ABSTRACT
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.
Subject(s)
Cognition Disorders/prevention & control , Hippocampus/drug effects , Molecular Targeted Therapy , Nerve Tissue Proteins/antagonists & inhibitors , Neuroprotective Agents/pharmacology , Repressor Proteins/antagonists & inhibitors , Tauopathies/prevention & control , Aging/psychology , Animals , Blood-Brain Barrier , Brain/metabolism , Cells, Cultured , Cognition Disorders/drug therapy , Donepezil/pharmacology , Drug Evaluation, Preclinical , Endothelial Cells/drug effects , Gene Expression Regulation/drug effects , Glycogen Synthase Kinase 3 beta/biosynthesis , Glycogen Synthase Kinase 3 beta/genetics , Interleukin-1beta/biosynthesis , Interleukin-1beta/genetics , Male , Maze Learning/drug effects , Mice , Mice, Inbred C57BL , Mice, Transgenic , Mitochondria/drug effects , Nerve Tissue Proteins/biosynthesis , Nerve Tissue Proteins/genetics , Neurogenesis/drug effects , Neuroglia/drug effects , Neuronal Plasticity/drug effects , Neuroprotective Agents/pharmacokinetics , Phosphorylation/drug effects , Prohibitins , Protein Processing, Post-Translational/drug effects , Repressor Proteins/biosynthesis , Repressor Proteins/genetics , Tauopathies/drug therapy , tau Proteins/metabolismABSTRACT
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.
Subject(s)
Blood-Brain Barrier/chemistry , Brain/diagnostic imaging , Induced Pluripotent Stem Cells/cytology , Neuroglia/cytology , Animals , Blood-Brain Barrier/diagnostic imaging , Brain/metabolism , Cell Differentiation , Cells, Cultured , Drug Evaluation, Preclinical , Humans , Induced Pluripotent Stem Cells/metabolism , Mice , Models, Biological , Neuroglia/metabolism , Permeability , Positron-Emission Tomography , Proof of Concept Study , RatsABSTRACT
Disseminated forms of neuroblastoma (NB), a tumor derived from neuroectodermal tissue, pose a major therapeutic challenge for pediatric oncology. By performing a comparative cDNA array analysis of metastatic neuroblasts versus primary xenograft from the human IGR-N-91 NB model, we were able to identify a set of downregulated developmental genes in metastatic neuroblasts. One of these genes was Wnt-5a, a member of the Wnt signaling pathway, known to be involved in the development of neural crest cells. Since we also found a significant decrease in Wnt-5a mRNA in unfavorable versus favorable categories in 37 primary NB tumors (P<0.007), we wondered whether retinoic acid (RA), which has a role in neural crest induction and differentiation, might reverse the aberrant negative regulation of Wnt-5a in metastatic malignant neuroblasts. Following treatment with 10 muM RA for 6 days, the MYCN-amplified IGR-N-91 cell lines underwent neuronal differentiation as assessed by reduced MYCN gene expression and neuritic extension. In these conditions, data showed an upregulation of Wnt-5a and PKC-theta; isoform expressions. Our study highlights, for the first time, the involvement of Wnt-5a, which has a role in embryonic and morphogenetic processes, in the response of malignant neuroblasts to RA. In conclusion, we demonstrated that RA, which is used in the treatment of high-risk NB patients with recurrent/residual disease in the bone marrow, is able to upregulate Wnt-5a gene expression.