title: Prilocaine hydrochloride protects zebrafish from lethal effects of ionizing radiation: role of hematopoietic cell expansion.
abstract: Drug repositioning is an approach of significant translatability, and the present study was undertaken to screen a collection of FDA approved small-molecule clinical compounds for identification of novel radioprotective agents. Screening of JHCCL (Johns Hopkins Clinical Compound Library), a collection of 1,400 FDA approved small molecules, lead to identification of prilocaine hydrochloride, a local anesthetic used widely during dental procedures, as a potential radioprotector. Prilocaine, at a concentration of 20 µM, protected zebrafish from radiation induced (20 Gy) pericardial edema (PE), microphthalmia and rendered 60 % survival advantage over radiation exposed controls. While 40 % survival advantage over radiation exposed controls was achieved with 10 µM prilocaine. Prilocaine, in a dose-dependent manner, scavenged, radiation-induced hydroxyl radicals and maximally (43 %) at the highest concentration (1 mM) tried in this study. However, prilocaine exerted a mild superoxide anion scavenging potential (around 5 %) at all the concentrations used within this study. Prilocaine, at 20 µM concentration, significantly increased erythropoiesis, a marker for HSC function, in caudal hematopoietic tissue (CHT) in wild type and anemic zebrafish embryos (1.48 and 0.85 folds respectively) when compared to untreated (1) and phenylhydrazine (PHZ) (0.41 fold) treated control groups respectively. These results suggest that prilocaine is a radioprotective agent and free radical scavenging and HSC expanding potential seems to be contributing towards its radioprotective action.
authors.forename: Manali
authors.initials: M
authors.lastname: Dimri
authors.forename: Jayadev
authors.initials: J
authors.lastname: Joshi
authors.forename: Nitisha
authors.initials: N
authors.lastname: Shrivastava
authors.forename: Subhajit
authors.initials: S
authors.lastname: Ghosh
authors.forename: Rina
authors.initials: R
authors.lastname: Chakraborti
authors.affiliation: Radiation Biosciences Division, Institute of Nuclear Medicine and Allied Sciences (INMAS), Defense Research and Development Organization (DRDO), Brig SK Majumdar Road, Timarpur Delhi-110054, India. prem_indra@yahoo.co.in.
authors.forename: Prem Kumar
authors.initials: PK
authors.lastname: Indracanti
mesh_terms: D000779:Anesthetics, Local / Q000494:pharmacology*; D000818:Animals; D004305:Dose-Response Relationship, Drug; D004353:Drug Evaluation, Preclinical; D058492:Drug Repositioning; D004625:Embryo, Nonmammalian / Q000528:radiation effects*; D004920:Erythropoiesis / Q000187:drug effects*; D016166:Free Radical Scavengers; D006412:Hematopoietic Stem Cells / Q000166:cytology / Q000187:drug effects*; D008970:Molecular Weight; D011318:Prilocaine / Q000494:pharmacology*; D011833:Radiation Injuries, Experimental / Q000517:prevention & control*; D011837:Radiation-Protective Agents; D015027:Zebrafish / Q000196:embryology* / Q000378:metabolism*
chemical_list: D000779:Anesthetics, Local; D016166:Free Radical Scavengers; D011837:Radiation-Protective Agents; D011318:Prilocaine