J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeToxÃ¢ÂÂ¢ Safety and Genotoxicity AnalysisPaul A Lapchak1*, Rene Bombien2 and Padmesh S Rajput3
- Corresponding Author:
- Paul A Lapchak, PhD, FAHA
Department of Neurology & Neurosurgery
Cedars-Sinai Medical Center
Advanced Health Sciences Pavilion, USA
E-mail: [email protected]
Received date: June 21, 2013; Accepted date: July 18, 2013; Published date: July 25, 2013
Citation: Lapchak PA, Bombien R, Rajput PS (2013) J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeTox™ Safety and Genotoxicity Analysis. J Neurol Neurophysiol 4:158. doi:10.4172/2155-9562.1000158
Copyright: © 2013 Lapchak PA, et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
J-147 is a broad spectrum neuroprotective phenyl hydrazide compound with significant neurotrophic properties related to the induction of brain-derived neurotrophic factor (BDNF). Because this molecule is pleiotropic, it may have substantial utility in the treatment of a wide range of neurodegenerative diseases including acute ischemic stroke (AIS), traumatic brain injury(TBI), and Alzheimer’s disease(AD) where both neuroprotection and neurotrophism would be beneficial. Because of the pleiotropic actions of J-147, we sought to determine the safety profile of the drug using multiple assay analysis. For CeeTox analyses, we used a rat hepatoma cell line (H4IIE) resulted in estimated CTox value (i.e.: sustained concentration expected to produce toxicity in a 14 day repeat dosing study) of 90 μM for J-147. The CeeTox panel shows that J-147 produced some adverse effects on cellular activities, in particular mitochondrial function, but only with high concentrations of the drug. J-147 was also not genetoxic with or without Aroclor-1254 treatment. For J-147, based upon extensive neuroprotection assay data previously published, and the CeeTox assay (CTox value of 90 μM) in this study, we estimated in vitro neuroprotection efficacy (EC50 range 0.06-0.115 μM)/toxicity ratio is 782.6-1500 fold and the neurotrophism (EC50 range 0.025 μM)/toxicity ratio is 3600, suggesting that there is a significant therapeutic safety window for J-147 and that it should be further developed as a novel neuroprotectiveneurotrophic agent to treat neurodegenerative disease taking into account current National Institute of Neurological Disorders and Stroke (NINDS) RIGOR guidelines.