitory adenosine A1 receptor is functionally

dominant in hippocampus and cerebral cortex, and underlies

adenosine’s role as an endogenous anticonvulsant [43]. Ac-

cordingly, any manipulation which increases extracellular

adenosine offers significant potential for both preventing and

halting epileptic seizures, the vast majority of which initiate

and propagate in these forebrain regions. Unlike the point-to-

point and activity-dependent changes in synaptic transmis-

sion effected by classical neurotransmitters, adenosine exerts

a tonic modulatory influence on neuronal activity. Thus the

anticonvulsant effects of adenosine are dissimilar mechanis-

tically to classical actions of glutamate and GABA, the neu-

rotransmitters targeted most often for the treatment of epi-

lepsy [168]. Adenosine itself is not packaged in vesicles, and

its non-synaptic release, such as from astrocytes and through

nucleoside transporters, can influence a neural “neighbor-

hood.” Akin to a broad-based influence of altered metabo-

lism, such as via ketogenic strategies, the presence of a tonic

level of adenosine in the extracellular space makes adenosine

a major player in the dynamics of nervous system activity

and even in determining the set point of normal physiology

versus pathology in brain function – such as by determining

seizure threshold. Indeed, local release of adenosine itself

[89] or regulating local metabolism of adenosine by reducing

its intracellular rephosphorylation by adenosine kinase [18]

both offer significant emerging potential for treating epi-

lepsy. Importantly, adenosine is effective in stopping sei-

zures which are pharmacoresistant [16], thus opening new

therapeutic opportunities for intractable epilepsy.

Physiological conditions which offer both high ATP lev-

els and increased extracellular adenosine are particularly

ideal for epilepsy and for many acute and chronic neurologi-

cal disorders characterized by metabolic dysfunction and

neuronal vulnerability or frank progressive neurodegenera-

tion. Enhanced ATP levels provide energy reserves for a

neuron to continue functioning under stress, essential for

maintaining cell calcium and other ion gradients across the

cell and mitochondrial membrane. Increased extracellular

adenosine, at levels permitting normal synaptic transmission,

plasticity and cognition, offers a neuroprotective buffer

against insults, reduces excitation, and averts excessive ATP

demand, expressly critical in cells with compromised energy

capacity. Ideally, metabolic strategies enhance ATP, increase

extracellular adenosine, and boost on-demand adenosine

within a neural neighborhood to provide local seizure control

and neuroprotection. As such, metabolic and dietary strate-

gies such as ketogenic diet therapy may increase regional or

global adenosine and increase overall seizure threshold as

described below.

THE REGULATION OF ADENOSINE AND BIO-

ENERGETICS BY KETOGENIC METABOLISM

Multiple lines of evidence suggest that adenosine, ATP,

and general cellular energy are upregulated by ketogenic

metabolism. To highlight these effects, it is necessary to re-

view the underlying biochemistry of ketosis. Due to re-

stricted carbohydrate intake, blood glucose is very low dur-

ing chronic consumption of a ketogenic diet (or prolonged

fasting). During conditions of limited glucose the liver main-

tains energy homeostasis by converting fatty acids and some

amino acids to ketone bodies (β-hydroxybutyrate, acetoace-

tate, acetone) which are then transported by the blood to

other tissues for use as fuel. The brain is particularly depend-

ent on this process, since it is poor both at using fatty acids

directly for fuel and at converting fatty acids to ketone bod-

ies; the brain is a unique tissue in this regard [65, 147].

While the enzymes involved in ketone body synthesis are

detectable in brain, they are present at far lower levels than

in liver [4, 27, 28].

Ketone bodies lead to energy production by conversion

to acetyl-CoA which then enters the mitochondrial tricar-

boxylic acid cycle, replacing pyruvate (derived from glyco-

lysis) as an acetyl-CoA source. The tricarboxylic acid cycle

then leads as usual to proton flow out of the mitochondria

matrix; this gradient in turn powers ATP production by ATP

synthase in the mitochondrial inner membrane. Not only can

ketone bodies substitute for glucose, metabolism of ketone

bodies is more efficient than that of glucose, leading to more

available energy for ATP synthesis. This effect derives from

the higher heat of combustion of ketone bodies compared to

pyruvate [187]; ketone body metabolism leads to reduction

of the mitochondrial NAD couple (NAD+/NADH) and oxi-

dation of the mitochondrial co-enzyme Q couple (Q/QH2).

The difference between the redox potentials of these couples

determines the magnitude of the proton gradient which in

turn determines the free energy (ΔG’) of ATP hydrolysis –

the increased difference with ketone body metabolism leads

to increased ΔG’ for ATP production [187]. Key aspects of

this energy cycle and its relationship to adenosine are sum-

marized in Fig. (1).

Experimental application of ketone bodies in vitro leads

to increased ATP/ADP and phosphocreatine/creatine ratios

and increased levels of the tricarboxylic acid cycle substrates

citrate and isocitrate [95, 173]. Overall, studies of ketogenic

metabolism in the brain demonstrate an increased energetic

status using measures ranging from respiration to mitochon-

drial density to levels of energy-storing substances such as

ATP and phosphocreatine. Importantly, the brain’s bioener-

getic response to ketosis appears to differ from peripheral

tissues so far examined – increases in cell energy predomi-

nate in brain (Table 2).

In addition to published neurochemical and biochemical

evidence, recent neurochemical evidence suggests a regional

upregulation of energy molecules in rats after maintenance

on a ketogenic diet. Preliminary results demonstrate in-

creased ATP or adenosine in specific brain regions [127,

143], including a significant increase in ATP and a strong

trend toward increased adenosine in cerebral cortex [127],

and upregulated ATP synthase gene expression in hippo-

campus [20, 141]. Field recordings from the CA1 region of

hippocampal slices show a reduced electrophysiological re-

sponse to hypoxia [20] and exogenous adenosine [127] after

ketogenic diet therapy, consistent with increased endogenous

adenosine. Hippocampal CA3 pyramidal neurons autoregu-

late their activity based on acute changes in intracellular

ATP and extracellular glucose consistent with the metabolic

consequences of ketogenic diet therapy [96]; detailed cellular

mechanisms are described below.

260 Current Neuropharmacology, 2009, Vol. 7, No. 3 Masino et al.

As noted above, ketogenic metabolism occurs during

restricted glucose and is characterized by increased ATP.

During single-cell patch clamp recordings, when extracellu-

lar glucose is reduced but not eliminated, and the level of

intracellular ATP is sufficient or high in the patch pipette,

CA3 pyramidal neurons regulate their own excitability by

releasing ATP, activating adenosine A1 receptors and open-

ing postsynaptic K+ channels [96]. In contrast, during single

cell recordings of CA3 pyramidal neurons, when extracellu-

lar glucose is reduced and intracellular ATP is low, CA3

pyramidal cells depolarize significantly [96]. These low

ATP/low glucose conditions are similar to an ischemic stroke,

where both oxidative phosphorylation and glucose availabil-

ity are interrupted. Thus, an autocrine regulation of CA3

neuron excitability during low glucose depends critically on

intracellular ATP; the subsequently increased extracellular

adenosine likely influences nearby neurons, particularly im-

portant in CA3, a region with recurring excitatory collaterals.

Overall this concurrent intracellular ATP / extracellular glu-

cose manipulation mimicking metabolic aspects of ketogenic

diet therapy provides a clear example of a situation where

intracellular ATP is high yet extracellular adenosine in-

creases – ideal for autocrine regulation by increasing seizure

threshold and promoting neuronal survival.

Evidence for autocrine neuronal regulation is consistent

with adenosine’s role as a neuroprotective agent, mobilized

proactively under these conditions by non-pathological

changes in altered metabolism. Similarly, ketone-based me-

tabolism [35] or a ketogenic diet [70] has already shown

neuroprotective properties in injury models in multiple brain

regions. While it seems counterintuitive for brain cells to

release ATP when extracellular glucose is low, ultimately

this process can save cell energy: under conditions of suffi-

cient ATP, there is a large ratio of ATP:adenosine (10,000:1)

inside the cell. Upon releasing a relatively small amount of

ATP, a coherent set of mechanisms degrade extracellular

ATP to adenosine, activate adenosine A1 receptors and re-

duce excitability. Thus, releasing a relatively small amount

of ATP during low glucose is a powerful preemptive strike

against a condition of increased excitability – potentially

placing energy demands which could exceed energy supply

and compromise neuronal function.

CLINICAL IMPLICATIONS

The clinical efficacy of a ketogenic diet is well-estab-

lished for pediatric epilepsy. It has been validated retrospec-

tively by multiple clinical sites [38, 62, 153, 188] and con-

firmed recently in a randomized controlled trial [135]. Simi-

lar to adenosine, the ketogenic diet is effective in medically-

refractory epilepsy, and thus reduces seizures via mecha-

nisms other than those targeted by antiepileptic drugs avail-

able currently [168]. A significant subset of pediatric epi-

lepsy patients become and remain seizure-free, and can re-

duce or eliminate their medication even after discontinuing

diet therapy. Most common side effects are short term, and

include hunger, constipation, and lethargy [135, 188]. How-

Fig. (1). The metabolic relationship between ketones and adenosine. Compounds upregulated by a ketogenic diet or exogenous ketones are

italicized. (1) During ketolytic metabolism, the ketone bodies β-hydroxybutyrate (and its b reakdown products acetone and acetoacetate) are

either generated locally or hepatically and transported via the blood to other tissues (such as brain). Ketones are converted intracellularly into

acetyl-CoA which enters the tricarboxylic acid cycle. (2) This mitochondrial energy cycle generates, at multiple steps (----), protons and elec-

trons that are channeled to the electron transport chain by NADH and FADH2 (β-hydroxybutyrate conversion to acetoacetate also contrib-

utes). Many steps of the tricarboxylic acid cycle are omitted for simplicity. (3) The electron transport chain drives an electrochemical gradi-

ent across the mitochondrial outer membrane and ultimately oxidative phosphorylation which forms ATP from ADP and phosphate (Pi) by

ATP synthase. (4) Enhanced ATP can be converted to phosphocreatine for energy storage, or broken down to its core molecule, adenosine.

Adenosine levels inside and outside of the cell membrane are influenced concurrently by an equilibrative transporter. Due to the very large

ATP / adenosine ratio inside the cell, a small increase in intracellular ATP could translate into a large relative increase in intracellular, and

thus extracellular, adenosine.

Adenosine, Ketogenic Diet and Epilepsy Current Neuropharmacology, 2009, Vol. 7, No. 3 261

ever, kidney stones can develop in 5-7% of children on the

diet [171].

The ketogenic diet may also offer benefits for adult epi-

lepsy [15], and recently has been shown to improve dramati-

cally or even reverse the metabolic syndrome which charac-

terizes type II diabetes [198]. Notably, a ketogenic diet was

more effective than a calorically restricted diet, and virtually

reversed metabolic syndrome in all persons who were able to

comply with the restrictions of dietary therapy [192]. Basic

research has also shown dramatic results in slowing tumor

growth in brain cancer [177], and synergistic effects of the

simultaneous use of a ketogenic diet and 2-deoxyglucose

[121], a metabolic manipulation which inhibits glycolysis,

increases adenosine [200] and decrease seizures [69, 181].

Thus, the therapeutic applications of a ketogenic diet and

metabolism-based therapies are broadening rapidly beyond

pediatric epilepsy to other chronic and prevalent conditions.

As a whole, the capacity for a ketogenic diet to increase

specifically the influence of endogenous adenosine offers

testable and clinically-relevant predictions; many of these

predictions are validated by published clinical and basic re-

search, lending further conceptual support [125, 126]. Below

we highlight briefly some of the central nervous system im-

plications of a relationship between a ketogenic diet and

adenosine. A subset is supported strongly by published re-

search, in particular neuroprotection and sleep. Data are

emerging for neurodegeneration, hyperdopaminergic disor-

ders and autism. In addition, we speculate upon major clini-

cal implications for pain.

Brain Injury

The attractive features of adenosine as an endogenous

anticonvulsant are recapitulated in its role as a neuroprotec-

tive molecule. Increasing adenosine’s inhibitory influence

via the adenosine A1 receptor protects neurons in virtually

any model of brain injury [45], and the adenosine A1 recep-

tor has long been a major focus of and goal for adenosine-

based neuroprotective therapies. Increasing the influence of

adenosine at A1 receptors offers neuroprotection either be-

fore [90] or after [190] the injury. Unfortunately, and akin to

epilepsy, the peripheral side effects of receptor-based strate-

gies have stymied drug development and adenosine A1 re-

ceptors have lost momentum as a primary neuroprotective

target.

Importantly, and as predicted based on a relationship

between ketone metabolism and adenosine, the ketogenic

diet or analogous metabolic strategies have shown neuropro-

tective properties in multiple brain injury models and brain

regions, including spinal cord injury [160]. Some of these

effects have been counterintuitive – neuroprotection was

observed after a ketogenic strategy such as fasting [35], or

after strategies that interrupted metabolism [102] or inhibited

glycolysis [111]. Importantly, neuroprotection was observed

even if altered metabolism was initiated after the injury

[152], making this a particularly promising strategy. Based

on differential consequences and responses in the central

nervous system versus the periphery (Table 2), a metabolic

strategy could lend new therapies and recommendations for

the treatment of brain injuries, and open a new and exciting

chapter for adenosine and neuroprotection.

Neurodegeneration

The neuroprotective effects of adenosine via altered me-

tabolism may extend to neurodegenerative diseases. Meta-

bolic dysregulation at the cellular level is a hallmark of many

chronic and neurodegenerative disorders [7], and often it is

unclear if it causes and/or results from the progressive neu-

ronal dysfunction. The brain has an extremely high fat con-

tent, and as noted in Table 2 offers some differential re-

sponses to metabolic manipulations as compared to periph-

eral tissues. These dual and unique features of brain compo-

sition and brain metabolism enhance therapeutic opportuni-

ties for chronic and progressive disorders [1], and suggest

the potential for limited or reduced peripheral side effects.

As one example, metabolic therapy may offer sympto-

matic delay or improvement even in a genetic, neurodegen-

erative disorder such as Huntington’s disease [41, 186]. Drug

treatments targeting type II diabetes, which, similar to a ke-

Table 2. Influence of Ketone Metabolism on Cellular En ergy

Energetic Molecules

Expression of Mitochondrial

Genes or Proteins

Mitochondria

Respiration

Brain

Increased ATP [37, 99, 127,

134, 143]

Increased phosphocreatine [20,

151]

Upregulated ATP synthase [20, 141]

Upregulated uncoupling protein

[182]

Unchanged succinate dehydrogenase

[167]

Increased number [20, 143]

Increased or reduced number

(region-dependent) [6]

Increased respiration [182]

Peripheral tis-

sues

Unchanged ATP production

[158]

Unchanged citrate synthase [158]

Unchanged succinate dehydrogenase

[137, 167]

Moderately increased size [48]

Unchanged [6]

Evidence for changes in cellular energy in brain and p eripheral tissues after ketogenic metabolism in vivo or in vitro. An increase or upregulation is indicated by italics throughout.

“Expression of genes or proteins” includes mRNA expression and protein expression via immunochemical or activity-based assays; here we include both cell and mitochondria-

related genes/proteins. Periph eral tissues include skeletal muscle and liver.

262 Current Neuropharmacology, 2009, Vol. 7, No. 3 Masino et al.

togenic diet, offer improved glycemic control, can reduce

symptoms and increase survival in mouse models of

Huntington’s disease [116, 122]. With gene therapy still be-

yond the near-term horizon, metabolic treatment strategies

which delay or reduce symptoms of disease could offer sig-

nificant improvements in quality of life for current patients

with Huntington’s disease and a host of neurodegenerative

conditions. In addition, at least some neurodegenerative dis-

eases are associated with an increased risk of seizures, such

as Alzheimer’s disease [3]. It is unknown whether subclini-

cal seizures may occur and contribute to the progression of

Alzheimer’s disease or other neurodegenerative diseases

in humans. Ultimately, similar to epilepsy, adenosine-based

metabolic therapies could limit acute dysfunction and offer

ongoing neuroprotection against progressive neuronal de-

cline and degeneration.

Sleep

Adenosine promotes sleep [165, 189], and treating sleep

disorders and enhancing the quality of sleep is a major con-

cern for public health [23]. The specific adenosine-based

mechanism established initially as sleep-promoting was in-

creased activity at the A1 receptor in the basal forebrain

[166]. More recently the adenosine A2A receptor has been

recognized for an important role in sleep [88, 174]. The

alerting effects of caffeine are attributed to its actions at

adenosine receptors in forebrain areas important for cogni-

tion as well as arousal centers, and it may be that endoge-

nous adenosine acting at both of the receptor subtypes in

brain that are antagonized by caffeine – A1 and A2A adeno-

sine receptors – play a role in sleep behaviors [8].

In keeping with adenosine’s role as a sleep-promoter, and

the potential for a ketogenic diet to increase ATP and ex-

tracellular adenosine, the ketogenic diet has been shown to

improve sleep quality and quantity in children with epilepsy,

especially normalizing the ultradian cycling between slow-

wave and paradoxical sleep [83]. Sleep electroencephalo-

graph (EEG) changes were observed consistently with keto-

genic diet therapy, and normalization or improvement in

sleep EEG was correlated with an improvement in seizures

[153]. In control subjects without a diagnosis of epilepsy,

effects are typically moderate and include reports of an in-

crease in the latency to enter rapid eye movement (REM)

sleep [106] and an increase in slow-wave sleep [2]. Whereas

a high-fat, low-carbohydrate ketogenic diet increased slow-

wave sleep, a high-carbohydrate, low-fat isocaloric diet de-

creased slow-wave sleep [159].

Recent evidence implicates the role of extracellular as-

trocyte-derived ATP as critical for the sleep-promoting in-

fluence of adenosine [82]. Furthermore, there is a well estab-

lished association between poor sleep and epilepsy [105].

With such a high prevalence and cost associated with these

co-morbidities, metabolic therapy appears to offer significant

promise. More research is needed in this area to determine

the therapeutic relationship among adenosine, a ketogenic

diet and sleep.

Autism

Multiple lines of evidence suggest that the influence of

adenosine may be insufficient in autism spectrum disorders

(ASD), and that increasing adenosine would reduce both

physiological and behavioral hallmarks of ASD. Preliminary

studies have shown that the ketogenic diet improves symp-

toms of autism [53], and Rett syndrome [80]. To our knowl-

edge, dysregulation of adenosine in brain has not been tested

directly with respect to symptoms of autism, although these

studies are underway. Nevertheless, adenosine is a purine

molecule with roles in both metabolism and neuronal signal-

ing, and abnormalities in purine metabolism have been

documented [19, 120, 142, 149, 150] in a subset of ASD.

Along with dysregulation of purine metabolism, ASD are

characterized by several behavioral and physiological hall-

marks of disordered adenosine: sleep disruption [25, 72,

184], markedly increased incidence of seizures [118, 195],

immune dysfunction [87, 91], and reports - including self-

reports - of increased anxiety and “sensitivity” and “hyperac-

tivity” of the nervous system [24, 78, 178]. Often there is a

dual diagnosis, with psychiatric comorbidities present in

least 70% of individuals diagnosed with ASD. The most

common comorbidities are social anxiety disorder, attention-

deficit/hyperactivity disorder, and oppositional defiant disor-

der [178].

Many of the behaviors exhibited by persons with autism

and/or reported by high-functioning persons with autism

involve stimuli that would be predicted to release ATP

and/or adenosine based on associated mechanical pressure,

increased neuronal activity, decreased pH or increased tem-

perature (ref. [45] and Table 1). For example, rocking, spin-

ning and Grandin’s well-known “Hug Machine” [49] all ex-

ert mechanical pressure or sudden changes in acceleration,

intense intellectual activity and focus can reduce anxiety

associated with ASD [78], and intense neuronal activity in-

creases extracellular adenosine [114]. Intense exercise causes

a metabolic decrease in pH [84], decreased pH has been

shown to increase adenosine [42, 146], and intense exercise

has been shown to increase brain adenosine [47] and im-

prove symptoms of autism [98]. Reports show improved

behavior, language and social function associated with a

fever in persons with autism [30], and basic research demon-

strates that a similar temperature increase in hippocampal

slices increases extracellular adenosine and inhibits neuronal

activity significantly [124].

Certainly many symptoms and behaviors of ASD are due

to aberrant neurochemistry, neuroanatomical development

and genetically-determined substrates. However, increasing

the inhibitory influence of adenosine could help significantly

with multiple behavioral and physiological sequelae. Impor-

tantly, increasing adenosine improves sleep, decreases sei-

zures and reduces anxiety – all physiological effects that

could be achieved by a metabolic strategy such as a keto-

genic diet and would improve quality of life significantly in

persons and families affected by ASD. Ketogenic diet ther-

apy and/or increasing adenosine could improve social and

behavioral symptoms and reduce or alleviate serious chronic

physiological symptoms which impact the ability to learn

and remember (sleep disruption/inadequate REM sleep/

seizures [86, 118]) and ultimately cause permanent brain

dysfunction and cognitive impairment (recurrent seizures)

[25, 26]. Given adenosine’s profound effects on neuronal

Adenosine, Ketogenic Diet and Epilepsy Current Neuropharmacology, 2009, Vol. 7, No. 3 263

activity, sleep and seizures, the relationship among metabo-

lism, autism and adenosine, including the efficacy of a keto-

genic diet in reducing symptoms of autism, needs to be ex-

plored directly.

Hyperdopaminergic Disorders

Dopamine and adenosine have long been known to be

opposing at numerous levels. Behaviorally, whereas adeno-

sine receptor antagonists (e.g. caffeine) are stimulants, such

properties belong to agonists of the dopamine system (e.g.

amphetamine). Biochemically, the two high affinity adeno-

sine receptors in brain each have an antagonistic dopaminer-

gic counterpart. Specifically, A1 and D1 receptors, and A2 A

and D2 receptors, have opposing effects on 2nd messenger

pathways, most notably the production of cyclic AMP

through heterotrimeric G-protein regulation of adenylate

cyclase [61, 97]. More recently, it has become apparent that

such interactions can involve direct receptor/receptor cross-

talk via A1/D1 and A2A/D2 receptor heteromers [54]. There-

fore, it is logical to explore modulation of adenosinergic ac-

tivity as a possible treatment for disorders of dopaminergic

function.

Thus far there is compelling evidence that adenosine an-

tagonists are useful in treating a hypodopaminergic disease,

namely Parkinson’s disease [197]. Conversely, the ketogenic

diet and an associated augmentation of adenosine may be of

use in hyperdopaminergic states. The list of clinical condi-

tions that are hypothesized to involve overactivity in the do-

pamine system is impressive, and includes conditions as di-

verse as schizophrenia, tardive dyskinesia, attention defi-

cit/hyperactivity disorder, Tourette’s syndrome, Huntington’s

disease, and drug addiction/relapse. Research in animal

models of some of these disorders suggests the beneficial

effects of promoting adenosine [12, 14, 39, 71, 92, 101, 113,

191]. Adenosine augmentation via ketogenic diet or analo-

gous metabolic strategies may be particularly useful in those

hyperdopaminergic disorders involving neurodegeneration,

offering the combined benefits of treating symptoms as well

as retarding the underlying degeneration.

Preliminary human data exist on the benefits of ketogenic

diet therapy and schizophrenia [148]. Ketogenic diet therapy

was tried because the physiological effects of other treat-

ments – such as electroconvulsive shock – result in de-

creased blood pH, and ketone metabolism increases acid

production. In addition, physicians noted carbohydrate crav-

ings and increased intake prior to a relapse and hypothesized

that persons with schizophrenia may have problematic or

altered carbohydrate metabolism. Despite the small sample

size and incomplete control over dietary therapy, promising

results were noted [148].

Like epilepsy, schizophrenia is a chronic condition char-

acterized by recurring episodes as well as significant propor-

tion of cases that remain intractable to therapies available

currently [107]. Finally, given the high coincident rates of

epilepsy and schizophrenia [164] and type II diabetes and

schizophrenia [39, 139, 144, 179], and the success of a vari-

ety of low carbohydrate and ketogenic diets in treating type

II diabetes [198] and adult epilepsy [5, 103, 104], dietary

therapy would seem like an optimal primary or adjuvant

therapy to reduce all of these medical conditions.

Pain

Control of chronic pain remains a major clinical problem.

For example, the strongest analgesics, the opiates, have been

viewed historically as poorly effective against neuropathic

pain; only a subset of patients respond well to opiates [163].

Anticonvulsant drugs are a non non-opiate alternative used

with success against neuropathic pain, yet they have their

own set of undesirable side effects. Pain relief using anticon-

vulsants demonstrates that an overall inhibition of neuronal

activity is a strategy that can alleviate pain, and so it is not

surprising that adenosine persists as a prized, but problem-

atic, target for pain relief [180]. Adenosine A1 receptor ago-

nists given systemically reduce chronic pain effectively in

experimental animals [31, 112], and conversely, genetic

knockout of the A1 receptor enhances pain sensitivity [90,

196]. Clinically, systemic adenosine alleviates neuropathic

pain [10], yet the presence of adenosine A1 receptors in the

heart and other peripheral tissues, and the short biological

half-life of adenosine in the blood, have stymied this type of

therapy. Side effects can be avoided with intrathecal adeno-

sine [9, 50], but this route of administration is obviously in-

vasive.

Based on evidence that ketogenic strategies increase

adenosine in the central nervous system, they will also be

likely to alleviate pain, although research on this topic has

only begun [203]. The parallels between ketogenic diets and

adenosine A1 receptor activation include their efficacy in

pharmocoresistant epilepsy, and neuronal inhibition via anti-

convulsants appears to be one mechanism for alleviating at

least a subset of neuropathic pain. We suggest that adeno-

sine-mediated central nervous system inhibition via meta-

bolic strategies such as ketogenic diet therapy will be effec-

tive against neuropathic pain.

Beyond these possible effects on the neural substrates of

pain generally, a ketogenic metabolism may have beneficial

effects with inflammatory pain by reducing inflammation

itself through several mechanisms. 1) adenosine A1 receptors

have been shown to be anti-inflammatory in a number of

tissues, including brain [68, 110, 183, 185]. 2) Compared to

glycolytic metabolism, ketolytic metabolism produces fewer

reactive oxygen species, which are known to contribute to

inflammation [81, 117, 187]; 3) the long-chain polyunsatu-

rated fatty acids in the ketogenic diet activate peroxisome

proliferator-activated receptors, an effect which will reduce

inflammation by inhibiting nuclear factor κB and other pro-

inflammatory pathways [13, 32, 33, 115]. Altogether, multi-

ple consequences of ketone metabolism, including increased

adenosine, appear to have much clinical promise as safe,

effective, non-addictive treatments for chronic neuropathic

and inflammatory pain conditions.

SUMMARY

Herein we highlight major implications of the emerging

relationship among adenosine, a ketogenic diet and epilepsy

and provide a broad and provocative overview of a subset of

the therapeutic predictions of this metabolic relationship.

The clinical implications discussed in detail are supported by

preliminary or historical data, or by infrequent publication in

disparate fields of research, and deserve further examination

and integration. An evidence–based metabolic treatment as

264 Current Neuropharmacology, 2009, Vol. 7, No. 3 Masino et al.

an adjuvant or alternate strategy is particularly attractive and

important as we seek cost-effective solutions for the diverse

conditions highlighted herein. Together these conditions

exact an enormous toll on health care and quality of life as

they are chronic, prevalent, increasing (particularly diabetes

and autism), and often comorbid (sleep disorders and epi-

lepsy, for example).

In the central nervous system, adenosine offers unparal-

leled yet untapped opportunities for seizure protection, neu-

roprotection, sleep, and pain relief, among others. Under-

standing the regulation of adenosine helps achieve these

long-standing clinical goals and extends beyond them to al-

leviating both acute and chronic conditions in adults and

children. In summary, the metabolic relationship among

adenosine, a ketogenic diet, and epilepsy could open major

new therapeutic applications and avoid peripheral side ef-

fects in a way that has eluded receptor-based strategies.

ACKNOWLEDGEMENTS

We acknowledge the support of NIH (NINDS), the Na-

tional Science Foundation and Trinity College.

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Effects of Ketogenic Diet on Increased Ethanol Consumption Induced by Social Stress in Female Mice

Article

Full-text available

Aug 2024

Stress is a critical factor in the development of mental disorders such as addiction, underscoring the importance of stress resilience strategies. While the ketogenic diet (KD) has shown efficacy in reducing alcohol consumption in male mice without cognitive impairment, its impact on the stress response and addiction development, especially in females, remains unclear. This study examined the KD’s effect on increasing ethanol intake due to vicarious social defeat (VSD) in female mice. Sixty-four female OF1 mice were divided into two dietary groups: standard diet (n = 32) and KD (n = 32). These were further split based on exposure to four VSD or exploration sessions, creating four groups: EXP-STD (n = 16), VSD-STD (n = 16), EXP-KD (n = 16), and VSD-KD (n = 16). KD-fed mice maintained ketosis from adolescence until the fourth VSD/EXP session, after which they switched to a standard diet. The Social Interaction Test was performed 24 h after the last VSD session. Three weeks post-VSD, the Drinking in the Dark test and Oral Ethanol Self-Administration assessed ethanol consumption. The results showed that the KD blocked the increase in ethanol consumption induced by VSD in females. Moreover, among other changes, the KD increased the expression of the ADORA1 and CNR1 genes, which are associated with mechanisms modulating neurotransmission. Our results point to the KD as a useful tool to increase resilience to social stress in female mice.

Effects of Ketogenic Diet on Increased Ethanol Consumption Induced by Social Stress in Female Mice

Preprint

Full-text available

Jul 2024

Stress is a critical factor in the development of mental disorders such as addiction, underscoring the importance of stress resilience strategies. While the ketogenic diet (KD) has shown efficacy in reducing alcohol consumption in male mice without cognitive impairment, its impact on the stress response and addiction development, especially in females, remains unclear. This study examined the KD's effect on increasing ethanol intake due to vicarious social defeat (VSD) in female mice. Sixty-four female OF1 mice were divided into two dietary groups: standard diet (n=32) and KD (n=32). These were further split based on exposure to four VSD or exploration sessions, creating four groups: EXP-STD (n=16), VSD-STD (n=16), EXP-KD (n=16), and VSD-KD (n=16). KD-fed mice maintained ketosis from adolescence until the fourth VSD/EXP session, after which they switched to a standard diet. The Social Interaction Test was performed 24 hours after the last VSD session. Three weeks post-VSD, the Drinking in the Dark test and Oral Ethanol Self-Administration assessed ethanol consumption. The results showed that KD blocked the increase in ethanol consumption induced by VSD in females. Moreover, among other changes, KD increased the expression of the ADORA1 and CNR1 genes, which are associated with mechanisms modulating neurotransmission. Our results pointed to KD as a useful tool to increase resilience to social stress in female mice.

Unveiling the epigenetic impact of vegan vs. omnivorous diets on aging: insights from the Twins Nutrition Study (TwiNS)

Article

Full-text available

Jul 2024
BMC MED

Background Geroscience focuses on interventions to mitigate molecular changes associated with aging. Lifestyle modifications, medications, and social factors influence the aging process, yet the complex molecular mechanisms require an in-depth exploration of the epigenetic landscape. The specific epigenetic clock and predictor effects of a vegan diet, compared to an omnivorous diet, remain underexplored despite potential impacts on aging-related outcomes. Methods This study examined the impact of an entirely plant-based or healthy omnivorous diet over 8 weeks on blood DNA methylation in paired twins. Various measures of epigenetic age acceleration (PC GrimAge, PC PhenoAge, DunedinPACE) were assessed, along with system-specific effects (Inflammation, Heart, Hormone, Liver, and Metabolic). Methylation surrogates of clinical, metabolite, and protein markers were analyzed to observe diet-specific shifts. Results Distinct responses were observed, with the vegan cohort exhibiting significant decreases in overall epigenetic age acceleration, aligning with anti-aging effects of plant-based diets. Diet-specific shifts were noted in the analysis of methylation surrogates, demonstrating the influence of diet on complex trait prediction through DNA methylation markers. An epigenome-wide analysis revealed differentially methylated loci specific to each diet, providing insights into the affected pathways. Conclusions This study suggests that a short-term vegan diet is associated with epigenetic age benefits and reduced calorie intake. The use of epigenetic biomarker proxies (EBPs) highlights their potential for assessing dietary impacts and facilitating personalized nutrition strategies for healthy aging. Future research should explore the long-term effects of vegan diets on epigenetic health and overall well-being, considering the importance of proper nutrient supplementation. Trial registration Clinicaltrials.gov identifier: NCT05297825

Complete remission of depression and anxiety using a ketogenic diet: case series

Article

Full-text available

May 2024

Background There is little data that describe the use of ketogenic metabolic therapy to achieve full remission of major depression and generalized anxiety disorder in clinical practice. We present a retrospective case series of three adults with major depression and generalized anxiety disorder with complex comorbidity, treated with personalized ketogenic metabolic therapy, who achieved complete remission of major depression and generalized anxiety disorder and improvements in flourishing, self-compassion, and metabolic health. Methods Three adults, ages 32–36, with major depression, generalized anxiety, other anxiety disorders, and comorbid psychiatric conditions were treated for 12–16 weeks with personalized whole food animal-based ketogenic metabolic therapy (1.5:1 ratio) in a specialized metabolic psychiatry practice. Interventions included twice-weekly visits with an experienced ketogenic registered dietitian; daily photo journaling and capillary blood BHB/glucose/GKI monitoring; virtual groups; family/friends support; nature walks and talks several times per week, and community building. Successful adoption of the ketogenic diet was defined as the achievement and maintenance of capillary BHB ≥ 0.8 mmol/L and GKI < 6. Remission was assessed by GAD-7 and PHQ-9, and quality of life was assessed subjectively and with validated scales for flourishing and self-compassion. Metabolic health was assessed by laboratories/biometric measures. Results Two patients achieved remission of major depression (PHQ-9 ≤ 4) and generalized anxiety (GAD-7 ≤ 4) within 7 weeks of therapeutic nutritional ketosis; one required 12 weeks. Anxiety responded and remitted more quickly than major depression. Flourishing and self-compassion increased steadily. Patients lost 10.9 to 14.8% of their initial body weight within 12 weeks and improved metabolically; one achieved optimal metabolic health. Conclusion Complete remission of major depression and generalized anxiety disorder occurred within 7–12 weeks of therapeutic nutritional ketosis during treatment with a personalized animal-based ketogenic diet (ratio 1.5:1) in adults with complex comorbid depression and anxiety engaged in a specialized metabolic psychiatry program.

The effects of 15-day complete fasting on the attentional network: An ERP study

Article

Nov 2024
BRAIN RES

Signals of energy availability in sleep: consequences of a fat-based metabolism

Article

Full-text available

Aug 2024

L. Amber O'Hearn

Humans can flexibly switch between two primary metabolic modes, usually distinguished by whether substrate supply from glucose can meet energy demands or not. However, it is often overlooked that when glucose use is limited, the remainder of energy needs may still be met more or less effectively with fat and ketone bodies. Hence a fat-based metabolism marked by ketosis is often conflated with starvation and contexts of inadequate energy (including at the cellular level), even when energy itself is in ample supply. Sleep and satiation are regulated by common pathways reflecting energy metabolism. A conceptual analysis that distinguishes signals of inadequate energy in a glucose-dominant metabolism from signals of a fat-based metabolism that may well be energy sufficient allows a reexamination of experimental results in the study of sleep that may shed light on species differences and explain why ketogenic diets have beneficial effects simultaneously in the brain and the periphery. It may also help to distinguish clinically when a failure of a ketogenic diet to resolve symptoms is due to inadequate energy rather than the metabolic state itself.

Impact of a ketogenic diet on sleep quality in people with relapsing multiple sclerosis

Article

Aug 2024

Inflammation and oxidative stress in epileptic children: from molecular mechanisms to clinical application of ketogenic diet

Article

Feb 2024
REV NEUROSCI

Childhood epilepsy affects up to 1 % of children. It has been shown that 30 % of patients are resistant to drug treatments, making further investigation of other potential treatment strategies necessary. One such approach is the ketogenic diet (KD) showing promising results and potential benefits beyond the use of current antiepileptic drugs. This study aims to investigate the effects of KD on inflammation and oxidative stress, as one of the main suggested mechanisms of neuroprotection, in children with epilepsy. This narrative review was conducted using the Medline and Google Scholar databases, and by searching epilepsy, drug-resistant epilepsy, child, children, ketogenic, ketogenic diet, diet, ketogenic, keto, ketone bodies (BHB), PUFA, gut microbiota, inflammation, inflammation mediators, neurogenic inflammation, neuroinflammation, inflammatory marker, adenosine modulation, mitochondrial function, MTOR pathway, Nrf2 pathway, mitochondrial dysfunction, PPARɣ, oxidative stress, ROS/RNS, and stress oxidative as keywords. Compelling evidence underscores inflammation and oxidative stress as pivotal factors in epilepsy, even in cases with genetic origins. The ketogenic diet effectively addresses these factors by reducing ROS and RNS, enhancing antioxidant defenses, improving mitochondrial function, and regulating inflammatory genes. Additionally, KD curbs pro-inflammatory cytokine and chemokine production by dampening NF-κB activation, inhibiting the NLRP3 inflammasome, increasing brain adenosine levels, mTOR pathway inhibition, upregulating PPARɣ expression, and promoting a healthy gut microbiota while emphasizing the consumption of healthy fats. KD could be considered a promising therapeutic intervention in patients with epilepsy particularly in drug-resistant epilepsy cases, due to its targeted approach addressing oxidative stress and inflammatory mechanisms.

Defining ketone supplementation: the evolving evidence for post-exercise ketone supplementation to improve recovery and adaptation to exercise

Article

Full-text available

Nov 2023
AM J PHYSIOL-CELL PH

Over the last decade, there has been a growing interest in the use of ketone supplements to improve athletic performance. These ketone supplements transiently elevate the concentrations of the ketone bodies acetoacetate (AcAc) and D-β-hydroxybutyrate (βHB) in the circulation. Early studies showed that ketone bodies can improve energetic efficiency in striated muscle compared to glucose oxidation and induce a glycogen-sparing effect during exercise. As such, most research has focused on the potential of ketone supplementation to improve athletic performance via ingestion of ketones immediately before or during exercise. However, subsequent studies generally observed no performance improvement, and particularly not under conditions that are relevant for most athletes. However, more and more studies are reporting beneficial effects when ketones are ingested after exercise. As such, the real potential of ketone supplementation may rather be in their ability to enhance post-exercise recovery and training adaptations. For instance, recent studies observed that post-exercise ketone supplementation (PEKS) blunts the development of overtraining symptoms, and improves sleep, muscle anabolic signaling, circulating erythropoietin levels, and skeletal muscle angiogenesis. In this review, we provide an overview of the current state-of-the-art about the impact of PEKS on aspects of exercise recovery and training adaptation, which is not only relevant for athletes but also in multiple clinical conditions. In addition, we highlight the underlying mechanisms by which PEKS may improve exercise recovery and training adaptation. This includes epigenetic effects, signaling via receptors, modulation of neurotransmitters, energy metabolism, and oxidative and anti-inflammatory pathways.

Environmental interventions reduced repetitive behavior in a mouse model

Article

Oct 2023
PHYSIOL BEHAV

Altered Lipid Metabolism in Brain Injury and Disorders

Article

Full-text available

Feb 2008
Subcell Biochem

Deregulated lipid metabolism may be of particular importance for CNS injuries and disorders, as this organ has the highest lipid concentration next to adipose tissue. Atherosclerosis (a risk factor for ischemic stroke) results from accumulation of LDL-derived lipids in the arterial wall. Pro-inflammatory cytokines (TNF-alpha and IL-1), secretory phospholipase A(2) IIA and lipoprotein-PLA(2) are implicated in vascular inflammation. These inflammatory responses promote atherosclerotic plaques, formation and release of the blood clot that can induce ischemic stroke. TNF-alpha and IL-1 alter lipid metabolism and stimulate production of eicosanoids, ceramide, and reactive oxygen species that potentiate CNS injuries and certain neurological disorders. Cholesterol is an important regulator of lipid organization and the precursor for neurosteroid biosynthesis. Low levels of neurosteroids were related to poor outcome in many brain pathologies. Apolipoprotein E is the principal cholesterol carrier protein in the brain, and the gene encoding the variant Apolipoprotein E4 is a significant risk factor for Alzheimer's disease. Parkinson's disease is to some degree caused by lipid peroxidation due to phospholipases activation. Niemann-Pick diseases A and B are due to acidic sphingomyelinase deficiency, resulting in sphingomyelin accumulation, while Niemann-Pick disease C is due to mutations in either the NPC1 or NPC2 genes, resulting in defective cholesterol transport and cholesterol accumulation. Multiple sclerosis is an autoimmune inflammatory demyelinating condition of the CNS. Inhibiting phospholipase A(2) attenuated the onset and progression of experimental autoimmune encephalomyelitis. The endocannabinoid system is hypoactive in Huntington's disease. Ethyl-eicosapetaenoate showed promise in clinical trials. Amyotrophic lateral sclerosis causes loss of motorneurons. Cyclooxygenase-2 inhibition reduced spinal neurodegeneration in amyotrophic lateral sclerosis transgenic mice. Eicosapentaenoic acid supplementation provided improvement in schizophrenia patients, while the combination of (eicosapentaenoic acid + docosahexaenoic acid) provided benefit in bipolar disorders. The ketogenic diet where >90% of calories are derived from fat is an effective treatment for epilepsy. Understanding cytokine-induced changes in lipid metabolism will promote novel concepts and steer towards bench-to-bedside transition for therapies.

A laboratory study of sleep in Asperger's syndrome

Article

Full-text available

Jan 2000

Asperger's syndrome (AS) is a pervasive developmental disorder that may fall along the autistic spectrum. We compared the sleep of eight patients with AS with that of participants matched for age and gender. Patients with AS showed decreased sleep rime in the first two-thirds of the night, increased number of shifts into REM sleep from a waking epoch, and all but one patient showed signs of REM sleep disruption. EEG sleep spindles were significantly decreased while K complexes and REM sleep rapid eye movements were normal. Three patients with AS, but none of the comparison participants, showed a pathological index of periodic leg movements in sleep. These observations show that sleep disorders are associated with AS and suggest that defective sleep control systems may be associated with the clinical picture of AS. NeuroReport 11:127-130 (C) 2000 Lippincott Williams & Wilkins.

Temporal and mechanistic dissociation of ATP and adenosine during ischemia in the mammalian hippocampus

Article

Full-text available

Jun 2007
J NEUROCHEM

Adenosine is well known to be released during cerebral metabolic stress and is believed to be neuroprotective. ATP release under similar circumstances has been much less studied. We have now used biosensors to measure and compare in real time the release of ATP and adenosine during in vitro ischaemia in hippocampal slices. ATP release only occurred following the anoxic depolarisation, whereas adenosine release was apparent almost immediately after the onset of ischaemia. ATP release required extracellular Ca2+. By contrast adenosine release was enhanced by removal of extracellular Ca2+, whilst TTX had no effect on either ATP release or adenosine release. Blockade of ionotropic glutamate receptors substantially enhanced ATP release, but had only a modest effect on adenosine release. Carbenoxolone, an inhibitor of gap junction hemichannels, also greatly enhanced ischaemic ATP release, but had little effect on adenosine release. The ecto-ATPase inhibitor ARL 67156, whilst modestly enhancing the ATP signal detected during ischaemia, had no effect on adenosine release. Adenosine release during ischaemia was reduced by pre-treament with homosysteine thiolactone suggesting an intracellular origin. Adenosine transport inhibitors did not inhibit adenosine release, but instead they caused a twofold increase of release. Our data suggest that ATP and adenosine release during ischaemia are for the most part independent processes with distinct underlying mechanisms. These two purines will consequently confer temporally distinct influences on neuronal and glial function in the ischaemic brain.

The effect of ketonemia on the course of epilepsy

Article

Jan 1921

R. M. Wilder

Epilepsy in adults: Results of treatment by ketogenic diet in one hundred cases

Article

Jan 1930
Arch Neurol

C.J. Barborka

The fact that hypotheses and methods of treatment for epilepsy are constantly changing, each as it is advanced being tried and found wanting, causes a healthy disbelief in any new form of treatment. Time alone will supply substantial reasons for altering what may be termed the traditional treatment for epilepsy. The use of diets high in fat and extremely low in carbohydrate in the treatment for idiopathic epilepsy was first suggested by Wilder¹ as a possible substitute for the fasting regimen which had previously been shown by Guelpa and Marie² and by Geyelin³ to influence seizures in many cases. Wilder originally proposed the diet on the theory that aceto-acetic acid should behave pharmacologically as an anesthetic. In such an event, the diet might act only as a palliative measure similar to the action of phenobarbital, and the value of a regimen that necessitated so much effort and

Multi-center study of the efficacy of the ketogenic diet.

Article

Dec 1998

To determine the efficacy of the ketogenic diet in multiple centers. A prospective study of the change in frequency of seizures in 51 children with intractable seizures who were treated with the ketogenic diet. Patients were enrolled from the clinical practices of 7 sites. The diet was initiated in-hospital and the patients were followed up for at least 6 months. Fifty-one children, aged 1 to 8 years, with more than 10 seizures per week, whose electroencephalogram showed generalized epileptiform abnormalities or multifocal spikes, and who had failed results when taking at least 2 appropriate anti-epileptic drugs. The children were hospitalized, fasted, and a 4:1 ketogenic diet was initiated and maintained. Frequency of seizures was documented from parental calendars and efficacy was compared with prediet baseline after 3, 6, and 12 months. The children were categorized as free of seizures, greater than 90% reduction, 50% to 90% reduction, or lower than 50% reduction in frequency of seizures. Eighty-eight percent of all children initiating the diet remained on it at 3 months, 69% remained on it at 6 months, and 47% remained on it at 1 year. Three months after initiating the diet, frequency of seizures was decreased to greater than 50% in 54%. At 6 months, 28 (55%) of the 51 initiating the diet had at least a 50% decrease from baseline, and at 1 year, 40% of those starting the diet had a greater than 50% decrease in seizures. Five patients (10%) were free of seizures at 1 year. Age, sex, principal seizure type, and electroencephalogram were not statistically related to outcome. The ketogenic diet is effective in substantially decreasing difficult-to-control seizures and can successfully be administered in a wide variety of settings.

Emergence: Labeled Autistic

Article

Feb 2014

Melissa Hough

Adenosine and the concept of ‘retaliatory metabolites’

Article

Feb 1984
TRENDS BIOCHEM SCI

Andrew C Newby

Adenosine can modulate a bewildering array of physiological processes including vascular tone, hormone action, neural function, platelet aggregation and lymphocyte differentiation. To explain this diversity, it has been proposed that adenosine is a hormone or a hormone second messenger. However, its unique mechanism of formation suggests instead that adenosine is a new type of cellular regulator for which the term ‘retaliatory metabolite’ is proposed.

Autoradiographic localization of adenosine receptors in rat brain using [3H]cyclohexyladenosine

Article

Jan 1982
NEUROSCIENCE

Adenosine (A1) receptor binding sites have been localized in rat brain by an in vitro light microscopic autoradiographic method. The binding of [3H]N6-cyclohexyladenosine to slide-mounted rat brain tissue sections has the characteristics of A1 receptors. It is saturable with high affinity and has appropriate pharmacology and stereospecificity. The highest densities of adenosine receptors occur in the molecular layer of the cerebellum, the molecular and polymorphic layers of the hippocampus and dentate gyrus, the medial geniculate body, certain thalamic nucleus, and the lateral septum. High densities also are observed in certain layers of the cerebral cortex, the piriform cortex, the caudate-putamen, the nucleus accumbens, and the granule cell layer of the cerebellum. Most white matter areas, as well as certain gray matter areas, such as the hypothalamus, have negligible receptor concentrations. These localizations suggest possible central nervous system sites of action of adenosine.

Direct measurement of adenosine release during hypoxia in the CA1 region of the rat hippocampal slice

Article

Aug 2004
J PHYSIOL-LONDON

• We have used an enzyme-based, twin-barrelled sensor to measure adenosine release during hypoxia in the CA1 region of rat hippocampal slices in conjunction with simultaneous extracellular field recordings of excitatory synaptic transmission. • When loaded with a combination of adenosine deaminase, nucleoside phosphorylase and xanthine oxidase, the sensor responded linearly to exogenous adenosine over the concentration range 10 nM to 20 M. • Without enzymes, the sensor when placed on the surface of hippocampal slices recorded a very small net signal during hypoxia of 40 ± 43 pA (mean ±s.e.m.; n= 7 ). Only when one barrel was loaded with the complete sequence of enzymes and the other with the last two in the cascade did the sensor record a large net difference signal during hypoxia (1226 ± 423 pA; n= 7 ). • This signal increased progressively during the hypoxic episode, scaled with the hypoxic depression of the simultaneously recorded field excitatory postsynaptic potential and was greatly reduced (67 ± 6.5 %; n= 9 ) by coformycin (0.5-2 M), a selective inhibitor of adenosine deaminase, the first enzyme in the enzymic cascade within the sensor. • For 5 min hypoxic episodes, the sensor recorded a peak concentration of adenosine of 5.6 ± 1.2 M ( n= 16 ) with an IC50 for the depression of transmission of approximately 3 M. • In slices pre-incubated for 3-6 h in nominally Ca2+-free artificial cerebrospinal fluid, 5 min of hypoxia resulted in an approximately 9-fold greater release of adenosine (48.9 ± 17.7 M; n= 6 ). • High extracellular Ca2+ (4 mM) both reduced the adenosine signal recorded by the sensor during hypoxia (3.5 ± 0.6 M; n = 4) and delayed the hypoxic depression of excitatory synaptic transmission.

Adenosine, Ketogenic Diet and Epilepsy: The Emerging Therapeutic Relationship Between Metabolism and Brain Activity

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