| Autor: |
Ibhazehiebo K; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Canada., Gavrilovici C; Alberta Children's Hospital Research Institute, University of Calgary, Canada.; Departments of Pediatrics, Clinical Neurosciences, Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada., de la Hoz CL; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Canada., Ma SC; Departments of Neurology and Neurobiology, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona, USA., Rehak R; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Canada., Kaushik G; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Canada., Meza Santoscoy PL; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Canada., Scott L; Alberta Children's Hospital Research Institute, University of Calgary, Canada.; Departments of Pediatrics, Clinical Neurosciences, Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada., Nath N; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Canada., Kim DY; Departments of Neurology and Neurobiology, Barrow Neurological Institute, St Joseph's Hospital and Medical Center, Phoenix, Arizona, USA., Rho JM; Alberta Children's Hospital Research Institute, University of Calgary, Canada.; Departments of Pediatrics, Clinical Neurosciences, Physiology and Pharmacology, Cumming School of Medicine, University of Calgary, Calgary, Canada., Kurrasch DM; Department of Medical Genetics, Cumming School of Medicine, University of Calgary, Calgary, Canada.; Alberta Children's Hospital Research Institute, University of Calgary, Canada. |
| Abstrakt: |
Despite the development of newer anti-seizure medications over the past 50 years, 30-40% of patients with epilepsy remain refractory to treatment. One explanation for this lack of progress is that the current screening process is largely biased towards transmembrane channels and receptors, and ignores intracellular proteins and enzymes that might serve as efficacious molecular targets. Here, we report the development of a novel drug screening platform that harnesses the power of zebrafish genetics and combines it with in vivo bioenergetics screening assays to uncover therapeutic agents that improve mitochondrial health in diseased animals. By screening commercially available chemical libraries of approved drugs, for which the molecular targets and pathways are well characterized, we were able to reverse-identify the proteins targeted by efficacious compounds and confirm the physiological roles that they play by utilizing other pharmacological ligands. Indeed, using an 870-compound screen in kcna1-morpholino epileptic zebrafish larvae, we uncovered vorinostat (Zolinza™; suberanilohydroxamic acid, SAHA) as a potent anti-seizure agent. We further demonstrated that vorinostat decreased average daily seizures by ∼60% in epileptic Kcna1-null mice using video-EEG recordings. Given that vorinostat is a broad histone deacetylase (HDAC) inhibitor, we then delineated a specific subset of HDACs, namely HDACs 1 and 3, as potential drug targets for future screening. In summary, we have developed a novel phenotypic, metabolism-based experimental therapeutics platform that can be used to identify new molecular targets for future drug discovery in epilepsy. |
