Seizure control by decanoic acid through direct AMPA receptor inhibition

Chang, Pishan; Augustin, Katrin; Boddum, Kim; Williams, Sarah; Sun, Min; Terschak, John A.; Hardege, Jörg D.; Chen, Philip E.; Walker, Matthew C.; Williams, Robin S. B.

doi:10.1093/brain/awv325

Cited by 185 publications

(200 citation statements)

References 62 publications

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“…Existing data, including those generated from our own laboratory, suggest concentrations of up to 250µM C10 are required to facilitate an increase in mitochondrial biogenesis, increased antioxidant capacity and AMPA receptor inhibition 5,6,12 . However, such a concentration appears achievable, as oral administration of C10 to mice leads to brain concentrations of up to 250µM 9,10 .…”

Section: Discussionmentioning

confidence: 99%

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

et al. 2017

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No. of tables: 1 2 SUMMARY Objective: The medium chain triglyceride ketogenic diet contains both octanoic (C8) and decanoic (C10) acids. The diet is an effective treatment for pharmacoresistant epilepsy. Whilst the exact mechanism for its efficacy is not known, it is emerging that C10, but not C8, interacts with targets that can explain anti-seizure effects, e.g. peroxisome proliferator-activated receptor-γ (PPARγ) (eliciting mitochondrial biogenesis and increased antioxidant status) and the α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptor. For such effects to occur, significant concentrations of C10 are likely to be required in the brain. Methods:In order to investigate how this might occur, we measured the β-oxidation rate of 13 C-labelled C8 and C10 in neuronal SH-SY5Y cells using isotope-ratio mass spectrometry. The effects of carnitine palmitoyl transferase I (CPT1) inhibition, with the CPT1 inhibitor etomoxir, on C8 and C10 β-oxidation were also investigated.Results: Both fatty acids were catabolised, as judged by 13 CO2 release. However, C10 was β-oxidised at a significantly lower rate; 20% of C8. This difference was explained by a clear dependence of C10 on CPT1 activity, which is low in neurons, whereas 66% of C8 β-oxidation was independent of CPT1. In addition, C10 β-oxidation was decreased further in the presence of C8.Significance: It is concluded that, since CPT1 is poorly expressed in the brain, C10 is relatively spared from β-oxidation and can accumulate. This is further facilitated by the presence of C8 in the MCT ketogenic diet, which has a sparing effect upon C10 β-oxidation.

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Section: Discussionmentioning

confidence: 99%

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

et al. 2017

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“…This type of fat is rapidly absorbed and metabolized to ketone bodies in the absence of dietary carbohydrate restriction (although downstream effects of this fat are difficult to disentangle from glucose metabolism [66,73]). Also, concerning seizures, evidence is mounting for medium-chain fatty acid actions apart from ketone body elevation [74,75]. More studies of medium-chain triglycerides and fatty acids and ketone body-augmenting treatments such as ketone esters are warranted in ASD patients and models.…”

Section: Discussionmentioning

confidence: 99%

Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse

Ruskin

Fortin

Bisnauth

et al. 2017

Physiology & Behavior

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The core symptoms of autism spectrum disorder are poorly treated with current medications. Symptoms of autism spectrum disorder are frequently comorbid with a diagnosis of epilepsy and vice versa. Medically-supervised ketogenic diets are remarkably effective nonpharmacological treatments for epilepsy, even in drug-refractory cases. There is accumulating evidence that supports the efficacy of ketogenic diets in treating the core symptoms of autism spectrum disorders in animal models as well as limited reports of benefits in patients. This study tests the behavioral effects of ketogenic diet feeding in the EL mouse, a model with behavioral characteristics of autism spectrum disorder and comorbid epilepsy. Male and female EL mice were fed control diet or one of two ketogenic diet formulas ad libitum starting at 5 weeks of age. Beginning at 8 weeks of age, diet protocols continued and performance of each group on tests of sociability and repetitive behavior was assessed. A ketogenic diet improved behavioral characteristics of autism spectrum disorder in a sex- and test-specific manner; ketogenic diet never worsened relevant behaviors. Ketogenic diet feeding improved multiple measures of sociability and reduced repetitive behavior in female mice, with limited effects in males. Additional experiments in female mice showed that a less strict, more clinically-relevant diet formula was equally effective in improving sociability and reducing repetitive behavior. Taken together these results add to the growing number of studies suggesting that ketogenic and related diets may provide significant relief from the core symptoms of autism spectrum disorder, and suggest that in some cases there may be increased efficacy in females.

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“…Thus, digitonin binding might help to trap GluA2 in a distinct closed state conformation. We hypothesize that the ATD-LBD interface represents a novel binding site for hydrophobic molecules with a possible therapeutic significance and may bind fatty acids that have recently been identified as novel AMPAR noncompetitive inhibitors 23,24 .…”

Section: Ion Channel Structurementioning

confidence: 99%

Channel opening and gating mechanism in AMPA-subtype glutamate receptors

Twomey

Yelshanskaya

Grassucci

et al. 2017

Nature

207

345

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Summary AMPA-subtype ionotropic glutamate receptors mediate fast excitatory neurotransmission throughout the central nervous system. Gated by the neurotransmitter glutamate, AMPA receptors are critical for synaptic strength and dysregulation of AMPA receptor-mediated signaling is linked to numerous neurological diseases. Here, we use cryo-electron microscopy to solve the structures of AMPA receptor-auxiliary subunit complexes in the apo, antagonist and agonist-bound states and elucidate the iris-like mechanism of ion channel opening. The ion channel selectivity filter is formed by the extended portions of the re-entrant M2 loops, while the helical portions of M2 contribute to extensive hydrophobic interfaces between AMPA receptor subunits in the ion channel. We show how the permeation pathway changes upon channel opening and identify conformational changes throughout the entire AMPA receptor that accompany activation and desensitization. Our findings provide a framework for understanding gating across the family of ionotropic glutamate receptors and the role of AMPA receptors in excitatory neurotransmission.

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Seizure control by decanoic acid through direct AMPA receptor inhibition

Cited by 185 publications

References 62 publications

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

Neuronal decanoic acid oxidation is markedly lower than that of octanoic acid: A mechanistic insight into the medium‐chain triglyceride ketogenic diet

Ketogenic diets improve behaviors associated with autism spectrum disorder in a sex-specific manner in the EL mouse

Channel opening and gating mechanism in AMPA-subtype glutamate receptors

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