The Effects of Oxiracetam (CT-848) on Local Cerebral Glucose Utilization after Focal Cerebral Ischemia in Rats.

Abstract

-The effects of oxiracetam on the reduction of brain metabolism induced by focal cerebral ischemia were investigated by measuring local cerebral glucose uti lization (LCGU) in rats 24 hr after left middle cerebral artery occlusion. Focal cere bral ischemia reduced LCGU in the entire ipsilateral cortex, the greatest reduction being in the lateral parts of the frontoparietal cortex. LCGU was slightly reduced in the contralateral cortex; this reduction was considered to be caused by diaschisis. Ox iracetam was administered intraperitoneally for 3 days prior to middle cerebral artery occlusion. In the ipsilateral cortex, LCGU reduction was minimized in the ischemic center areas by oxiracetam at a dose of 400 mg/kg and in more extensive areas, by a dose of 800 mg/kg. Moreover, oxiracetam at a dose of 800 mg/kg enhanced metabo lism impaired by diaschisis in the caudal areas of the contralateral cortex. These find ings suggest that oxiracetam minimizes the reduction of brain function induced by ischemia and may therefore be useful in the treatment of cerebrovascular disease.The pharmacological actions of oxiracetam are similar to those of other pyrrolidone de rivatives, including piracetam, aniracetam and pramiracetam. Oxiracetam and other pyrroli done derivatives have been reported to im prove memory and learning ability in normal animals (1) and to prevent amnesia and the decrease in brain acetylcholine level induced by scopolamine and electroshock in rats (2 4). Oxiracetam and piracetam stimulate high affinity choline uptake in the rat hippocampus (5). Thus, the effects of pyrrolidone deriva tives may be related to the enhancement of brain cholinergic mechanisms. In addition, ox iracetam and other pyrrolidone derivatives have been shown to augment hippocampal long-term potentiation in rats (6) and guinea pigs (7,8). These investigations suggest that pyrrolidone derivatives enhance cerebral func tion in normal brain and protect it in impaired brain. Since we have recently found that ox iracetam protects rats and mice against cere bral hypoxia, we expected to find that ox iracetam had protective effects against cere bral ischemia in this experiment.Focal cerebral ischemia induced by middle cerebral artery (MCA) occlusion (9) is a use ful model (9, 10) for studying ischemic brain damage, as well as cerebral blood flow (11, 12), energy metabolism (13), and neurotrans mitters (14,15). Sokoloff (16) showed that cerebral functional activity was closely coupled to energy metabolism, especially glucose con sumption. In this study, we investigated

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“…In this study, the MSI results showed that the levels of glucose and citric acid increased, whereas the levels of ATP, ADP, and AMP decreased after the 2-VO surgery. The increase in glucose caused by the 2-VO surgery was likely due to the lower glucose utilization in the brain as suggested by a previous report 53 . The increased levels of citric acid and decreased levels of downstream products, including glutamate and aspartate, could have been caused by the arrest of the TCA cycle at the step from citrate to α-ketoglutarate.…”

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“…In recent years, there is an increasing clinical application of nootropic drugs for the therapy of central nervous system diseases such as traumatic brain injury and cerebral hemorrhage. Previous evidences suggested that Oxiracetam, a new nootropic drug, improved local cerebral glucose utilization (Hokonohara, Sako, Shinoda, Tomabechi, & Yonemasu, 1992) promoted the synthesis of proteins and nucleic acids, and produced a protective effect in cerebrovascular damage (Kometani et al, 1991). Another study clearly indicated Oxiracetam inhibited cells apoptosis in brain tissues and facilitated neurological function recovery .…”