Parkinson's Disease, the Dopaminergic Neuron and Gammahydroxybutyrate.

Abstract

The high energy demands of the substantia nigra pars compacta dopaminergic (DASNc) neurons render these neurons vulnerable to degeneration. These energy demands are a function of their long and extensively arborized axons and very large number of transmitter release sites, and are further augmented by their natural pacemaking activity. Pacemaking is driven by the rhythmic entry of Ca2+ into the cell and, while the entry of Ca2+ into the neuron stimulates energy (ATP) production, the extrusion of Ca2+ conversely saps the energy that is generated. DASNc neurons are said to be operating at a delicate equilibrium where any further stress or environmental demand may lead to their decompensation and degeneration. In experimental models of Parkinson’s disease, reducing the energy requirements of these neurons by trimming the size of the neuronal arbor or by impeding the entry of Ca2+ into the cell has been shown to be protective. Increasing the energy supply to these neurons with d-beta-hydroxybutyrate has also been shown to be protective. The use of gammahydroxybutyrate holds great promise as a neuroprotective in Parkinson’s disease because it can act as an energy source for the cell while simultaneously arresting its pacemaking activity and the entry of Ca2+ into the cell. Short clinical trials of gammahydroxybutyrate in Parkinson’s disease have already demonstrated its immediate capacity to significantly reduce daytime fatigue and sleepiness and to improve sleep at night.