The Radical Scavenger Edaravone (3-Methyl-1-phenyl-2-pyrazolin-5-one) Reacts with a Pterin Derivative and Produces a Cytotoxic Substance That Induces Intracellular Reactive Oxygen Species Generation and Cell Death

Abstract

Cytotoxic effects of the combined use of edaravone (3-methyl-1-phenyl-2-pyrazolin-5-one), a radical scavenger and an approved medicine for acute brain infarction in Japan, with a pterin derivative, were examined in vitro. When pancreatic cancer cell line Panc-1 cells were incubated with 50 to 400 M of a pterin derivative, 2-(N,N-dimethylaminomethyleneamino)-6-formyl-3-pivaloylpteridine-4-one (DFP), and the equivalent dose of edaravone, reactive oxygen species (ROS), were generated, and cell death was induced. ROS generation and the loss of mitochondrial membrane potential (MMP) preceding cell death were simultaneously monitored using time-lapse microscopy with an ROSsensitive dye and a probe to monitor MMP, respectively. Cell death was also estimated quantitatively by 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium bromide assay. ROS generation and cell death were prominent when more than 100 M of each agent was used in combination, whereas the sole use of each agent did not show any effects even at the highest dose, 400 M. Chemical analysis revealed that DFP and edaravone react immediately in aqueous solution and produce a new compound named DFP-E. DFP-E chemically reacted with NADH much faster than DFP and generated ROS, and biologically, it was much more cell-permeable than DFP. These findings collectively indicated that the combined use of DFP with edaravone produced DFP-E, which caused intracellular ROS generation and cell death. Cell death was observed in normal cells, and edaravone reacted with another pterin derivative to yield an ROS-generating compound. As a result, care should be taken with the clinical use of edaravone when pterin derivatives stay in the body.Edaravone (Fig. 1, left), a free radical scavenger, has neuroprotective effects (Watanabe et al

Edaravone Protects Against Apoptotic Neuronal Cell Death and Improves Cerebral Function After Traumatic Brain Injury in Rats

“…Consistent with these data, edaravone was previously shown to inhibit free radical-mediated DNA peroxidation and decrease numbers of 8-OHdG-positive cells in the brain following neonatal hypoxic-ischemia [22]. Furthermore, edaravone inhibited and absorbed free radical production and decreased numbers of 4-HNE-and 8-OHdG-positive cells in the brain at an early time point after infarction [25] and ischemia [11,25,26].…”

“…Following the initial mechanical insult, secondary effects including blood-brain barrier disruption, excitotoxic damage, and free radical production (such as O 2 -and •OH) are induced due to the circulatory disturbance caused by ischemia [8][9][10]. 3-Methyl-1-phenyl-pyrazolin-5-one (edaravone) is a novel brain-permeable free radical scavenger which interacts biochemically with a wide range of free radicals (O 2 -and •OH), donates electrons, and eventually transforms itself to the stable chemical, 2-oxo-3-(phenylhydrazono)-butanoic acid (OPB) [11]. Experimentally, edaravone was shown to inhibit O 2 -and •OH production induced by brain injury and to reduce brain edema in a rat ischemic stroke model [12].…”

The Novel Free Radical Scavenger, Edaravone, Increases Neural Stem Cell Number Around the Area of Damage Following Rat Traumatic Brain Injury

“…Edaravone interacts biochemically with a wide range of free radicals including O 2 -and Á OH to which it donates electrons and thus transforms into the stable chemical, 2-oxo-3-(phenylhydrazono)-butanoic acid (Arai et al 2008). Edaravone inhibited O 2 -and Á OH production induced by brain injury and reduced brain edema in the rat ischemic stroke model (Nishi et al 1989).…”

Interaction of tetracyanoethylene (TCE) with active methylene compounds: synthesis, reactions and spectral characterization of some novel 2-pyrazoline-5-one compounds. Computational studies on the synthesized molecules by DFT

“…Pyrazolones have all found wide use in many fields. Their greatest utility resides in pharmaceuticals [1][2][3][4][5][6][7][8][9][10][11][12][13][14][15][16][17], dyes (textile and photography) [18][19][20], lesser extent in plastics [21], and agrochemicals [22]. Pyrazolones exhibit a wide range of biological properties [1]: analgesic, cells [12].…”