Summary:  Purpose: Status epilepticus (SE) can result in acute neuronal injury with subsequent long‐term age‐dependent behavioral and histologic sequelae. To investigate potential mechanisms that may underlie SE‐related neuronal injury, we studied the occurrence of programmed cell death (PCD) in the hippocampus in the kainic acid (KA) model.Methods: In adult rats, KA‐induced SE resulted in DNA fragmentation documented at 30 h after KA injection. Ceramide, a known mediator of PCD in multiple neural and nonneural tissues, increased at 2–3 h after KA intraperitoneal injection, and then decreased to control levels before increasing again from 12 to 30 h after injection. MK801 pretreatment prevented KA‐induced increases in ceramide levels and DNA fragmentation, whether there was reduction in seizure severity or not (achieved with 5 mg/kg and 1 mg/kg of MK801, respectively).Results: Both ceramide increases and DNA fragmentation were observed after KA‐induced SE in adult and in P35 rats. Ceramide did not increase after KA‐induced SE in P7 pups, which also did not manifest any DNA fragmentation. Intrahippocampal injection of the active ceramide analogue C2‐ceramide produced widespread DNA fragmentation, whereas the inactive ceramide analogue C2‐dihydroceramide did not.Conclusions: Our data support the hypotheses that (a) N‐methyl‐d‐aspartate–receptor activation results in ceramide increases and in DNA fragmentation; (b) ceramide is a mediator of PCD after SE; and (c) there are age‐related differences in PCD and in the ceramide response after SE. Differences in the ceramide response could, potentially, be responsible for observed age‐related differences in the response to SE.

Anthrax lethal toxin, composed of protective antigen and lethal factor, was tested for cytotoxicity to human melanoma cell lines and normal human cells. Eleven of 18 melanoma cell lines were sensitive to anthrax lethal toxin (IC₅₀ < 400 pmol/L) and 10 of these 11 sensitive cell lines carried the V599E BRAF mutation. Most normal cell types (10 of 15) were not sensitive to anthrax lethal toxin and only 5 of 15 normal human cell types were sensitive to anthrax lethal toxin (IC₅₀ < 400 pmol/L). These cells included monocytes and a subset of endothelial cells. In both melanoma cell lines and normal cells, anthrax toxin receptor expression levels did not correlate with anthrax lethal toxin cytotoxicity. Furthermore, an anthrax toxin receptor–deficient cell line (PR230) did not show any enhanced sensitivity to anthrax lethal toxin when transfected with anthrax toxin receptor. Anthrax lethal toxin toxicity correlated with elevated phosphorylation levels of mitogen-activated protein/extracellular signal-regulated kinase kinase (MEK) 1/2 in both melanoma cell lines and normal cells. Anthrax lethal toxin–sensitive melanoma cell lines and normal cells had higher phospho-MEK1/2 levels than anthrax lethal toxin–resistant melanoma cell lines and normal tissue types. U0126, a specific MEK1/2 inhibitor, was not toxic to anthrax lethal toxin–resistant melanoma cell lines but was toxic to 8 of 11 anthrax lethal toxin–sensitive cell lines. These results show that anthrax lethal toxin toxicity correlates with elevated levels of active MEK1/2 pathway but not with anthrax toxin receptor expression levels in both normal and malignant tissues. Anthrax lethal toxin may be a useful therapeutic for melanoma patients, especially those carrying the V599E BRAF mutation with constitutive activation of the mitogen-activated protein kinase pathway.

A photochemically dissociating ligand in Ru(bpy)₂(dmphen)Cl₂ [bpy = 2,2′-bipyridine; dmphen = 2,9-dimethyl-1,10-phenanthroline] was found to be more cytotoxic on the ML-2 Acute Myeloid Leukemia cell line than Ru(bpy)₂(H₂O)₂ ²⁺ and prototypical cisplatin. Our findings illustrate the potential potency of diimine ligands in photoactivatable Ru(II) complexes.