The effect of 3-hydroxybutyrate and its derivatives on the growth of glial cells.

Sodium salts of D-3-hydroxybutyrate (D-3-HB), DL-3-hydroxybutyrate (DL-3-HB) and methyl (D)-3-hydroxybutyrate (M-3-HB), are derivatives of 3-hydroxybutyric acid (3-HB), a ketone body that is produced in vivo in animals including human. D-3-HB is the most common degradation product of microbial polyhydroxyalkanoates (PHA) that have been investigated for tissue engineering application. This study evaluated the in vitro effect of PHA degradation product 3-HB and its derivatives (collectively called 3-HB derivatives) on cell apoptosis and cytosolic Ca(2+) concentration of mouse glial cells. Results showed that the percentage of cells undergoing apoptosis decreased significantly in the presence of 3-HB and its derivatives as evidenced by flow cytometry. The in vitro study on cytosolic Ca(2+) concentration demonstrated that 3-HB derivatives dramatically elevated the cytosolic Ca(2+) concentration. Both the extracellular and intracellular Ca(2+) contributed as the sources of such Ca(2+) concentration elevation. The effect of 3-HB derivatives on cytosolic Ca(2+) concentration could be reduced by nitredipine, an L-type voltage-dependent calcium channel antagonist. In comparison, M-3-HB worked more efficiently than D-3-HB and DL-3-HB did as M-3-HB is more efficient in permeation into the cells. All results indicated that 3-HB derivatives had an inhibitory effect on cell apoptosis which is mediated by signaling pathways related to the elevation of cytosolic Ca(2+) concentration. This positive effect helps explain the biocompatibility observed for PHA, it also points to the possibility of 3-HB derivatives regardless of chirality to become an effective neural protective agent.