Metabolic management of neuronal hyperexcitability: a new approach to treat epilepsy. – METANEX

We examine the mice model of Alzheimer's disease and fed them on a standard laboratory diet alone or supplemented with pyruvate and beta-hydroxybutyrate to check whether their pathological features would be abated. We used the ultimate parameter of energy metabolism, by which its function can be assessed called redox state, to see whether the energy substrate consumed with feed can repair the metabolic defects. We also analysed how this supplementation influenced the condition of glucose depots (glycogen) in the brain. We examined the differences in neuronal excitability and fundamental neuronal traits in mice fed on standard or supplemented diets.

In mice model of Alzheimer's disease, we showed that if they were fed on standard diet, all well-known abnormalities characteristic for the disease were present. To the contrary, if the mice diet was supplemented with energy substrates, these pathological features were totally absent: their EEGs were free from epileptic episodes. To go into the mechanisms of this effect we performed the experiments with brain slices. We showed in brain slices taken from mice pups (Ivanov et al., 2011) and from very young mice (Ivanov and Zilberter, 2011), that neuronal responses to stimulation including molecular features of energy metabolism, as well as spontaneous activity of neuronal networks - all strongly depend on the availability of oxygen to the brain preparation. This finding is important because it shows the necessity of refining the experimental procedure in brain slices and it calls for more accuracy in interpretation of data obtained in vitro. This finding also allowed us to confidently analyze the data we collected in experiments with brain slices. We showed that the standard incubation solution containing glucose alone provides much less support to the neurons in slices and that enrichment of the solution with additional energy carriers - beta-hydroxybutyrate, pyruvate or lactate enhanced neuronal metabolism and synaptic function.

Our results show that the neuroprotective effects of metabolic manipulations clearly proved in the century-long success of the ketogenic diet in treatment of plethora of brain diseases can be achieved in more practical and efficient way. Modifying energy metabolism allows to bypass an insufficient biochemical pathway (mostly glucose-based) and to switch it to an alternative pathway. Further research including that into cognitive parameters of intact animals and human subjects will move us closer to the practical applications and developing a true treatment of the disease’s reason instead of mending its consequences.

Ivanov A, Mukhtarov M, Bregestovski P, Zilberter Y. Lactate Effectively Covers Energy Demands during Neuronal Network Activity in Neonatal Hippocampal Slices. Front Neuroenergetics.2011;3:2. Epub2011 May 6.
Ivanov A, Zilberter Y. Critical state of energy metabolism in brain slices:
the principal role of oxygen delivery and energy substrates in shaping neuronal activity. Front Neuroenergetics. 2011;3:9. Epub 2011 Dec 29.

While neurodegenerative disorders and epilepsy are widespread and costly diseases, current treatment options are limited and primarily target
symptoms, rather than causes. Metabolic stress is a feature common to many NDDs an epilepsies. However, the mechanisms linking impairments in
energy supply and utilization to neuropathology are unclear. We suggest that impaired neuronal energy homeostasis is a primary reason for
the high seizure susceptibility in AD and epileptic patients, and the impaired synaptic plasticity in AD. Metabolic failure leads to abnormal
neuronal signaling,resulting in an energy deficit, which triggers further aberrant neuronal activity, in a pathological, positive feedback loop.
This vicious cycle can however be interrupted by the timely supply of an appropriate alternative energy source e.g., ketone bodies. In this
project we will elucidate the mechanisms of neuronal metabolic protection in the developing and mature brains, in order to provide a rational
basis for the treatment of NDDs and epilepsies.