1. ATP Maintenance via Two Types of ATP Regulators Mitigates Pathological Phenotypes in Mouse Models of Parkinson's Disease.
- Author
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Nakano M, Imamura H, Sasaoka N, Yamamoto M, Uemura N, Shudo T, Fuchigami T, Takahashi R, and Kakizuka A
- Subjects
- Animals, Cell Death drug effects, Culture Media, Disease Models, Animal, Estrogens pharmacology, Glycolysis, Glycosides administration & dosage, Glycosides pharmacology, HEK293 Cells, Humans, Mice, Mitochondria drug effects, Mitochondria metabolism, PC12 Cells, Parkinson Disease metabolism, Parkinson Disease pathology, Pregnenolone administration & dosage, Pregnenolone analogs & derivatives, Pregnenolone pharmacology, Rats, Small Molecule Libraries pharmacology, Adenosine Triphosphate metabolism, Estrogens administration & dosage, Parkinson Disease drug therapy, Small Molecule Libraries administration & dosage
- Abstract
Parkinson's disease is assumed to be caused by mitochondrial dysfunction in the affected dopaminergic neurons in the brain. We have recently created small chemicals, KUSs (Kyoto University Substances), which can reduce cellular ATP consumption. By contrast, agonistic ligands of ERRs (estrogen receptor-related receptors) are expected to raise cellular ATP levels via enhancing ATP production. Here, we show that esculetin functions as an ERR agonist, and its addition to culture media enhances glycolysis and mitochondrial respiration, leading to elevated cellular ATP levels. Subsequently, we show the neuroprotective efficacies of KUSs, esculetin, and GSK4716 (an ERRγ agonist) against cell death in Parkinson's disease models. In the surviving neurons, ATP levels and expression levels of α-synuclein and CHOP (an ER stress-mediated cell death executor) were all rectified. We propose that maintenance of ATP levels, by inhibiting ATP consumption or enhancing ATP production, or both, would be a promising therapeutic strategy for Parkinson's disease., (Copyright © 2017 The Authors. Published by Elsevier B.V. All rights reserved.)
- Published
- 2017
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