ABSTRACT
Multiple pathogenic factors have been suggested to play a role in the development of Alzheimer's disease (AD). The multifactorial nature of AD also suggests the potential use of compounds with polypharmacology as effective disease-modifying agents. Recently, we have developed a bivalent strategy to include cell membrane anchorage into the molecular design. Our results demonstrated that the bivalent compounds exhibited multifunctional properties and potent neuroprotection in a cellular AD model. Herein, we report the mechanistic exploration of one of the representative bivalent compounds, 17MN, in MC65 cells. Our results established that MC65 cells die through a necroptotic mechanism upon the removal of tetracycline (TC). Furthermore, we have shown that mitochondrial membrane potential and cytosolic Ca2+ levels are increased upon removal of TC. Our bivalent compound 17MN can reverse such changes and protect MC65 cells from TC removal induced cytotoxicity. The results also suggest that 17MN may function between the Aß species and RIPK1 in producing its neuroprotection. Colocalization studies employing a fluorescent analog of 17MN and confocal microscopy demonstrated the interactions of 17MN with both mitochondria and endoplasmic reticulum, thus suggesting that 17MN exerts its neuroprotection via a multiple-site mechanism in MC65 cells. Collectively, these results strongly support our original design rationale of bivalent compounds and encourage further optimization of this bivalent strategy to develop more potent analogs as novel disease-modifying agents for AD.
Subject(s)
Alzheimer Disease/drug therapy , Cholesterol/analogs & derivatives , Curcumin/analogs & derivatives , Neuroprotective Agents/pharmacology , Alzheimer Disease/pathology , Alzheimer Disease/physiopathology , Amyloid beta-Peptides/metabolism , Animals , Apoptosis/drug effects , Apoptosis/physiology , Brain/drug effects , Brain/pathology , Brain/physiopathology , Calcium/metabolism , Caspase 3/metabolism , Cell Line, Tumor , Cholesterol/chemistry , Cholesterol/pharmacology , Curcumin/chemistry , Curcumin/pharmacology , Endoplasmic Reticulum/drug effects , Endoplasmic Reticulum/pathology , Endoplasmic Reticulum/physiology , Humans , Male , Membrane Potential, Mitochondrial/drug effects , Membrane Potential, Mitochondrial/physiology , Mice, Inbred C57BL , Molecular Structure , Neuroprotective Agents/chemistry , Peptide Fragments/metabolism , Receptor-Interacting Protein Serine-Threonine Kinases/metabolismABSTRACT
Critically ill patients routinely receive H(2) antagonists for stress ulcer prophylaxis while at risk for gastrointestinal bleeding. In these patients it is often difficult to assess accurately the cause of adverse effects such as thrombocytopenia. We evaluate the literature to better define thrombocytopenia related to H(2) antagonist administration and discuss mechanism, potential as a risk factor and case reports describing the severity and duration of thrombocytopenia.
