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3-Methyl-1-phenyl-2-pyrazolin-5-one is a neuroprotective agent used for the purpose of aiding neurological recovery following acute brain ischemia and subsequent cerebral infarction. It acts as a potent antioxidant and strongly scavenges free radicals, protecting against oxidative stress and neuronal apoptosis. It has been marketed solely in Japan by Mitsubishi Pharma since 2001. and marketed in India by Edinburgh Pharmaceuticals by the brand name Arone 3-Methyl-1-phenyl-2-pyrazolin-5-one (CAS NO.: 89-25-8) has been shown to attenuate methamphetamine- and 6-OHDA-induced dopaminergic neurotoxicity in the striatum and substantia nigra, and does not affect methamphetamine-induced dopamine release or hyperthermia. It has also been demonstrated to protect against MPTP-mediated dopaminergic neurotoxicity to the substantia nigra, though notably not to the striatum. In the present study, we used a murine model of hypoxia/ischemia. Thirty minutes of hypoxia/ischemia produced markedly damage to the ipsilateral cortex, hippocampus, and striatum, as determined by TTC staining. On the other hand, we showed that peripheral administration of 3-Methyl-1-phenyl-2-pyrazolin-5-one protected brain from hypoxia/ischemic injury as evidenced by reduction in infarct volume and hemispheric swelling. Improvement of neurological score was also observed in the same animals that showed reduction in infarct volume and hemispheric swelling. Simultaneously, we found that 3-Methyl-1-phenyl-2-pyrazolin-5-one can effectively suppress ER dysfunction in vivo and in vitro. Moreover, the present findings indicate that the protective effect of 3-Methyl-1-phenyl-2-pyrazolin-5-one on ischemic injury may be medicated in part by restoration of ER dysfunction. In cerebral ischemia, excessive generation of oxygen free radicals followed by lipid peroxidation is thought to play an important role in the secondary injury (Seki et al., 1998). Exogenous radical scavengers have been demonstrated to suppress oxidative stress and thus prevent ischemic injury (Zoratti and Szabo, 1995; Crompton, 1999). 3-Methyl-1-phenyl-2-pyrazolin-5-one has been shown to exert a protective effect against cerebral ischemic injury by inhibiting OH- and iron-dependent lipid peroxidations, both of which are essential in mediating ischemic cell damage (Watanabe et al., 1994). On the other hand, ample evidence suggested that ER damage is involved in neuronal cell death induced by cerebral ischemia (Kumar et al., 2003; Tajiri et al., 2004). Thus, in the present study, we investigated the effect of 3-Methyl-1-phenyl-2-pyrazolin-5-one on ER dysfunction under pathological conditions. In mice subjected to 30-min hypoxia/ischemia followed by a given period of recovery, we observed an increase in the level of the transcription factor CHOP and activation of caspase-12 in the ischemic cortex. The results indicate that hypoxia/ischemia caused severe ER damage and triggered ER stress-associated apoptosis. On the other hand, treatment with 3-Methyl-1-phenyl-2-pyrazolin-5-one significantly inhibited caspase-12 activation and CHOP induction. In addition, we observed suppression of phospho-eIF2a, upstream of CHOP. Therefore, the protective effects of 3-Methyl-1-phenyl-2-pyrazolin-5-one in hypoxia/ischemic injury may be partly due to inhibition of ER stress and subsequent apoptotic signaling pathway. We found that 3-Methyl-1-phenyl-2-pyrazolin-5-one also inhibited ER stress even if the condition was nonischemic. Treatment of cells with Tm, an inducer of ER stress, caused ER dysfunction as indicated by the induction of representative genes related to ER stress. However, Tm did not cause the production of ROS in primary cultured glial cells. Thus, it was suggested that ER stress does not induce ROS production in glial cells. In addition, other free radical scavengers, such as NAC and ebselen, provided no protection against ER dysfunction. The results indicated that the property of inhibiting ER stress is specific to edaravone. Thus, the protective effect of 3-Methyl-1-phenyl-2-pyrazolin-5-one against hypoxia/ischemia may involve a novel pathway that directly attenuates ER stress in addition to suppressing ROS production. Considering the findings of the present study, we speculate that 3-Methyl-1-phenyl-2-pyrazolin-5-one has multiple effects, although the mechanism of its actions needs to be elucidated further. In summary, the present results suggest that 3-Methyl-1-phenyl-2-pyrazolin-5-one provided protection against ER dysfunction induced by hypoxia/ischemia, and the protective effect may be mediated by an inhibition of ER stress as well as the radical scavenging action. Therefore, the restoration of ER dysfunction by 3-Methyl-1-phenyl-2-pyrazolin-5-one may be a novel neuroprotective mechanism. Furthermore, on the basis of its protection against ER damage, 3-Methyl-1-phenyl-2-pyrazolin-5-one may also be useful for treating other neurodegenerative diseases, such as Alzheimer's disease and Parkinson's disease. Want to learn more information about 3-Methyl-1-phenyl-2-pyrazolin-5-one, you can access the guidechem.com. Guidechem.com is just a place for you to look for some chemicals.
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