Carbamazepine Is a Radioprotector and Radiation Damage Mitigator for Murine Hematopoietic Cell Line 32D Cl 3

Abstract 4772

The search for new radiation mitigators includes targeted new- indication testing of known drugs. Carbamazepine (cbz) has been used for decades in the treatment of trigeminal neuralgia, epilepsy, mania and bipolar disorders, and has recently been demonstrated to reduce liver damage in a mouse model of alpha-1-antitrypsin deficiency by a mechanism that stimulates the proteasomal and autophagic pathway allowing degradation and clearing of abnormally folded antitrypsin. Because of its potential mitochondrial membrane ion channel effects, we tested cbz action on the irradiation survival of murine hematopoietic progenitor 32D cl 3 cells that were incubated for 1 hour in 1, 10 or 100 μ M cbz either before or after irradiation. Cells were irradiated to doses ranging from 0 to 8 Gy, plated in 4% methylcellulose, incubated for seven days at 37°C, and colonies of greater than 50 cells counted. Data was analyzed using linear quadratic or single-hit, multi-target models. Cbz added before irradiation resulted in radioprotection by an increased Do of 2.1 + 0.1 Gy (p = 0.0117), 2.3 + 0.1 Gy (p = 0.010), or 3.6 + 0.7 Gy (p = 0.0026) for 1, 10 or 100 μ M, respectively, compared to 1.5 + 0.1 Gy for control irradiated 32D cl 3 cells, with no significant change in the ñ (shoulder on the survival curve). Cbz added after irradiation mitigated against damage by an increase in the shoulder (ñ) on the survival curve with no significant change in the Do. Control irradiated 32D cl 3 cells had a ñ of 1.4 + 0.3 compared to 10.1 + 4.2 (p = 0.0113), 5.5 + 1.7 (p = 0.0185) or 3.6 + 0.8 (p = 0.0144) for cells treated after irradiation with 1, 10 or 100 μ M cbz, respectively. Cbz is known to stabilize ion channels in both cellular and mitochondrial membranes. Since irradiation induced apoptosis involves influx of calcium across the mitochondrial membrane followed by induction of nitric oxide synthase, nitric oxide and peroxynitrite formation, destabilization of the mitochondrial membrane and cytoplasmic release of cytochrome C; cbz-stabilization of mitochondrial ion channels may be the mechanism of this novel radiation mitigative effect of a commonly used drug.

Supported by NIAID grant U19AI068021.