title: J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeTox™Safety and Genotoxicity Analysis.
abstract: 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 CToxvalue (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 (CToxvalue of 90 μM) in this study, we estimated in vitro neuroprotection efficacy (EC50range 0.06-0.115 μM)/toxicity ratio is 782.6-1500 fold and the neurotrophism (EC50range 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 neuroprotective-neurotrophic agent to treat neurodegenerative disease taking into account current National Institute of Neurological Disorders and Stroke (NINDS) RIGOR guidelines.
authors.affiliation: Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, USA.
authors.forename: Paul A
authors.initials: PA
authors.lastname: Lapchak
authors.affiliation: Division of Cardiothoracic Surgery, Cedars-Sinai Medical Center, Los Angeles, USA.
authors.forename: Rene
authors.initials: R
authors.lastname: Bombien
authors.affiliation: Department of Neurology, Advanced Health Sciences Pavilion, Los Angeles, USA.
authors.forename: Padmesh S
authors.initials: PS
authors.lastname: Rajput