Depression is a major health problem worldwide. Most prescribed antidepressants, the selective serotonin reuptake inhibitors (SSRI) show limited efficacy and delayed onset of action, partly due to the activation of somatodendritic 5-HT 1A -autoreceptors by the excess extracellular serotonin (5-HT) produced by SSRI in the raphe nuclei. Interestingly, intranasal C-1A-siRNA administration produced the same effects, thus opening the way to the therapeutic use of C-1A-siRNA. Hence, C-1A-siRNA represents a new approach to treat mood disorders, as monotherapy or in combination with SSRI.3

Diets containing a high proportion of fat with respect to protein plus carbohydrates are capable of inducing ketone body production in the liver, which provides an energetic alternative to glucose. Some ketogenic diets have been tested as therapeutic strategies for treating metabolic disorders related to a deficiency in glucose-driven ATP generation. However, ketone bodies are not capable of providing extra tricarboxylic acid cycle intermediates, limiting the anabolic capacity of the cell. Therefore, it is reasonable to hypothesize that supplementing a ketogenic diet with anaplerotic compounds such as triheptanoin may improve ketogenic diet effectiveness. The present study tests this hypothesis in APP/PS1 (APPswe/PS1dE9) transgenic mice, used as a model of familial Alzheimer's disease because impaired energy supply to neurons has been linked to this neurodegenerative process. Triheptanoin supplementation to a ketogenic diet for three months and starting at the age of three months reduces the memory impairment of APP/PS1 mice at the age of 6 months. The Aβ production and deposition were not significantly altered by the ketogenic diet, supplemented or not by triheptanoin. However, mice fed with triheptanoin-rich ketogenic diet have shown decreased astroglial response in the vicinity of Aβ plaques and decreased expression of the pro-inflammatory cytokine interferon-γ in astrocytes. These findings correlate with transcriptional up-regulation of the ROS detoxifying mechanisms Sirt1 and Pparg, thus linking triheptanoin with improved mitochondrial status. Present findings support the concept that ketogenic diets supplemented with anaplerotic compounds can be considered potential therapeutic strategies at early stages of Alzheimer's disease.

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Whole body cytosolic phosphoenolpyruvate carboxykinase knockout (PEPCK-C KO) mice die early after birth with profound hypoglycemia therefore masking the role of PEPCK-C in adult, non-gluconeogenic tissues where it is expressed. To investigate whether PEPCK-C deletion in the liver was critically responsible for the hypoglycemic phenotype, we reexpress this enzyme in the liver of PEPCK-C KO pups by early postnatal administration of PEPCK-C-expressing adenovirus. This maneuver was sufficient to partially rescue hypoglycemia and allow the pups to survive and identifies the liver as a critical organ, and hypoglycemia as the critical pathomechanism, leading to early postnatal death in the whole-body PEPCK-C knockout mice. Pathology assessment of survivors also suggest a possible role for PEPCK-C in lung maturation and muscle metabolism.

SummaryTriheptanoin enriched diets have been successfully used in the experimental treatment of various metabolic disorders. Maximal therapeutic effect is achieved in the context of a ketogenic diet where triheptanoin oil provides 30-40% of daily caloric intake. However, studies using triheptanoin-rich diets in the pre-clinical setting are hindered by the difficulty to administer to lab animals as a solid foodstuff. In the present study, we have successfully synthesized triheptanoin to the highest standards of purity from glycerol and heptanoic acid, using sulfonated charcoal, previously studied in esterification reactions by Yurui and Prager (Aust. J. Chem. 1989Chem. , 42, 1003Chem. -1005, as a catalyst. Then, triheptanoin oil was formulated as a solid, stable and palatable diet using a ketogenic base and a combination of four commercially available formulation agents; hydrophilic fumed silica, hydrophobic fumed silica, microcrystalline cellulose and talc.Diet compliance and safety was tested on C57Bl/6 mice over a 15-week period, comparing overall status and body weight change.Formulation of Solid Triheptanoin-Rich Ketogenic Diet for Rodents. 3 Practical applicationsThis work provides a complete description of, (i) an effective and cost-effective synthesis of triheptanoin and, (ii) the formulation of a solid, stable and palatable triheptanoin-rich (39% of caloric intake) ketogenic diet for rodents. Rodent triheptanoin-rich diets have practical applications in pre-clinical screening of the therapeutic efficacy of triheptanoin in different rodent models of human diseases. On the other hand, using the same solidification procedure, other oils could be incorporated into rodent ketogenic diet to study its high dose/long term effect on mammal health and development. This approach could be extremely valuable as ketogenic diet is widely used clinically for epilepsy treatment.