In Vitro Effect of Lithium on Carbamazepine-Induced Inhibition of Murine and Human Bone Marrow-Derived Granulocyte-Macrophage, Erythroid, and Megakaryocyte Progenitor Stem Cells

Abstract

Lithium (Li) is a known agent capable of producing leukocytosis, first observed in manic depressive patients receiving Li as therapy; however, a certain percentage of cases are nonresponsive to Li therapy. These patients are responsive to carbamazepine (CBZ); however, severe hematopoietic side effects have been associated with CBZ treatment such as leukopenia. We report here the results of dose-response studies (0.1-100 micrograms/ml) that demonstrate CBZ treatment inhibits both murine and human bone marrow-derived granulocyte-macrophage (CFU-GM), erythroid (BFU-E), and megakaryocyte progenitor (CFU-Meg) cells. The addition of Li prior to and simultaneously with CBZ to marrow cultures was effective in reversing the CBZ-induced toxicity only in the presence of an optimal Li dose (1.0 mM) known to stimulate bone marrow function. However, when the addition of Li was delayed 24 hr to CBZ-treated cultures no protective effect was observed for any marrow progenitor. Thus, the time of Li-CBZ exposure is critical to observe the protective effect of Li. These results demonstrate that the leukopenia associated with CBZ treatment may be due to the ability of CBZ to inhibit marrow progenitor cells and suggest Li may be an effective agent to reverse the marrow toxic effects of CBZ.