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) andmethyl (D)-3-hydroxybutyrate (M-3-HB), are derivatives of 3-hydroxybutyric acid (3-HB), aketone body that is produced in vivo in animals including human. D-3-HB is the most commondegradation product of microbial polyhydroxyalkanoates (PHA) that have been investigated fortissue engineering application. This study evaluated the in vitro effect of PHA degradationproduct 3-HB and its derivatives (collectively called 3-HB derivatives) on cell proliferation,apoptosis and cytosolic Ca²⁺ concentration of mouse glial cells. Results showed that thepercentage of cells undergoing apoptosis decreased significantly in the presence of 3-HB and itsderivatives as evidenced by flow cytometry. The in vitro study on cytosolic Ca²⁺ concentrationdemonstrated that 3-HB derivatives elevated dramatically the cytosolic Ca²⁺ concentration. Boththe extracellular and intracellular Ca²⁺ contributed as the sources of such Ca²⁺ concentrationelevation. The effect of 3-HB derivatives on cytosolic Ca²⁺ concentration could be reduced bynitredipine, an L-type voltage-dependent calcium channel antagonist. In comparison, M-3-HBworked more efficiently than D-3-HB and DL-3-HB did as M-3-HB is most efficient inpermeation into the cells. All results indicated that 3-HB derivatives had an inhibitory effect oncell apoptosis which is mediated by signaling pathways related to the elevation of cytosolic Ca²⁺concentration. This positive effect helps explain the biocompatibility observed for PHA, it alsopoints to the possibility of 3-HB derivatives regardless of chirality to become an effective neuralprotective agent.