RESUMEN
Alzheimer's disease (AD) is one of the most common forms of dementia. Current anti-AD therapeutics exploit the cholinergic hypothesis of its pathophysiology; they aim to inhibit cerebral cholinesterases. K1234 is a novel hybrid molecule derived from Huperzine A and 7-MEOTA-huperzine which shows increased potency in acetylcholinesterase inhibition in vitro compared to the compounds themselves. The study focused on description of the pharmacokinetic behaviour of K1234, blood-brain barrier penetration, identification of the main in vitro and in vivo metabolites. K1234 is relatively non-toxic compound, that is rapidly absorbed after i.p. administration reaching Cmax within minutes, with extensive distribution into tissues and fast metabolism in mice. The dominant metabolic pathway appears to be glucuronidation of the parent molecule and its phase-I metabolites. The passage of K1234 across the blood-brain-barrier in mice appears to be limited, as it reached only approximately one third of the AUC of plasma.
Asunto(s)
Enfermedad de Alzheimer , Inhibidores de la Colinesterasa , Acetilcolinesterasa/metabolismo , Acridinas , Enfermedad de Alzheimer/tratamiento farmacológico , Animales , Inhibidores de la Colinesterasa/farmacología , Cromatografía Líquida de Alta Presión , RatonesRESUMEN
Being among the top five causes of death in the developed world, Alzheimer's disease represents a major socio-economic issue. We administered a single intramuscular dose of two new hybrid anti-Alzheimer's compounds, with 7-methoxytacrine (7-MEOTA; acetylcholinesterase inhibitor) and tryptophan (inhibitor of amyloid accumulation) in their structure, to rats. Using validated ultra-high-performance liquid chromatography coupled to high-resolution mass spectrometry (UHPLC-HRMS) methods, we uncovered their inability to enter the site of action - the brain. We discuss four possible explanations: i) physico-chemical properties, ii) lack of active/facilitated transport, iii) effective efflux and/or iv) extensive metabolism. High-resolution mass spectrometric analyses proved that the compounds are easily hydrolysed at amide bond between tryptophan and the linker both in vitro and in vivo. Contrary to the parent compounds these metabolites - analogues of 7-MEOTA - can enter the brain in significant amounts.
Asunto(s)
Encéfalo/metabolismo , Inhibidores de la Colinesterasa/farmacocinética , Tacrina/análogos & derivados , Triptófano/farmacocinética , Enfermedad de Alzheimer , Animales , Barrera Hematoencefálica , Cromatografía Líquida de Alta Presión , Hidrólisis , Masculino , Ratas , Ratas Wistar , Tacrina/farmacocinética , Espectrometría de Masas en TándemRESUMEN
Epigenetic changes are considered to be a frequent event during tumour development. Hypermethylation of promoter CpG islands represents an alternative mechanism for inactivation of tumour suppressor genes, DNA repair genes, cell cycle regulators and transcription factors. The aim of this study was to investigate promoter methylation of specific genes in samples of sinonasal carcinoma by comparison with normal sinonasal tissue. To search for epigenetic events we used methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA) to compare the methylation status of 64 tissue samples of sinonasal carcinomas with 19 control samples. We also compared the human papilloma virus (HPV) status with DNA methylation. Using a 20% cut-off for methylation, we observed significantly higher methylation in RASSF1, CDH13, ESR1 and TP73 genes in the sinonasal cancer group compared with the control group. HPV positivity was found in 15/64 (23.4 %) of all samples in the carcinoma group and in no sample in the control group. No correlation was found between DNA methylation and HPV status. In conclusion, our study showed that there are significant differences in promoter methylation in the RASSF1, ESR 1, TP73 and CDH13 genes between sinonasal carcinoma and normal sinonasal tissue, suggesting the importance of epigenetic changes in these genes in carcinogenesis of the sinonasal area. These findings could be used as prognostic factors and may have implications for future individualised therapies based on epigenetic changes.
Asunto(s)
Carcinoma de Células Escamosas/genética , Carcinoma de Células Escamosas/fisiopatología , Metilación de ADN , Genes Supresores de Tumor , Neoplasias de Cabeza y Cuello/genética , Neoplasias de Cabeza y Cuello/fisiopatología , Cadherinas/genética , Cadherinas/metabolismo , Carcinoma de Células Escamosas/diagnóstico , Carcinoma de Células Escamosas/virología , ADN (Citosina-5-)-Metiltransferasa 1 , ADN (Citosina-5-)-Metiltransferasas/genética , ADN (Citosina-5-)-Metiltransferasas/metabolismo , Activación Enzimática , Epigenómica , Neoplasias de Cabeza y Cuello/diagnóstico , Neoplasias de Cabeza y Cuello/virología , Humanos , Papillomaviridae/aislamiento & purificación , Pronóstico , Regiones Promotoras Genéticas/genética , Carcinoma de Células Escamosas de Cabeza y CuelloRESUMEN
Ovarian cancer is the leading cause of death from gynaecologic tumours, but the molecular and especially epigenetic events underlying the transformation are poorly understood. Various methylation changes have been identified and show promise as potential cancer biomarkers. The aim of this study was to investigate promoter methylation of selected tumour suppressor genes in ovarian cancer by comparison with normal ovarian tissue. To search for epigenetic events we used methylation-specific multiplex ligation-dependent probe amplification to compare the methylation status of 44 tissue samples of ovarian cancer with 30 control samples. Using a 20% cut-off for methylation, we observed significantly higher methylation in genes NTKR1, GATA4 and WIF1 in the ovarian cancer group compared with the control group. These findings could potentially be used in screening of ovarian cancer, and may have implications for future chemotherapy based on epigenetic changes.