CeeToxâ„¢ Analysis of CNB-001 a Novel Curcumin-Based Neurotrophic/Neuroprotective Lead Compound to Treat Stroke: Comparison with NXY-059 and Radicut

Author(s): Lapchak PA, McKim JM Jr


In the present study, we used a comprehensive cellular toxicity (CeeTox) analysis panel to determine the toxicity profile for CNB-001 [4-((1E)-2-(5-(4-hydroxy-3-methoxystyryl-)-1-phenyl-1H-pyrazoyl-3-yl)vinyl)-2-methoxy-phenol)], which is a hybrid molecule created by combining cyclohexyl bisphenol A, a molecule with neurotrophic activity and curcumin, a spice with neuro-protective activity. CNB-001 is a lead development compound since we have recently shown that CNB-001 has significant preclinical efficacy both in vitro and in vivo. In this study, we compared the CeeTox profile of CNB-001 with two neuroprotective molecules that have been clinically tested for efficacy: the hydrophilic free radical spin trap agent NXY-059 and the hydrophobic free radical scavenger edaravone (Radicut). CeeTox analyses using a rat hepatoma cell line (H4IIE) resulted in estimated C(Tox) value (i.e., sustained concentration expected to produce toxicity in a rat 14-day repeat dose study) of 42 μM for CNB-001 compared with >300 μM for both NXY-059 and Radicut. The CeeTox panel suggests that CNB-001 produces some adverse effects on cellular adenosine triphosphate content, membrane toxicity, glutathione content, and cell mass (or number), but only with high concentrations of the drug. After a 24-h exposure, the drug concentration that produced a half-maximal response (TC(50)) on the measures noted above ranges from 55 to 193 μM. Moreover, all CNB-001-induced changes in the markers were coincident with loss of cell number, prior to acute cell death as measured by membrane integrity, suggesting a cytostatic effect of CNB-001. NXY-059 and Radicut did not have acute toxic effects on H4IIE cells. We also found that CNB-001 resulted in an inhibition of ethoxyresorufin-o-deethylase activity, indicating that the drug may affect cytochrome P4501A activity and that CNB-001 was metabolically unstable using a rat microsome assay system. For CNB-001, an estimated in vitro efficacy/toxicity ratio is 183-643-fold, suggesting that there is a significant therapeutic safety window for CNB-001 and that it should be further developed as a novel neuroprotective agent to treat stroke.

Similar Articles

Modulation of 5-lipoxygenase in proteotoxicity and Alzheimer's disease

Author(s): Valera E, Dargusch R, Maher PA, Schubert D

A broadly neuroprotective derivative of curcumin

Author(s): Liu Y, Dargusch R, Maher P, Schubert D

Novel curcumin derivative CNB-001 mitigates obesity-associated insulin resistance

Author(s): Panzhinskiy E, Hua Y, Lapchak PA, Topchiy E, Lehmann TE, et al.

Suppressive effects of a pyrazole derivative of curcumin on airway inflammation and remodeling

Author(s): Narumoto O, Matsuo Y, Sakaguchi M, Shoji S, Yamashita N, et al.

Neurovascular injury in acute hyperglycemia and diabetes: A comparative analysis in experimental stroke

Author(s): Elgebaly MM, Ogbi S, Li W, Mezzetti EM, Prakash R, et al.

The science of stroke: mechanisms in search of treatments

Author(s): Moskowitz MA, Lo EH, Iadecola C

Design, synthesis and insulin-sensitising effects of novel PTP1B inhibitors

Author(s): Tang YB, Lu D, Chen Z, Hu C, Yang Y, et al.

Discovery of novel PTP1B inhibitors with antihyperglycemic activity

Author(s): Liu Z, Chai Q, Li YY, Shen Q, Ma LP, et al.

Suramin derivatives as inhibitors and activators of protein-tyrosine phosphatases

Author(s): McCain DF, Wu L, Nickel P, Kassack MU, Kreimeyer A, et al.