Studies on pathogenesis of hypoxic ischemic encephalopathy by using microPET image

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(Introduction) Hypoxic-ischemic encephalopathy (HIE) is induced by intrauterine or perinatal distress and causes neuronal cell loss that presents clinically as either motor dysfunction, stupor, seizure or other neurological sequelae. It is generally accepted that free radicals, including nitric oxide (NO), play an important role in the pathophysiology of ischemic neuronal death. Recently, it has been reported that decreased levels of tetrahydrobiopterin (BH4) may also cause neuronal cell loss in HIE. In this study, we investigated the change in plasma and brain BH4 levels using a newborn piglet hypoxic ischemic (HI) model and evaluated FDG microPET imaging in the brain. (Methods) The animals used in this study were piglets a few days old with a mean weight of 2 kg. The animals were ventilated with a mixture of 6% oxygen and 94% nitrogen, followed by clamping of the bilateral common carotid arteries for 45 minutes. The clamps were then removed and the animals resuscitated with pure oxyg … More en. These HI animals represented the experimental model while sham-treated animals served as controls. Blood samples were obtained at 0, 4, 8 and 12 hours after resuscitation. Plasma biopterin and neopterin levels were determined using high performance liquid chromatography after iodine oxidation in acidic conditions. (Results) In plasma, biopterin concentrations after HI insult increased more at 0 h (377.9 ± 78.7 nM) than before HI insults (80.1 ± 4.3 nM). The values of plasma biopterin peaked at 4 h (604.8 ± 200.9 nM) and slightly decreased at 12 h (445.9 ± 57.8 nM). Plasma neopterin was not detectable in any sample from experimental piglets. However, the biopterin concentration in the cerebral cortex did not increase until 12 hours after HI insults. The brains of the experimental animals on gross examination appeared edematous but no cysts were observed at 12 h. In microPET imaging, HI insult significantly reduced the intense (18)F-FDG uptake by brain tissue after 24 h. (Conclusion) We identified the imbalance of biopterin levels between plasma and brain tissue in the acute phase of HI insult in the cerebral cortex. MicroPET imaging showed low activity in brain tissue after HI. It seemed to enlarge neuronal damage because of the increase in superoxide production due to insufficiency of BH4 production in the brain. Less