Prinz M

References (5)

Title : Dicer Deficiency Differentially Impacts Microglia of the Developing and Adult Brain - Varol_2017_Immunity_46_1030
Author(s) : Varol D , Mildner A , Blank T , Shemer A , Barashi N , Yona S , David E , Boura-Halfon S , Segal-Hayoun Y , Chappell-Maor L , Keren-Shaul H , Leshkowitz D , Hornstein E , Fuhrmann M , Amit I , Maggio N , Prinz M , Jung S
Ref : Immunity , 46 :1030 , 2017
Abstract : Microglia seed the embryonic neuro-epithelium, expand and actively sculpt neuronal circuits in the developing central nervous system, but eventually adopt relative quiescence and ramified morphology in the adult. Here, we probed the impact of post-transcriptional control by microRNAs (miRNAs) on microglial performance during development and adulthood by generating mice lacking microglial Dicer expression at these distinct stages. Conditional Dicer ablation in adult microglia revealed that miRNAs were required to limit microglial responses to challenge. After peripheral endotoxin exposure, Dicer-deficient microglia expressed more pro-inflammatory cytokines than wild-type microglia and thereby compromised hippocampal neuronal functions. In contrast, prenatal Dicer ablation resulted in spontaneous microglia activation and revealed a role for Dicer in DNA repair and preservation of genome integrity. Accordingly, Dicer deficiency rendered otherwise radio-resistant microglia sensitive to gamma irradiation. Collectively, the differential impact of the Dicer ablation on microglia of the developing and adult brain highlights the changes these cells undergo with time.
ESTHER : Varol_2017_Immunity_46_1030
PubMedSearch : Varol_2017_Immunity_46_1030
PubMedID: 28636953

Title : 1,4-Substituted 4-(1H)-pyridylene-hydrazone-type inhibitors of AChE, BCHE, and amyloid-beta aggregation crossing the blood-brain barrier - Prinz_2013_Eur.J.Pharm.Sci_49_603
Author(s) : Prinz M , Parlar S , Bayraktar G , Alptuzun V , Erciyas E , Fallarero A , Karlsson D , Vuorela P , Burek M , Forster C , Turunc E , Armagan G , Yalcin A , Schiller C , Leuner K , Krug M , Sotriffer CA , Holzgrabe U
Ref : Eur J Pharm Sci , 49 :603 , 2013
Abstract : Given the fundamentally multifactorial character of Alzheimer's disease (AD), addressing more than one target for disease modification or therapy is expected to be highly advantageous. Here, following the cholinergic hypothesis, we aimed to inhibit both acetyl- and butyrylcholinesterase (AChE and BCHE) in order to increase the concentration of acetylcholine in the synaptic cleft. In addition, the formation of the amyloid beta fibrils should be inhibited and already preformed fibrils should be destroyed. Based on a recently identified AChE inhibitor with a 1,4-substituted 4-(1H)-pyridylene-hydrazone skeleton, a substance library has been generated and tested for inhibition of AChE, BCHE, and fibril formation. Blood-brain barrier mobility was ensured by a transwell assay. Whereas the p-nitrosubstituted compound 18C shows an anti-AChE activity in the nanomolar range of concentration (IC50=90nM), the bisnaphthyl substituted compound 20L was found to be the best overall inhibitor of AChE/BCHE and enhances the fibril destruction.
ESTHER : Prinz_2013_Eur.J.Pharm.Sci_49_603
PubMedSearch : Prinz_2013_Eur.J.Pharm.Sci_49_603
PubMedID: 23643737

Title : Design, synthesis and evaluation of novel 2-(aminoalkyl)-isoindoline-1,3-dione derivatives as dual-binding site acetylcholinesterase inhibitors - Ignasik_2012_Arch.Pharm.(Weinheim)_345_509
Author(s) : Ignasik M , Bajda M , Guzior N , Prinz M , Holzgrabe U , Malawska B
Ref : Arch Pharm (Weinheim) , 345 :509 , 2012
Abstract : A new series of 2-(diethylaminoalkyl)-isoindoline-1,3-dione derivatives intended as dual binding site cholinesterase inhibitors were designed using molecular modeling and evaluated as inhibitors of acetylcholinesterase (AChE), butyrylcholinesterase (BuChE), and the formation of the beta-amyloid (Abeta) plaques. For AChE inhibitory activity, the spectrophotometric method of Ellman and the electrophoretically mediated microanalysis assay were used, giving good results. Most of the synthesized compounds had AChE inhibitory activity with IC(50) values ranging from IC(50) = 0.9 to 19.5 microM and weak Abeta anti-aggregation inhibitory activity. These results support the outcome of docking studies which tested compounds targeting both the catalytic active site (CAS) and the peripheral anionic site (PAS) of AChE. The most promising selective AChE inhibitors are compounds 10 (IC(50) = 1.2 microM) and 11 (IC(50) = 1.1 microM), with 6-7 methylene chains, which also inhibit Abeta fibril formation.
ESTHER : Ignasik_2012_Arch.Pharm.(Weinheim)_345_509
PubMedSearch : Ignasik_2012_Arch.Pharm.(Weinheim)_345_509
PubMedID: 22467516

Title : Identification and characterization of diarylimidazoles as hybrid inhibitors of butyrylcholinesterase and amyloid beta fibril formation - Karlsson_2012_Eur.J.Pharm.Sci_45_169
Author(s) : Karlsson D , Fallarero A , Brunhofer G , Guzik P , Prinz M , Holzgrabe U , Erker T , Vuorela P
Ref : Eur J Pharm Sci , 45 :169 , 2012
Abstract : In this contribution, a chemical collection of aromatic compounds was screened for inhibition on butyrylcholinesterase (BChE)'s hydrolase activity using Ellman's reaction. A set of diarylimidazoles was identified as highly selective inhibitors of BChE hydrolase activity and amyloid beta (Abeta) fibril formation. New derivatives were synthesized resulting in several additional hits, from which the most active was 6c, 4-(3-ethylthiophenyl)-2-(3-thienyl)-1H-imidazole, an uncompetitive inhibitor of BChE hydrolase activity (IC(5)(0) BChE=0.10 muM; K(i)=0.073 +/- 0.011 muM) acting also on Abeta fibril formation (IC(5)(0)=5.8 muM). With the aid of structure-activity relationship (SAR) studies, chemical motifs influencing the BChE inhibitory activity of these imidazoles were proposed. These bifunctional inhibitors represent good tools in basic studies of BChE and/or promising lead molecules for AD therapy.
ESTHER : Karlsson_2012_Eur.J.Pharm.Sci_45_169
PubMedSearch : Karlsson_2012_Eur.J.Pharm.Sci_45_169
PubMedID: 22108346

Title : Interaction of (benzylidene-hydrazono)-1,4-dihydropyridines with beta-amyloid, acetylcholine, and butyrylcholine esterases - Alptuzun_2010_Bioorg.Med.Chem_18_2049
Author(s) : Alptuzun V , Prinz M , Horr V , Scheiber J , Radacki K , Fallarero A , Vuorela P , Engels B , Braunschweig H , Erciyas E , Holzgrabe U
Ref : Bioorganic & Medicinal Chemistry , 18 :2049 , 2010
Abstract : Approved drugs for the treatment of Alzheimer's disease belong to the group of inhibitors of the acetylcholinesterase (AChE) and NMDA receptor inhibitors. However none of the drugs is able to combat or reverse the progression of the disease. Thus, the recently reported promising multitarget-directed molecule approach was applied here. Using the lead compound DUO3, which was found to be a potent inhibitor of the AChE and butyrylcholinesterase (BuChE) as well as an inhibitor of the formation of the amyloid (Abeta) plaque, new non-permanently positively charged derivatives were synthesized and biologically characterized. In contrast to DUO3 the new bisphenyl-substituted pyridinylidene hydrazones 5 are appropriate to cross the blood-brain barrier due to their pK(a) values and lipophilicity, and to inhibit both the AChE and BuChE. More important some of the pyridinylidene hydrazones inhibit the Abeta fibril formation completely and destruct the already formed fibrils significantly.
ESTHER : Alptuzun_2010_Bioorg.Med.Chem_18_2049
PubMedSearch : Alptuzun_2010_Bioorg.Med.Chem_18_2049
PubMedID: 20149667