ABSTRACT
Neurological disorders are undoubtedly among the most alarming diseases humans might face. In treatment of neurological disorders, the blood-brain barrier (BBB) is a challenging obstacle preventing drug penetration into the brain. Advances in dendrimer chemistry for central nervous system (CNS) treatments are presented here. A poly(amido)amine (PAMAM) dendrimer bioconjugate with a streptavidin adapter for the attachment of dendrons or any biotinylated drug is constructed. In vitro studies on porcine or murine models and in vivo mouse studies are performed and reveal the permeation of dendronized streptavidin (DSA) into the CNS. The bioconjugate is taken up mainly by the caveolae pathway and transported across the BBB via transcytosis escaping from lysosomes. After transcytosis DSA are delivered to astrocytes and neurons. Furthermore, DSA offer high biocompatibility in vitro and in vivo. In summary, a new strategy for implementing therapeutic PAMAM function as well as drug delivery in neuropathology is presented here.
ABSTRACT
Mutations in chromatin modifier genes are frequently associated with neurodevelopmental diseases. We herein demonstrate that the chromodomain helicase DNA-binding protein 7 (Chd7), frequently associated with CHARGE syndrome, is indispensable for normal cerebellar development. Genetic inactivation of Chd7 in cerebellar granule neuron progenitors leads to cerebellar hypoplasia in mice, due to the impairment of granule neuron differentiation, induction of apoptosis and abnormal localization of Purkinje cells, which closely recapitulates known clinical features in the cerebella of CHARGE patients. Combinatory molecular analyses reveal that Chd7 is required for the maintenance of open chromatin and thus activation of genes essential for granule neuron differentiation. We further demonstrate that both Chd7 and Top2b are necessary for the transcription of a set of long neuronal genes in cerebellar granule neurons. Altogether, our comprehensive analyses reveal a mechanism with chromatin remodellers governing brain development via controlling a core transcriptional programme for cell-specific differentiation.
Subject(s)
Brain/metabolism , Cell Differentiation/genetics , DNA-Binding Proteins/genetics , Gene Expression Regulation, Developmental , Neurons/metabolism , Animals , Brain/cytology , Brain/growth & development , Cerebellum/cytology , Cerebellum/growth & development , Cerebellum/metabolism , Chromatin/genetics , Chromatin/metabolism , DNA-Binding Proteins/metabolism , Gene Expression Profiling , Humans , Mammals/genetics , Mammals/growth & development , Mammals/metabolism , Mice, Inbred C57BL , Mice, Knockout , Mice, Transgenic , Neurons/cytologySubject(s)
Abscess/therapy , Drainage/methods , Escherichia coli Infections/therapy , Magnetic Resonance Imaging, Interventional , Pregnancy Complications, Infectious/therapy , Staphylococcal Infections/therapy , Abscess/diagnostic imaging , Abscess/microbiology , Adult , Anti-Bacterial Agents/therapeutic use , Catheters, Indwelling , Drainage/instrumentation , Escherichia coli Infections/diagnostic imaging , Escherichia coli Infections/microbiology , Female , Humans , Pregnancy , Pregnancy Complications, Infectious/diagnostic imaging , Pregnancy Complications, Infectious/microbiology , Staphylococcal Infections/diagnostic imaging , Staphylococcal Infections/microbiology , Treatment OutcomeABSTRACT
The design and synthesis of a polyphenylene dendrimer (PPD 3) with discrete binding sites for lipophilic guest molecules and characteristic surface patterns is presented. Its semi-rigidity in combination with a precise positioning of hydrophilic and hydrophobic groups at the periphery yields a refined architecture with lipophilic binding pockets that accommodate defined numbers of biologically relevant guest molecules such as fatty acids or the drug doxorubicin. The size, architecture, and surface textures allow to even penetrate brain endothelial cells that are a major component of the extremely tight blood-brain barrier. In addition, low to no toxicity is observed in in vivo studies using zebrafish embryos. The unique PPD scaffold allows the precise placement of functional groups in a given environment and offers a universal platform for designing drug transporters that closely mimic many features of proteins.
Subject(s)
Dendrimers/administration & dosage , Dendrimers/chemistry , Doxorubicin/administration & dosage , Polymers/administration & dosage , Animals , Brain/cytology , Cell Line/drug effects , Chemistry Techniques, Synthetic , Dendrimers/pharmacokinetics , Doxorubicin/chemistry , Drug Carriers , Drug Design , Embryo, Nonmammalian/drug effects , Endothelial Cells/drug effects , Endothelial Cells/metabolism , Humans , Hydrophobic and Hydrophilic Interactions , Mice , Polymers/chemistry , Polymers/pharmacokinetics , Tissue Distribution , Zebrafish/embryologyABSTRACT
Alcohol has been the most important knockout drug in history and literature and continues to play an essential role up to now. Blunt force to the head in the form of a knockout punch is another mechanism leading to a transient loss of consciousness. Diethyl ether and chloroform are among the classical knockout substances. Although they have meanwhile been replaced by modern sedatives and hypnotics, their use is still observed in isolated cases.
Subject(s)
Alcoholic Beverages/history , Anesthetics/history , Chloroform/history , Ether/history , Illicit Drugs/history , Medicine in the Arts , Paintings/history , Sodium Oxybate/history , Unconsciousness/history , History, 16th Century , History, 17th Century , History, 18th Century , History, 19th Century , History, 20th Century , History, Ancient , HumansABSTRACT
Owing to the rapid progress in the development of synthetic pharmaceuticals, the classical knockout drugs such as chloroform and diethyl ether have been superseded by highly effective sedative and hypnotic drugs (e. g. methyprylone, clozapine and especially benzodiazepines). These are frequently given to the victim unnoticed by adding them to an alcoholic drink. In this way, alcohol still plays an important role as an interaction partner. The article presents relevant case examples together with their criminalistic background.
Subject(s)
Benzodiazepines/history , Drug Overdose/history , Hypnotics and Sedatives/history , Poisoning/history , Substance-Related Disorders/history , Female , Germany , History, 20th Century , Humans , MaleABSTRACT
Currently, gamma-hydroxybutyric acid (GHB/"liquid ecstasy") is frequently abused as a knockout substance. Its detection and the interpretation of the results present numerous problems which are illustrated by case reports. In this context, hair analysis and the increasing significance of gamma-butyrolactone (GBL) are also discussed.
