Protective Effect of DM-9384, a Novel Pyrrolidone Derivative, against Experimental Cerebral Anoxia

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Abstract
The protective effects of DM-9384 [N-(2,6-dimethylphenyl)-2-(2-oxo-1-pyrrolidinyl) acetamide] against cerebral anoxia were investigated using various animal models. Oral administration of DM-9384 resulted in a significant prolongation of survival time in mice and rats subjected to the normobaric hypoxia; its minimal effective doses were 30 and 10 mg/kg, respectively. A significant protection by this drug against hypobaric hypoxia, histotoxic anoxia and cerebral ischemia also occurred in mice at a dose of 100 mg/kg, p.o. Bifemelane (100-300 mg/kg, p.o.) was protective against these models except for hypobaric hypoxia, and the effects piracetam, aniracetam and pramiracetam (1000 mg/kg, p.o.) were variable depending on the type of anoxia model used. DM-9384 (100 mg/kg and lower) attenuated the hypolocomotion and the disturbance of cerebral energy metabolism such as a decrease in ATP, an increase in lactate and lactate/pyruvate ratio induced by hypoxia in rats. The spontaneous motor activity, uptake and utilization of brain glucose in normal animals, however, were not influenced by this drug. Based on these results, DM-9384 is characterized as a broad spectrum anti-anoxic drug with negligible CNS depression, and the cerebral protective effect of this drug may be, at least in part, attributable to its ability to improve the cerebral energy metabolic disturbance.