ABSTRACT
Small molecule modulators of mitochondrial function have been attracted much attention in recent years due to their potential therapeutic applications for neurodegenerative diseases. The mitochondrial translocator protein (TSPO) is a promising target for such compounds, given its involvement in the formation of the mitochondrial permeability transition pore in response to mitochondrial stress. In this study, we performed a ligand-based pharmacophore design and virtual screening, and identified a potent hit compound, 7 (VH34) as a TSPO ligand. After validating its biological activity against amyloid-ß (Aß) induced mitochondrial dysfunction and in acute and transgenic Alzheimer's disease (AD) model mice, we developed a library of analogs, and we found two most active compounds, 31 and 44, which restored the mitochondrial membrane potential, ATP production, and cell viability under Aß-induced mitochondrial toxicity. These compounds recovered learning and memory function in acute AD model mice with improved pharmacokinetic properties.
Subject(s)
Alzheimer Disease/drug therapy , Mitochondria/drug effects , Neuroprotective Agents/pharmacology , Protein Aggregation, Pathological/drug therapy , Small Molecule Libraries/pharmacology , Alzheimer Disease/metabolism , Alzheimer Disease/pathology , Amyloid beta-Peptides/antagonists & inhibitors , Amyloid beta-Peptides/metabolism , Animals , Cell Survival/drug effects , Cells, Cultured , Disease Models, Animal , Drug Evaluation, Preclinical , Humans , Ligands , Mice , Mitochondria/metabolism , Molecular Structure , Neuroprotective Agents/chemical synthesis , Neuroprotective Agents/chemistry , Protein Aggregation, Pathological/metabolism , Protein Aggregation, Pathological/pathology , Small Molecule Libraries/chemical synthesis , Small Molecule Libraries/chemistry , Transcriptional Regulator ERG/antagonists & inhibitors , Transcriptional Regulator ERG/metabolismABSTRACT
BACKGROUND: To determine the aqueous humour levels of vascular endothelial growth factor (VEGF) and erythropoietin (EPO) in eyes with diabetic macular oedema before and after intravitreal EPO injection. DESIGN: Prospective interventional case series. PARTICIPANTS: Eleven eyes of 11 patients with diabetic macular oedema, and 10 eyes of 10 patients with cataract surgery as controls. MAIN OUTCOMES MEASURES: EPO and VEGF levels in aqueous humour before and after intravitreal EPO injection in patients and compared with controls. METHODS: Eyes with diabetic macular oedema received an intravitreal injection of EPO (1000 IU/0.05 mL), followed by various intraocular procedures at different intervals (1-54 days) after injection. An aqueous humour sample was obtained and aqueous humour levels of EPO and VEGF were measured using enzyme-linked immunosorbent assay. RESULTS: The aqueous levels of EPO and VEGF were significantly elevated in diabetic macular oedema eyes compared to control eyes (P < 0.05). EPO levels in patients correlated with VEGF levels (r = 0.816, P = 0.002) and central macular thickness at baseline (r = 0.618, P = 0.043). After intravitreal EPO injection, aqueous EPO levels were significantly elevated, whereas aqueous VEGF levels were varied according to the time interval since injection. Visual acuity and central macular thickness were not different after injection, compared to before injection. Aqueous EPO levels did not correlate with serum EPO levels(r = 0.299, P = 0.371). CONCLUSIONS: EPO is locally expressed and is correlated with VEGF in eyes with diabetic macular oedema. The role of EPO and the effect of intravitreal EPO in patients with diabetic macular oedema need to be further defined.
Subject(s)
Aqueous Humor/metabolism , Diabetic Retinopathy/metabolism , Erythropoietin/administration & dosage , Erythropoietin/metabolism , Macular Edema/metabolism , Vascular Endothelial Growth Factor A/metabolism , Adult , Diabetic Retinopathy/diagnosis , Diabetic Retinopathy/drug therapy , Enzyme-Linked Immunosorbent Assay , Epoetin Alfa , Female , Fluorescein Angiography , Humans , Intravitreal Injections , Macular Edema/diagnosis , Macular Edema/drug therapy , Male , Middle Aged , Prospective Studies , Recombinant Proteins , Tomography, Optical Coherence , Visual Acuity/physiologyABSTRACT
BACKGROUND: To determine the effect on macular function of removal of the internal limiting membrane (ILM) during epiretinal membrane surgery. DESIGN: Prospective, interventional study. PARTICIPANTS: Twenty-two eyes of 22 patients with idiopathic epiretinal membranes undergoing surgery. METHODS: Histologic analysis of the ILM specimens were classified based on amount of retinal tissue fragments attached to the removed ILM. The ophthalmic examinations were assessed prospectively. MAIN OUTCOME MEASURES: The visual acuity, optical coherence tomography, and multifocal electroretinography at baseline, 1 and 3 months after surgery. RESULTS: The visual acuity at baseline, 1 and 3 months after surgery were not different between the small and large retinal debris groups. On multifocal electroretinography, there was no significant difference in response of the N1 amplitude, N1 latency, and P1 amplitude between the small and large retinal debris groups at baseline, and 1 and 3 months after surgery. However, compared to the small debris group, the P1 latencies in the foveal areas were delayed in the large debris group at 1 and 3 months (P = 0.020, P = 0.047, respectively). The central retinal thickness was significantly reduced in the large debris group, while the status of the photoreceptor line was not different based on optical coherence tomography between the small and large debris groups 3 months after surgery (P = 0.047). CONCLUSION: Large amounts of retinal debris attached to the removed ILM did not affect visual acuity. However, the ultrastructural findings of Muller cell damage might be related to subtle macular dysfunction on multifocal electroretinography after surgery.