RESUMEN
Neurodegenerative diseases, including Alzheimer's and Parkinson's disease, are characterized by increased protein aggregation in the brain, progressive neuronal loss, increased inflammation, and neurogenesis impairment. We analyzed the effects of a new purine derivative drug, PDD005, in attenuating mechanisms involved in the pathogenesis of neurodegenerative diseases, using both in vivo and in vitro models. We show that PDD005 is distributed to the brain and can rescue cognitive deficits associated with aging in mice. Treatment with PDD005 prevents impairment of neurogenesis by increasing sex-determining region Y-box 2, nestin, and also enhances synaptic function through upregulation of synaptophysin and postsynaptic density protein 95. PDD005 treatment also reduced neuro-inflammation by decreasing interleukin-1ß expression, activation of astrocytes, and microglia. We identified prohibitin as a potential target in mediating the therapeutic effects of PDD005 for the treatment of cognitive deficit in aging mice. Additionally, in the current study, glycogen synthase kinase appears to attenuate tau pathology.
Asunto(s)
Trastornos del Conocimiento/prevención & control , Hipocampo/efectos de los fármacos , Terapia Molecular Dirigida , Proteínas del Tejido Nervioso/antagonistas & inhibidores , Fármacos Neuroprotectores/farmacología , Proteínas Represoras/antagonistas & inhibidores , Tauopatías/prevención & control , Envejecimiento/psicología , Animales , Barrera Hematoencefálica , Encéfalo/metabolismo , Células Cultivadas , Trastornos del Conocimiento/tratamiento farmacológico , Donepezilo/farmacología , Evaluación Preclínica de Medicamentos , Células Endoteliales/efectos de los fármacos , Regulación de la Expresión Génica/efectos de los fármacos , Glucógeno Sintasa Quinasa 3 beta/biosíntesis , Glucógeno Sintasa Quinasa 3 beta/genética , Interleucina-1beta/biosíntesis , Interleucina-1beta/genética , Masculino , Aprendizaje por Laberinto/efectos de los fármacos , Ratones , Ratones Endogámicos C57BL , Ratones Transgénicos , Mitocondrias/efectos de los fármacos , Proteínas del Tejido Nervioso/biosíntesis , Proteínas del Tejido Nervioso/genética , Neurogénesis/efectos de los fármacos , Neuroglía/efectos de los fármacos , Plasticidad Neuronal/efectos de los fármacos , Fármacos Neuroprotectores/farmacocinética , Fosforilación/efectos de los fármacos , Prohibitinas , Procesamiento Proteico-Postraduccional/efectos de los fármacos , Proteínas Represoras/biosíntesis , Proteínas Represoras/genética , Tauopatías/tratamiento farmacológico , Proteínas tau/metabolismoRESUMEN
The development of effective central nervous system (CNS) drugs has been hampered by the lack of robust strategies to mimic the blood-brain barrier (BBB) and cerebrovascular impairments in vitro. Recent technological advancements in BBB modeling using induced pluripotent stem cells (iPSCs) allowed to overcome some of these obstacles, nonetheless the pertinence for their use in drug permeation study remains to be established. This mandatory information requires a cross comparison of in vitro and in vivo pharmacokinetic data in the same species to avoid failure in late clinical drug development. Here, we measured the BBB permeabilities of 8 clinical positron emission tomography (PET) radioligands with known pharmacokinetic parameters in human brain in vivo with a newly developed in vitro iPSC-based human BBB (iPSC-hBBB) model. Our findings showed a good correlation between in vitro and in vivo drug brain permeability (R2 = 0.83; P = 0.008) which contrasted with the limited correlation between in vitro apparent permeability for a set of 18 CNS/non-CNS compounds using the in vitro iPSCs-hBBB model and drug physicochemical properties. Our data suggest that the iPSC-hBBB model can be integrated in a flow scheme of CNS drug screening and potentially used to study species differences in BBB permeation.
Asunto(s)
Barrera Hematoencefálica/química , Encéfalo/diagnóstico por imagen , Células Madre Pluripotentes Inducidas/citología , Neuroglía/citología , Animales , Barrera Hematoencefálica/diagnóstico por imagen , Encéfalo/metabolismo , Diferenciación Celular , Células Cultivadas , Evaluación Preclínica de Medicamentos , Humanos , Células Madre Pluripotentes Inducidas/metabolismo , Ratones , Modelos Biológicos , Neuroglía/metabolismo , Permeabilidad , Tomografía de Emisión de Positrones , Prueba de Estudio Conceptual , RatasRESUMEN
Neuropilin-1/-2 (+33 NRPs), VEGF-A165 co-receptors, are over-expressed during cancer progression. Thus, NRPs targeted drug development is challenged using a multistep in silico/in vitro screening procedure. The first fully non-peptidic VEGF-A165/NRPs protein-protein interaction antagonist (IC50=34 µM) without effect on pro-angiogenic kinases has been identified (compound-1). This hit showed breast cancer cells anti-proliferative activity (IC50=0.60 µM). Compound-1 treated NOG-xenografted mice significantly exerted tumor growth inhibition, which is correlated with Ki-67(low) expression and apoptosis. Furthermore, CD31(+)/CD34(+) vessels are reduced in accordance with HUVEC-tube formation inhibition (IC50=0.20 µM). Taking together, compound-1 is the first fully organic inhibitor targeting NRPs.