Pre-Clinical Testing of New Hydroxybutyrate Analogues.

摘要

One of the hallmarks of Parkinson Disease is a deficit in Complex I of the mitochondrial complex chain in the tyrosine hydroxylase (THf)+ neurons in the substantia nigra pars compacta (SNpc) of the brain. This situation allows the dopamine neuron to be put under oxidative stress, thus leaving the DA neuron vulnerable to free radical attack. In attempts to reverse the deficit in Complex I in the cell, in earlier experiments, we used a ketone body, D-beta- hydroxybutyrate (DBHB) in the presence of MPTP to increase oxidative phosphorylation. This change in phosphorylation state afforded protection to the SNpc TH+neurons. One drawback to the use of DBHB is that it is short- acting. In our present experiment, we used a DBHB analogue, glyceryl tris(3- hydroxybutyrate, G3HB) which is the basic DBHB structure that has been altered. Compared to DBHB which increased DBHB levels in plasma by almost 100%, G3HB increased plasma DBHB levels by less than 50%, Increasing the assay sample volume increases brain tissue DBHB levels . In the in vivo studies, the combination of MPTP and G3HB seemed to cause significant mortality in the two strains of mice that we used. This high mortality rate may be strain or breeding house dependent. More studies need to be done to sort this situation out.