ABSTRACT
Brain-derived neurotrophic factor (BDNF) plays a fundamental role in neuronal synaptic plasticity. A decrease of plasticity in the brain may be related to the pathogenesis of neurodegenerative or psychiatric disorders. Pyrethroid insecticides, which affect sodium channels in neurons, are widely used to control insect pests in agriculture and in the home. We previously found that deltamethrin (DM), a type II pyrethroid, increased Bdnf mRNA expression in cultured rat cortical neurons. However, the cyano group at the α-position of type II pyrethroids is likely susceptible to hydrolytic degradation and, its degraded product, hydrogen cyanide, could generate a cellular toxicity in the human body. To determine if the cyano group is required for the Bdnf exon IV-IX (Bdnf eIV-IX) mRNA expression induced by type II pyrethroids, for this study we synthesized a series of derivatives, in which the cyano group at the α-position was replaced with an ethynyl group. Then we added various substituents at the terminal position of the ethynyl group, and biologically evaluated the effects of these derivatives on Bdnf eIV-IX mRNA expression. These ethynyl derivatives induced the Bdnf eIV-IX mRNA expression in a concentration-dependent manner, at varying levels but lower levels than that evoked by DM. The mechanisms for the Bdnf induction and the morphological changes of neurons were the same whether the cyano or ethynyl group was included in the compounds.
Subject(s)
Brain-Derived Neurotrophic Factor/genetics , Insecticides/pharmacology , Neurons/drug effects , Pyrethrins/pharmacology , RNA, Messenger/drug effects , Animals , Cerebral Cortex/cytology , Cerebral Cortex/drug effects , Cerebral Cortex/metabolism , Insecticides/chemical synthesis , Insecticides/chemistry , Molecular Conformation , Neurons/cytology , Neurons/metabolism , Pyrethrins/chemical synthesis , Pyrethrins/chemistry , RNA, Messenger/genetics , Rats , Rats, Sprague-Dawley , Real-Time Polymerase Chain Reaction , Sodium Channels/metabolism , Structure-Activity RelationshipSubject(s)
Cerebellum/blood supply , Intracranial Aneurysm/diagnostic imaging , Vertebral Artery/abnormalities , Vertebral Artery/diagnostic imaging , Aneurysm, Ruptured/diagnostic imaging , Aneurysm, Ruptured/etiology , Cerebral Angiography , Female , Humans , Intracranial Aneurysm/etiology , Middle AgedABSTRACT
PURPOSE: A major obstacle in the treatment of ovarian carcinoma is the intrinsic/acquired resistance to cisplatin-based chemotherapy. Cu-transporting ATPase (ATP7B) has been reported to be associated with cisplatin resistance in vitro. However, the clinical significance of this transporter has not previously been addressed. Our goal was to investigate ATP7B expression in ovarian carcinoma and whether its expression correlates with prognosis and reduced responsiveness to cisplatin treatment. EXPERIMENTAL DESIGN: We retrospectively examined the expression of ATP7B and p53 in primary ovarian carcinoma and its association with chemotherapeutic effect. Tissues were surgically removed from 104 ovarian carcinomas patients who received cisplatin-based chemotherapy. We performed immunohistochemical analysis of ATP7B and p53 using a monoclonal antibody against ATP7B and DO7 antibody against p53 protein in 104 ovarian carcinomas and adjacent nonneoplastic tissues. The significance of ATP7B and p53 in the prognosis of patients with ovarian carcinomas was also examined in the survival analysis of mortality follow-up data covering the period between 1988 and 2001. Furthermore, mutation analysis at the six Cu-binding domain and ATP-binding domain, which may be important for cisplatin transport, were performed using single-strand conformational polymorphism after reverse transcriptase-PCR. RESULTS: A variable degree of cytoplasmic staining of ATP7B in tumor cells was observed in 34.6% (36 of 104 cases) of the analyzed carcinomas. ATP7B expression was not observed in adjacent nonneoplastic tissues. ATP7B positivity in poorly/moderately differentiated carcinoma was significantly higher than that in low malignant potential tumor/well-differentiated carcinoma (P = 0.0276). Patients with ATP7B-positive tumors had a significantly inferior response to chemotherapy compared with the patients with ATP7B-negative tumors (P = 0.025). The multivariate Cox regression analysis revealed that ATP7B expression (hazard ratio, 1.8; 95% confidence interval, 1.0-3.2, P = 0.048), as well as International Federation of Gynecologists and Obstetricians stage (hazard ratio, 2.0; 95% confidence interval, 1.1-3.6, P = 0.018), was prognostic for poor disease outcome after adjustment for p53 expression, grade, and residual tumor. p53 expression was detected in 31.5% (26/104 cases). No mutation was observed on the six Cu-binding domain or ATP-binding domain in human ovarian carcinomas expressing ATP7B gene. CONCLUSIONS: This study demonstrates that overexpression of ATP7B in ovarian carcinoma is correlated with unfavorable clinical outcome in patients treated with cisplatin-based chemotherapy. Therefore, ATP7B expression may be considered as a predictive marker of chemoresistance for cisplatin-based chemotherapy in patients with ovarian carcinoma. We further predict that drugs targeting ATP7B might be useful in combination with cisplatin-based regimen for the improvement of patients with ovarian carcinoma.
