Ketogenic diet in neuromuscular and neurodegenerative diseases

Abstract

An increasing number of data demonstrate the utility of ketogenic diets in a variety of metabolic diseases as obesity, metabolic syndrome, and diabetes. In regard to neurological disorders, ketogenic diet is recognized as an effective treatment for pharmacoresistant epilepsy but emerging data suggests that ketogenic diet could be also useful in amyotrophic lateral sclerosis, Alzheimer, Parkinson's disease, and some mitochondriopathies. Although these diseases have different pathogenesis and features, there are some common mechanisms that could explain the effects of ketogenic diets. These mechanisms are to provide an efficient source of energy for the treatment of certain types of neurodegenerative diseases characterized by focal brain hypometabolism; to decrease the oxidative damage associated with various kinds of metabolic stress; to increase the mitochondrial biogenesis pathways; and to take advantage of the capacity of ketones to bypass the defect in complex I activity implicated in some neurological diseases. These mechanisms will be discussed in this review.

Figure 1

Glucose is necessary not only to supply energy for the central nervous system but also to produce pyruvate that can be transformed into oxaloacetate. Oxaloacetate must be maintained at a level sufficient to allow citric acid cycle function (i.e., the condensation between acetyl-CoA and oxaloacetate). Oxaloacetate is unstable and must be refurnished (this kind of reactions is called anaplerotic). The main way to produce oxaloacetate is from pyruvate that derives from glucose. In mammals pyruvate cannot be produced from acetyl-CoA as shown in the figure.

Figure 2

A reduced availability of dietary carbohydrates leads to an increased liver production of KBs. The liver cannot utilize KBs because it lacks the mitochondrial enzyme succinyl-CoA: 3-ketoacid (oxoacid) CoA transferase (SCOT) necessary for activation of acetoacetate to acetoacetyl-CoA. KBs are utilized by tissues, in particular by brain. KBs enter the citric acid cycle after being converted to acetyl-CoA by succinyl-CoA: 3-CoA transferase (SCOT) and methylacetoacetyl-CoA thiolase (MAT).