A morphometric study of the synapses on dendritic shafts and spines was performed in the rat caudate nucleus and the CAI area of the hippocampus under chronic haloperidol treatment. In the nucleus caudatus, the synaptic density on dendritic shafts increased by 83% and those on spines by 53%. Most of the parameters measured in axospinous synapses were significantly increased: the area of presynaptic axon terminals (20%), the number of mitochondria per axon terminal (51%), the length of active zone (11%), the area of postsynaptic density (23%), and the perimeter of postsynaptic density (12.5%). The area of postsynaptic spines showed no changes. In the synapses on dendritic shafts, the area of presynaptic terminals decreased (31%), the area of mitochondria per terminal decreased (40%), the length of active zone increased (14%), and other parameters were unchanged. There were no significant differences in the same parameters measured in the hippocampus. The data are discussed as morphological correlates of behavioral supersensitivity and dopamine D2 receptor up-regulation.
The anti-cancer potential of the natural estrogen metabolite 2-methoxyestradiol is associated with microtubuli interaction, anti-angiogenetic effects and inhibition of superoxide dismutase leading to apoptosis. The effectors of apoptotic signaling through 2-methoxyestradiol, however, are cell type-dependent. We investigated the effect of 2-methoxyestradiol on several events associated with apoptosis in rat DS-sarcoma cells. Translocation of the pro-apoptotic protein Bax to mitochondria was identified as an initial apoptotic event that was accompanied by a decrease in mitochondrial transmembrane potential and the formation of reactive oxygen species (ROS) followed by mitochondrial release of apoptosis inducing factor and endonuclease G. In addition, 2-methoxyestradiol treatment caused upregulation of death receptor ligands FasL and TNF␣ and induced caspase-8 activation. The pan caspase inhibitor Z-VAD-FMK did not suppress apoptotic cell death, however, indicating that the major pro-apoptotic effect of 2-methoxyestradiol is mediated by a caspase-independent mechanism. Furthermore, ROS do not seem to play a pivotal role in the toxic/apoptotic effect of 2-methoxyestradiol in DS-sarcoma cells because supplementation with various antioxidants provided only limit protection. Colony formation was not affected by antioxidants. Therefore, in DS-sarcoma cells, the breakdown of mitochondrial integrity with the subsequent release of mitochondrial nucleases is the main factor in 2-methoxyestradiol mediated cell death. © 2003 Wiley-Liss, Inc. Key words: 2-methoxyestradiol; apoptosis; Bax; AIF; endonuclease G; mitochondria; reactive oxygen speciesThe estrogen metabolite 2-methoxyestradiol (2-ME) is a highly potent anti-cancer agent that effectively induces apoptosis in tumor cells, both in vitro and in vivo. 1 Although 2-ME is formed from 17-estradiol, 2 its anti-cancer action is not dependent on estrogen receptor binding 3 and several molecular mechanisms have been attributed to 2-ME-mediated cell death and apoptosis. 2-ME has a strong anti-angiogenic effect and interacts with microtubuli, resulting in cell cycle arrest at G2/M phase. 4 D'Amato et al. 5 reported that 2-ME inhibits tubulin polymerization by interacting with the colchicine site. 2-ME also increases the insoluble polymerized fraction of cellular tubulin similar to the anti-cancer drug Taxol. 6 In addition, 2-ME increases the superoxide anions, by inhibiting superoxide dismutase (SOD). 7 Investigations of different estradiols and estrones showed that an alkoxy-group at position 2 is responsible for the SOD-inhibiting activity. 8 In leukaemia cells, the 2-ME-mediated inhibition of SOD seems to be of great importance because in these cells ROS-formation is crucial for apoptosis induction that has been shown by ambroxol, a superoxide anion quencher and the antioxidant N-acetyl-cysteine inhibit 2-ME-induced apoptosis. 7 This mechanism may not apply to all cell lines: in hepatoma cells, 2-ME treatment also leads to both generation of reactive species and apoptotic cel...
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