Caprylic Triglyceride as a Novel Therapeutic Approach to Effectively Improve the Performance and Attenuate the Symptoms Due to the Motor Neuron Loss in ALS Disease

Abstract

Amyotrophic lateral sclerosis (ALS) is a neurodegenerative disorder of motor neurons causing progressive muscle weakness, paralysis, and finally death. ALS patients suffer from asthenia and their progressive weakness negatively impacts quality of life, limiting their daily activities. They have impaired energy balance linked to lower activity of mitochondrial electron transport chain enzymes in ALS spinal cord, suggesting that improving mitochondrial function may present a therapeutic approach for ALS. When fed a ketogenic diet, the G93A ALS mouse shows a significant increase in serum ketones as well as a significantly slower progression of weakness and lower mortality rate. In this study, we treated SOD1-G93A mice with caprylic triglyceride, a medium chain triglyceride that is metabolized into ketone bodies and can serve as an alternate energy substrate for neuronal metabolism. Treatment with caprylic triglyceride attenuated progression of weakness and protected spinal cord motor neuron loss in SOD1-G93A transgenic animals, significantly improving their performance even though there was no significant benefit regarding the survival of the ALS transgenic animals. We found that caprylic triglyceride significantly promoted the mitochondrial oxygen consumption rate in vivo. Our results demonstrated that caprylic triglyceride alleviates ALS-type motor impairment through restoration of energy metabolism in SOD1-G93A ALS mice, especially during the overt stage of the disease. These data indicate the feasibility of using caprylic acid as an easily administered treatment with a high impact on the quality of life of ALS patients.

“Preconditioning” with latrepirdine, an adenosine 5′-monophosphate-activated protein kinase activator, delays amyotrophic lateral sclerosis progression in SOD1G93A mice

“…A prophylactic treatment with a high ketogenic diet in SOD1 mice increased energy production in mitochondria and showed a significant increase in motor neuron survival and decreased weight loss (Zhao et al 2006). Moreover, caprylic triglyceride attenuated ALS motor function deficits in SOD1 G93A mice by significantly enhancing the mitochondrial oxygen uptake (Zhao et al 2012). A high-energy diet increased survival in SOD1 G86R mice by 20% (Depuis et al 2004).…”

Sirtuins as therapeutic targets of ALS

“…This defect in energy metabolism has been linked to lower activities of mitochondrial electron transport chain enzymes in ALS spinal cord [5], and improving mitochondrial function may represent a therapeutic approach for ALS. Our recent findings suggest that medium chain triglyceride (MCT) treatment could lead to an increased blood ketone level, protect motor neuron loss and attenuate ALS-type motor impairment, possibly through promoting oxygen consumption rate [6]. Altered sirtuin levels have been observed in both SOD1-G93A mouse models [7] and patient tissue [8], suggesting that the sirtuin family may be a disease target both in ALS mouse models and humans.…”

Ketosis as a treatment for multiple metabolic and neurodegenerative pathologies

“…Transgenic animal models of neurodegenerative diseases showed positive outcomes induced by ketogenic diet. Increased motor neuron number was reported in ALS transgenic models in response to ketosis (Zhao et al 2006;Zhao et al 2012), reduced lesion volume was described after TBI [50], increased cell survival and decreased seizure frequency in kainate-induced seizure models were observed [51] and suppressed inflammatory cytokines and chemokines in an experimental model of multiple sclerosis was reported [52].…”