The Nervous System and Metabolic Dysregulation: Emerging Evidence Converges on Ketogenic Diet Therapy

Abstract

A link between metabolism and brain function is clear. Since ancient times, epileptic seizures were noted as treatable with fasting, and historical observations of the therapeutic benefits of fasting on epilepsy were confirmed nearly 100 years ago. Shortly thereafter a high fat, low-carbohydrate ketogenic diet (KD) debuted as a therapy to reduce seizures. This strict regimen could mimic the metabolic effects of fasting while allowing adequate caloric intake for ongoing energy demands. Today, KD therapy, which forces predominantly ketone-based rather than glucose-based metabolism, is now well-established as highly successful in reducing seizures. Cellular metabolic dysfunction in the nervous system has been recognized as existing side-by-side with nervous system disorders – although often with much less obvious cause-and-effect as the relationship between fasting and seizures. Rekindled interest in metabolic and dietary therapies for brain disorders complements new insight into their mechanisms and broader implications. Here we describe the emerging relationship between a KD and adenosine as a way to reset brain metabolism and neuronal activity and disrupt a cycle of dysfunction. We also provide an overview of the effects of a KD on cognition and recent data on the effects of a KD on pain, and explore the relative time course quantified among hallmark metabolic changes, altered neuron function and altered animal behavior assessed after diet administration. We predict continued applications of metabolic therapies in treating dysfunction including and beyond the nervous system.

Ketogenic Diets and Thermal Pain: Dissociation of Hypoalgesia, Elevated Ketones, and Lowered Glucose in Rats

“…31,44 Consistent with this prediction, recently we found that feeding with a KD for 3–4 weeks reduced sensitivity to thermal pain in rats. 43 Establishing broader applicability and identifying key mechanisms of the KD in vivo are essential to uncover novel targets for pain relief.…”

Identification of multi-targeting and synergistic neuromodulators of epilepsy associated protein-targets in Ayurvedic herbs using network pharmacological approach

“…hsa04080" (Neuroactive-ligand-receptor interaction pathway) have a maximum number of EP proteins involved in them. These findings support previous studies according to which there exists a therapeutic relationship between brain activity and metabolism to treat neurological disorders (Masino et al, 2009) (Ruskin and Masino, 2012). Although direct correlation of the "path: hsa04080" and epilepsy could not be established, but this pathway has remained as an important source for the development of various therapeutic strategies against various neurological disorders (Kong et al, 2015).…”

Intermittent metabolic switching, neuroplasticity and brain health

“…23). During the past 50 years, it was established that ketones can constrain neuronal network activity and ketogenic diets can benefit many patients with epilepsy 24 . More recently, it was shown that rats maintained on ADF exhibit resistance to seizure-induced hippocampal damage and associated cognitive impairment 25 and that IF can reduce seizure frequency in children who do not fully respond to a ketogenic diet 26 .…”