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J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeTox(™) Safety and Genotoxicity Analysis.

Lapchak PA, Bombien R, Rajput PS - J Neurol Neurophysiol (2013)

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, USA.

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 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 neuroprotective-neurotrophic agent to treat neurodegenerative disease taking into account current National Institute of Neurological Disorders and Stroke (NINDS) RIGOR guidelines.

No MeSH data available.


Related in: MedlinePlus

CTox Ranking ProfileCTox ranking values for toxic control compounds and J-147 are provided in parentheses. Metabolic Stability
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Figure 4: CTox Ranking ProfileCTox ranking values for toxic control compounds and J-147 are provided in parentheses. Metabolic Stability

Mentions: For each compound studied, a CTox value was generated by CeeTox Inc., using a patented proprietary algorithm [49]. CTox values were generated from the TC50 values in this report. The CTox ranking for J-147, which is an estimate of a sustained concentration expected or necessary to produce toxicity in a rat 14 day repeat dose study was 90 μM. To validate the CeeTox assay, rotenone [50,51], a mitochondrial inhibitor that directly interferes with electron transport chain to inhibit ATP synthesis was used as well as camptothecin [52–54], a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I were used. The CTox ranking for rotenone and camptothecin were 0.03 and 0.1 μM, respectively (Figure 4).


J-147 a Novel Hydrazide Lead Compound to Treat Neurodegeneration: CeeTox(™) Safety and Genotoxicity Analysis.

Lapchak PA, Bombien R, Rajput PS - J Neurol Neurophysiol (2013)

CTox Ranking ProfileCTox ranking values for toxic control compounds and J-147 are provided in parentheses. Metabolic Stability
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4215638&req=5

Figure 4: CTox Ranking ProfileCTox ranking values for toxic control compounds and J-147 are provided in parentheses. Metabolic Stability
Mentions: For each compound studied, a CTox value was generated by CeeTox Inc., using a patented proprietary algorithm [49]. CTox values were generated from the TC50 values in this report. The CTox ranking for J-147, which is an estimate of a sustained concentration expected or necessary to produce toxicity in a rat 14 day repeat dose study was 90 μM. To validate the CeeTox assay, rotenone [50,51], a mitochondrial inhibitor that directly interferes with electron transport chain to inhibit ATP synthesis was used as well as camptothecin [52–54], a cytotoxic quinoline alkaloid which inhibits the DNA enzyme topoisomerase I were used. The CTox ranking for rotenone and camptothecin were 0.03 and 0.1 μM, respectively (Figure 4).

Bottom Line: 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.

View Article: PubMed Central - PubMed

Affiliation: Department of Neurology and Neurosurgery, Cedars-Sinai Medical Center, Los Angeles, USA.

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 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 neuroprotective-neurotrophic agent to treat neurodegenerative disease taking into account current National Institute of Neurological Disorders and Stroke (NINDS) RIGOR guidelines.

No MeSH data available.


Related in: MedlinePlus