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SUMMARY:From Bench to Patients\; Decanoic/Octanoic Acid &amp\; Brain Energ
 y Metabolism - Professor Simon Heales | University College London 
DTSTART:20230913T140000Z
DTEND:20230913T150000Z
UID:TALK194446@talks.cam.ac.uk
CONTACT:Lisa Arnold
DESCRIPTION:Ketogenic diets\, as a treatment for patients with epilepsy ha
 ve been known for a considerable period.  Whilst effective\, in particular
  for patients with pharmacoreistant epilepsy\, compliance is an issue.  Fu
 rthermore\, despite many years of use\, the mechanism whereby the diet exe
 rts its beneficial effects is not known. With this in mind\, we set about 
 to characterise biochemical changes in response to exposure to octanoic (C
 8) and/or decanoic (C10) acid\, key components of the medium chain triglyc
 eride form of the diet.  As compromised energy metabolism\, including loss
  of mitochondrial function\, is reported to be associated with seizures th
 is became the focus of our study. Using a neuronal cell line (SHSY5Y cells
 )\, C10 (250µM) but not C8 (250µM) was found to increase activities of c
 itrate synthase and complex I\, mitochondrial membrane potential and mitoc
 hondrial DNA content.  Activation of PPARɤ\, via C10\, was proposed to be
  the mechanism for these changes. In addition to these findings\, C10\, in
  contrast to C8\, was found to be dependent upon the carnitine shuttle for
  oxidation.  As the carnitine shuttle may be relatively poorly expressed i
 n the brain\, this could lead to accumulation of C10.  With regards to thi
 s\, co incubation of C8 (20%) with C10 (80%) further slowed the oxidation 
 of C10. This sparing effect\, by C8\, upon C10 may permit its gradual accu
 mulation therefore also enabling it to act as fuel reserve.  Extending our
  studies to the Dravet mouse model\, our findings\, in vitro\, were replic
 ated in the brain of these animals.  Furthermore\, the 80:20 (C10:C8) rati
 o was found to provide superior seizure control and greater brain C10 accu
 mulation compared to conventional fatty acid ratios. Consideration of thes
 e findings permitted a feasibility trial to proceed for patients with drug
  resistant epilepsy.  This trial\, which allowed a relatively liberal diet
 \, used a formulation (K-Vita) consisting of 80% C10 and 20% C8 and had a 
 paediatric and adult arm.  Data form the study revealed an overall 50% red
 uction in seizures. In contrast to traditional diets\, there was no eviden
 ce of ketosis.  However\, both plasma C10 and C8 were elevated.  K-Vita ha
 s now received approval as a food for special medical purposes in adults a
 nd children.\n
LOCATION:MRC MBU\, Level 7 Lecture Theatre\, The Keith Peters Building\, C
 B2 0XY
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