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 - PubMed (original) (raw)
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
Wei Zhao et al. PLoS One. 2012.
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.
Conflict of interest statement
Competing Interests: The authors have declared that no competing interests exist.
Figures
Figure 1. Caprylic triglyceride is well tolerated and attenuated ALS-type motor impairment in SOD1-G93A mouse model.
(A) Average body weight in wild type (WT) animals (n = 6–7 per group); (B) Motor function as assessed by rotarod test in WT animals (n = 5–7 per group); (C) Average body weight in SOD1-G93A (ALS) animals (n = 17–18 per group); (D) Motor function as assessed by rotarod test in SOD1-G93A animals (n = 13–14 per group). Arrows indicate where the caprylic triglyceride group showed improved motor function as compared to the control by two way ANOVA analysis, F = 6.56, p = 0.01 followed by Bonferroni post-test, *p<0.05. All data are mean ± SEM.
Figure 2. Effect of Caprylic triglyceride on food intake and lifespan of SOD1-G93A animals.
(A) Food intake in SOD1-G93A animals treated with caprylic triglyceride (n = 18) or an isocaloric control diet (n = 17); (B) Mice in the two treatment groups (n = 11) were monitored daily and survival curve was plotted in GraphPad Prism.
Figure 3. Glucose tolerance, ketone, triglyceride and corticosterone levels following caprylic triglyceride treatment.
(A) Fasting serum glucose level and (B) glucose tolerance test in SOD1-G93A animals on control or caprylic triglyceride; (C) Blood ketone level at pre-symptomatic (10 weeks) or post-symptomatic (17 weeks) stage; (D) Plasma total triglyceride levels. (E) Plasma corticosterone level. All data are mean ± SEM, n = 4–5 for (A, B), n = 5 for (C) and n = 6–7 for (D, E) *p<0.05 by two-tailed t-test).
Figure 4. Nissl-stained motor neuron count in the lumbar spinal cord.
(A) Representative photomicrographs of Nissl-stained sections at the ventral horn area of the lumbar spinal cord; (B) Motor neuron counts. Data are mean ± SEM, n = 3–4 per group, *p<0.05 by two-tailed t-test.
Figure 5. Mitochondrial bioenergetic profile in the spinal cord of WT and SOD1 G93A mice on control or caprylic triglyceride diet.
Mitochondria were isolated by differential centrifugation from the whole spinal cord of SOD1-G93A mice on control or caprylic triglyceride diet and oxygen consumption rates were analyzed using Seahorse XF24 extracellular flux analyzer. (A) A representative trace of OCR in the presence of pyruvate and malate. Adenosine diphosphate (ADP), oligomycin (O), carbonyl cyanide 4-(trifluoromethoxy)phenylhydrazone (FCCP) and a mixture of rotenone, antimycin A, N,N,N’,N’-tetramethylphenylenediamine and ascorbate (RATA) were injected at the indicated time points to measure basal, state 3, state 4o, maximal and complex IV OCR as indicated. OCR in the presence of pyruvate and malate in (B) SOD1-G93A (ALS) and (D) wild type (WT) mice. (C) Spare respiratory capacity of mitochondria from WT and ALS mice on control or caprylic triglyceride diet. Data are mean ± SEM, n = 3 for all groups, *p<0.05 as compared to control by two-tailed student t-test.
References
- Strong M, Rosenfeld J (2003) Amyotrophic lateral sclerosis: A review of current concepts. Amyotrophic Lateral Sclerosis and Other Motor Neuron Disorders 4: 136–143. - PubMed
- Bruijn LI, Miller TM, Cleveland DW (2004) Unraveling the mechanisms involved in motor neuron degeneration in ALS. Annual Review of Neuroscience 27: 723–749. - PubMed
- Cleveland DW, Rothstein JD (2001) From Charcot to Lou Gehrig: Deciphering selective motor neuron death in ALS. Nature Reviews Neuroscience 2: 806–819. - PubMed
- Rosen DR, Siddique T, Patterson D, Figlewicz DA, Sapp P, et al. (1993) Mutations in Cu/Zn Superoxide-Dismutase Gene Are Associated with Familial Amyotrophic-Lateral-Sclerosis. Nature 362: 59–62. - PubMed
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