ABSTRACT
We find that a common mutation that increases angiotensin I-converting enzyme activity occurs with higher frequency in male patients suffering from refractory temporal lobe epilepsy. However, in their brains, the activity of the enzyme is downregulated. As an explanation, we surprisingly find that carbamazepine, commonly used to treat epilepsy, is an inhibitor of the enzyme, thus providing a direct link between epilepsy and the renin-angiotensin and kallikrein-kinin systems.
Subject(s)
Angiotensin-Converting Enzyme Inhibitors/pharmacology , Anticonvulsants/pharmacology , Carbamazepine/pharmacology , Epilepsy, Temporal Lobe/physiopathology , Peptidyl-Dipeptidase A/physiology , Alleles , Animals , Anterior Temporal Lobectomy , Disease Models, Animal , Dose-Response Relationship, Drug , Epilepsy, Temporal Lobe/genetics , Epilepsy, Temporal Lobe/pathology , Epilepsy, Temporal Lobe/surgery , Genotype , Humans , INDEL Mutation , Male , Mice , Mice, Inbred C57BL , Peptidyl-Dipeptidase A/genetics , Polymorphism, Genetic/genetics , Temporal Lobe/drug effects , Temporal Lobe/pathologyABSTRACT
Organotellurium(IV) compounds have been reported to have multiple biological activities including cysteine protease-inhibitory activity, mainly cathepsin B. As cathepsin B is a highly predictive indicator for prognosis and diagnosis of cancer, a possible antitumor potential for these new compounds is expected. In this work, it was investigated the effectiveness of organotellurium(IV) RT-04 to produce lethal effects in the human promyelocytic leukaemia cell line HL60. Using the MTT tetrazolium reduction test, and trypan blue exclusion assay, the IC50 for the compound after 24 h incubation was 6.8 and 0.35 microM, respectively. Moreover, the compound was found to trigger apoptosis in HL60 cells, inducing DNA fragmentation and caspase-3, -6, and -9 activations. The apoptsosis-induced by RT-04 is probably related to the diminished Bcl-2 expression, observed by RT-PCR, in HL60-treated cells. In vivo studies demonstrated that the RT-04 treatment (2.76 mg/kg given for three consecutive days) produces no significant toxic effects for bone marrow and spleen CFU-GM. However, higher doses (5.0 and 10 mg/kg) produced a dose-dependent reduction in the number of CFU-GM of RT-04-treated mice. These results suggest that RT-04 is able to induce apoptosis in HL60 cells by Bcl-2 expression down-modulation. Further studies are necessary to better clarify the effects of this compound on bone marrow normal cells.
