Triheptanoin triglyseridi vähensi ALS-hiirillä motoneuronien tuhoutumista 33%

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ALStuttu:n jäsen
Tuoreen alustavan tutkimuksen mukaan triheptanoin-niminen triglyseridi vähensi ALS-hiirillä motoneuronien tuhoutumista 33%.


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https://alsnewstoday.com/ALS+May+be...ervention,+Therapeutic+Effect+of+Triheptanoin

Animal Study Suggests ALS Motor Neuron Loss May be Delayed with Triheptanoin

September 20, 2016

Teresa Pais, PhDby Teresa Pais, PhD

Because of increasing evidence of metabolic disturbances in amyotrophic lateral sclerosis patients, researchers at the University of Queensland tested whether ALS could be targeted at the metabolic level. Results indicate that by increasing energy sources with the triglyceride supplement triheptanoin, they could delay motor neuron loss in an animal model.

The study, titled “Triheptanoin Protects Motor Neurons and Delays the Onset of Motor Symptoms in a Mouse Model of Amyotrophic Lateral Sclerosis,” was published in the journal PlosOne.

In ALS patients, cells are unable to produce normal levels of energy due to defects in mitochondria, the main cellular production site of the energy-carrying molecule ATP. Both patients and animal models of ALS have shown abnormalities in the pathways leading to ATP production such as glucose uptake, glycolysis, TCA, and the electron transport chain.

Triheptanoin is a synthetic fat which is broken down in the liver into substances that can be used to generate energy. It is already being used as a dietary supplement by individuals enrolled in medical research studies about metabolic disorders.

In the current study, researchers gave either control or triheptanoin-containing diet treatments to pre-symptomatic animals in the same dose used to treat patients with metabolic disorders. They found that treated mice showed 33 percent less motor neuron loss in the spinal cord. The scientists suggest that triheptanoin’s neuroprotective effect is due to increased mitochondrial function and improved energy supply.
Additionally, triheptanoin improved motor symptoms such as grip strength and body balance. It also delayed loss of body weight. The effects could be due in part to increased expression of enzymes involved in muscle metabolism.

The study revealed that triheptanoin is a promising new treatment approach for ALS in order to delay motor neuron loss and the onset of motor symptoms. Still, the authors are aware that they will have to increase animal numbers and initiate treatment in symptomatic stages, which would be the case in ALS patients.
“Thus, while triheptanoin was given at a presymptomatic stage of disease in mice, it is difficult to correlate our findings to the clinical course of disease in patients. Given the difficulty in diagnosing ALS, future studies are required to evaluate the extent to which triheptanoin can preserve motor neurons and motor function when treatment is initiated in ALS models with obvious muscle and/or neuronal impairments,” the authors explained in the study report.


Varsinainen tutkimuspaperi:

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0161816

josta lyhennelmäosio:

Abstract

There is increasing evidence that energy metabolism is disturbed in Amyotrophic Lateral Sclerosis (ALS) patients and animal models. Treatment with triheptanoin, the triglyceride of heptanoate, is a promising approach to provide alternative fuel to improve oxidative phosphorylation and aid ATP generation. Heptanoate can be metabolized to propionyl-CoA, which after carboxylation can produce succinyl-CoA and thereby re-fill the tricarboxylic acid (TCA) cycle (anaplerosis). Here we tested the hypothesis that treatment with triheptanoin prevents motor neuron loss and delays the onset of disease symptoms in female mice overexpressing the mutant human SOD1G93A (hSOD1G93A) gene. When oral triheptanoin (35% of caloric content) was initiated at P35, motor neuron loss at 70 days of age was attenuated by 33%. In untreated hSOD1G93A mice, the loss of hind limb grip strength began at 16.7 weeks. Triheptanoin maintained hind limb grip strength for 2.8 weeks longer (p<0.01). Loss of balance on the rotarod and reduction of body weight were delayed by 13 and 11 days respectively (both p<0.01). Improved motor function occurred in parallel with alterations in the expression of genes associated with muscle metabolism. In gastrocnemius muscles, the mRNA levels of pyruvate, 2-oxoglutarate and succinate dehydrogenases and methyl-malonyl mutase were reduced by 24–33% in 10 week old hSOD1G93A mice when compared to wild-type mice, suggesting that TCA cycling in skeletal muscle may be slowed in this ALS mouse model at a stage when muscle strength is still normal. At 25 weeks of age, mRNA levels of succinate dehydrogenases, glutamic pyruvic transaminase 2 and the propionyl carboxylase β subunit were reduced by 69–84% in control, but not in triheptanoin treated hSOD1G93A animals. Taken together, our results suggest that triheptanoin slows motor neuron loss and the onset of motor symptoms in ALS mice by improving TCA cycling.

Wikipedia
https://en.wikipedia.org/wiki/Triheptanoin :

"Triheptanoin is a triglyceride that is composed of three seven-carbon fatty acids. These odd-carbon fatty acids are able to provide anaplerotic substrates for the TCA cycle. Triheptanoin is used clinically in humans to treat inherited metabolic diseases, such as pyruvate carboxylase deficiency and carnitine palmitoyltransferase II deficiency. It also appears to increase the efficacy of the ketogenic diet as a treatment for epilepsy.
Since triheptanoin is composed of odd-carbon fatty acids, it can produce ketone bodies with five carbon atoms, as opposed to even-carbon fatty acids which are metabolized to ketone bodies with four carbon atoms. The five-carbon ketones produced from triheptanoin are beta-ketopentanoate and beta-hydroxypentanoate. Each of these ketone bodies easily crosses the blood–brain barrier and enters the brain."
 
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