SUMMARYPurpose: The metabolic and biochemical changes that occur during epileptogenesis remain to be determined. 18 F-Fluorodeoxyglucose positron emission tomography (FDG-PET) and proton magnetic resonance spectroscopy ( 1 H MRS) are noninvasive techniques that provide indirect information on ongoing pathologic changes. We, therefore, utilized these methods to assess changes in glucose metabolism and metabolites in the rat lithium-pilocarpine model of epilepsy as markers of epileptogenesis from baseline to chronic spontaneous recurrent seizures (SRS). Methods: PET and MRS were performed at baseline, and during the acute, subacute, silent, and chronic periods after lithium-pilocarpine induced status epilepticus (SE). Sequential changes in glucose metabolism on 18 F-FDG PET using SPM2 and the ratios of percent injected dose per gram (%ID)/g of regions of interest (ROIs) in the bilateral amygdala, hippocampus, basal ganglia with the thalamus, cortex, and hypothalamus normalized to the pons were determined. Voxels of interest (VOIs) on 1 H MRS were obtained at the right hippocampus and the basal ganglia. NAA/Cr levels and Cho/Cr at various time points were compared to baseline values. Key Findings: Of 81 male Sprague-Dawley rats, 30 progressed to SRS.18 F-FDG PET showed widespread global hypometabolism during the acute period, returning to baseline level during the subacute period. Glucose metabolism, however, declined in part of the hippocampus during the silent period, with the hypometabolic area progressively expanding to the entire limbic area during the chronic period. 1 H MRS showed that the NAA/Cr levels in the hippocampus and basal ganglia were reduced during the acute period and were not restored subsequently from the subacute to the chronic period without any significant change in the Cho/Cr ratio throughout the entire experiment. Significance: Serial metabolic and biochemical changes in the lithium-pilocarpine model of epilepsy indirectly represent the process of human epileptogenesis. Following initial irreversible neural damage by SE, global glucose metabolism transiently recovered during the subacute period without neuronal recovery. Progressive glucose hypometabolism in the limbic area during the silent and chronic periods may reflect the important role of the hippocampus in the formation of ongoing epileptic network during epileptogenesis.

ABSTRACT:It is not known whether deeper or longer hypothermia (HT) can achieve better neuroprotection against hypoxic ischemic encephalopathy (HIE) in neonates. To compare the neuroprotective effects of different durations and temperatures of postischemic HT in neonatal rats with severe HIE, 7-d-old rats were subjected to the Rice-Vannucci model for 150 min hypoxia. Only the rats with identified brain lesions in diffusion-weighted MRI were assigned to normothermia (NT, 36°C/48 h) or four HT (HT-30°C/48 h; HT-30°C/24 h; HT-33°C/48 h; and HT-33°C/24 h) groups.1 H-magnetic resonance spectroscopy ( 1 H-MRS) and T2-weighted MRI were obtained serially, and functional studies were performed. HT groups showed significantly greater residual hemispheric volume and better rotarod and cylinder tests than did the NT group at 5 wk postischemia. HT groups also showed lower lactate-plus-lipid level in 1 H-MRS than did the NT group at 7 d postischemia. All of these outcome variables, however, did not differ among the 4 HT subgroups, despite a trend toward greater residual brain volume in the 48-h HT versus 24-h HT subgroups. In conclusion, neither reducing the target temperature from 33 to 30°C nor prolonging the duration from 24 to 48 h produced further improvements in neurologic outcomes in neonatal rat with HIE. (Pediatr Res 68: 303-308, 2010) H ypothermia (HT) is one of the most promising neuroprotective modalities against hypoxic ischemic encephalopathy (HIE) in neonatal brain (1). However, in neonates with severe HIE, little neuroprotection could be achieved using current HT protocols in which whole-body or head cooling is performed for 48 to 72 h by maintaining the core temperature within a range of 33.5 to 34.5°C (2-5). In animal studies, the efficacy of postischemic HT was also limited in the subgroup with severe ischemic injury (6,7). To treat severe HIE by HT, a recent review suggested a "deeper" and "more prolonged" cooling (8). However, no controlled clinical trials have tested this supposition and several experimental studies failed to clearly demonstrate an effect of postischemic HT protocols with different target temperatures or duration in a perinatal HIE model (9 -11).The 7-d-old rat with unilateral carotid artery ligation and subsequent exposure to 8% hypoxia is the most commonly used model to evaluate the efficacy of therapeutic interventions in the developing brain (12), and several studies have used this Rice-Vannucci model (RVM) to test the effects of HT (10,11,(13)(14)(15)(16)(17)(18)(19). However, an experimental design composed of a shorter duration of hypoxia, representing "mild" ischemic lesions, is not appropriate for evaluating the neuroprotective effect of HT against severe HIE. To date, few experimental studies have used the RVM with hypoxia exposure longer than 120 min (10,13,19), but none of these have reported the long-term neuroprotective effect of postischemic HT.The aim of this study was to investigate the long-term neuroprotective effect of various postischemic HT protocols with different t...

In intracerebral hemorrhage (ICH), delayed secondary neural damages largely occur from perihematomal edema (PHE) resulting from the disruption of the blood-brain barrier (BBB). PHE is often considered the principal cause of morbidity and mortality in patients with ICH. Nevertheless, the main cellular mechanism as well as the specific BBB component involved in the formation of PHE after ICH remains elusive. Herein, we evaluated the role of AQP4, a water channel expressed on the astrocytes of the BBB, in the formation of PHE in ICH. The static and dynamic functions of the BBB were evaluated by analyzing the microstructure and leakage assay. Protein changes in the PHE lesion were analyzed and the control mechanism of AQP4 expression by reactive oxygen species was also investigated. Delayed PHE formation due to BBB disruption after ICH was confirmed by the decreased coverage of multiple BBB components and increased dynamic leakages. Microstructure assay showed that among the BBB components, AQP4 showed a markedly decreased expression in the PHE lesions. The decrease in AQP4 was due to microenvironmental ROS derived from the hemorrhage and was restored by treatment with ROS scavenger. AQP4-deficient mice had significantly larger PHE lesions and unfavorable survival outcomes compared with wild-type mice. Our data identify AQP4 as a specific BBB-modulating target for alleviating PHE in ICH. Further comprehensive studies are needed to form the preclinical basis for the use of AQP4 enhancers as BBB modulators for preventing delayed cerebral edema after ICH.