RESUMO
We describe the interactions of two benzimidazole derivatives, astemizole (AST) and lansoprazole (LNS), with anomalous aggregates of tau protein (neurofibrillary tangles). Interestingly, these compounds, with important medical applications in the treatment of allergies and gastrointestinal disorders respectively, specifically bind to aggregated variants of tau protein and to paired helical filaments isolated from brains of Alzheimer's disease (AD) patients. These ligands appear to be a powerful tool to tag brain-isolated tau-aggregates and heparin-induced polymers of recombinant tau. The interactions of AST and LNS with tau aggregates were assessed by classical radioligand assays, surface plasmon resonance, and bioinformatic approaches. The affinity of AST and LNS for tau aggregates was comparatively higher than that for amyloid-beta polymers according to our data. This is relevant since senile plaques are also abundant but are not pathognomonic in AD patients. Immunochemical studies on paired helical filaments from brains of AD patients and surface plasmon resonance studies confirm these findings. The capacity of these drugs to penetrate the blood-brain barrier was evaluated: i) in vitro by parallel artificial membrane permeability assay followed by experimental Log P determinations; and ii) in vivo by pharmacokinetic studies comparing distribution profiles in blood and brain of mice using HPLC/UV. Importantly, our studies indicate that the brain/blood concentration ratios for these compounds were suitable for their use as PET radiotracers. Since neurofibrillary tangles are positively correlated with cognitive impairment, we concluded that LNS and AST have a great potential in PET neuroimaing for in vivo early detection of AD and in reducing the formation of neurofibrillary tangles.
Assuntos
2-Piridinilmetilsulfinilbenzimidazóis , Doença de Alzheimer/diagnóstico , Astemizol , Inibidores Enzimáticos , Antagonistas não Sedativos dos Receptores H1 da Histamina , Proteínas tau/metabolismo , 2-Piridinilmetilsulfinilbenzimidazóis/química , 2-Piridinilmetilsulfinilbenzimidazóis/farmacocinética , Doença de Alzheimer/metabolismo , Doença de Alzheimer/patologia , Astemizol/química , Astemizol/farmacocinética , Encéfalo/efeitos dos fármacos , Encéfalo/metabolismo , Encéfalo/patologia , Cromatografia Líquida de Alta Pressão , Biologia Computacional , Relação Dose-Resposta a Droga , Interações Medicamentosas , Técnicas Eletroquímicas , Tomografia com Microscopia Eletrônica/métodos , Inibidores Enzimáticos/química , Inibidores Enzimáticos/farmacocinética , Antagonistas não Sedativos dos Receptores H1 da Histamina/química , Antagonistas não Sedativos dos Receptores H1 da Histamina/farmacocinética , Humanos , Lansoprazol , Modelos Moleculares , Emaranhados Neurofibrilares/efeitos dos fármacos , Emaranhados Neurofibrilares/patologia , Emaranhados Neurofibrilares/ultraestrutura , Ensaio Radioligante , Ressonância de Plasmônio de Superfície , Trítio/farmacocinética , Proteínas tau/ultraestruturaRESUMO
INTRODUCTION AND MATERIAL: Nine brains belonging to early onset Alzheimer disease (E280A-PS1 mutation) affected individuals from Antioquia, Colombia, were analyzed by neuropathological standard techniques. All individuals were ascertained from genealogies descendents from a common ancestor that shows a dominant autosomical pattern of inheritance. RESULTS: All cases analyzed were carriers to the E280A-PS1 mutation. This type of mutation produce beta-amyloid deposits of 42 aminoacids in the CNS. The mean of onset age was 48.4 years with an average of evolution time of 7.55 years and a mean of death age of 56.55. Although, all the cases showed symmetrical atrophy and them was more severe in the hippocampal region, a definitive anterior pattern (temporo-frontal) was showed. The higher the time of evolution of disease the lower the brain weight. CONCLUSIONS: All types of senile plaques and abundant neurofibrillary tanggles were found. In the stem, similar lesions were found but they were in lower number. Only the mesencephalic region showed a significative positive correlation between the number of senile plaques and the number of neurofibrillary tanggels (p < 0.05, r = 0.76). Only the parietal region showed a significant positive correlation between the number of senile plaques and the disease evolution time (p < 0.02, r = 0.74). Particularly, the cerebellum only showed senile plaques but neurofibrillary degeneration was not observed. With the exception of the Hirano bodies, all findings traditionally described were observed.