ENERGY METABOLISM

这项研究的总体目标是研究围产期大脑因缺氧缺血而受损的高能生化机制，以及如何通过特定的治疗方式预防或减少脑损伤。具体目标包括：1)表征围产期脑缺氧缺血期间高能磷酸盐储备的最早变化，并将这些变化与脑能量利用、脑葡萄糖利用、谷氨酸和一氧化氮神经毒性以及细胞内钙积累的扰动相关；2)利用31P磁共振(MR)方法和酶荧光技术将脑高能磷酸盐储备中的浓度与缺氧缺血期间发生的变化相关联；3)表征围产期脑缺氧缺血恢复过程中发生的继发性(延迟性)能量衰竭，并将这种变化与缺氧缺血性脑损伤的存在和严重程度相关联；4)确定糖皮质激素地塞米松保护围产期脑缺氧缺血性损伤的潜在生化机制；5)确定硫酸镁对围产期缺氧缺血性脑损伤的保护作用，如果是，则确定其作用机制；以及6)进一步研究围产期脑缺氧缺血恢复过程中弥散加权和T2加权成像变化的存在和范围，并将任何变化与脑水肿的性质和程度以及相关的神经病理改变相关联。出生后7天的大鼠将接受单侧脑缺氧缺血，在此期间和之后，动物将接受必要的程序，以获得连续的31P和1H核磁共振谱，这将允许测量高能磷酸盐储备和其他代谢产物因侮辱而发生的变化。其他动物将在脑缺氧缺血后的特定时间间隔接受磁共振成像。其他实验将阐明地塞米松、硫酸镁和L-NAME对发育中大鼠缺氧缺血性脑损伤的神经保护作用。分析程序将包括核磁共振光谱的连续测量，以及使用酶促荧光技术对高能磷酸盐储备和其他代谢物的脑组织分析。

The overall objective of this research component is to investigate the high-energy biochemical mechanisms whereby the perinatal brain is damaged by hypoxia-ischemia and how brain injury can be prevented or reduced through specific modalities of therapy. Specific Aims include: 1) to characterize the earliest alterations in high-energy phosphate reserves which occur during perinatal cerebral hypoxia-ischemia and to correlate these changes with perturbations in cerebral energy utilization, cerebral glucose utilization, glutamate and nitric oxide neurotoxicity, and intracellular calcium accumulation; 2) to correlate the concentrations in cerebral high-energy phosphate reserves and the changes which occur during hypoxia-ischemia using 31P magnetic resonance (MR) spectroscopic methods and enzymatic, fluorometric techniques; 3) to characterize the secondary (delayed) energy failure which occurs during recovery from perinatal cerebral hypoxia-ischemia and to correlate the alterations with the presence and severity of hypoxia-ischemic brain damage; 4) to ascertain underlying biochemical mechanisms whereby the glucocorticosteroid, dexamethasone, protects the perinatal brain from hypoxic-ischemic damage; 5) to determine the protective influence of magnesium sulfate on perinatal hypoxic-ischemic brain damage and, if so, to ascertain its mechanism of action; and 6) to investigate further the presence and extend of alterations in diffusion-weighted and T2-weighted imaging during recovery from perinatal cerebral hypoxia-ischemia and to correlate any changes with the nature and extent of cerebral edema and associated neuropathologic alterations. Seven-days postnatal rats will undergo unilateral cerebral hypoxia-ischemia, during and following which the animals will undergo those procedures necessary to obtain sequential 31P and 1H NMR spectra which will allow for measurements of the alterations in high-energy phosphate reserves and other metabolites which result from the insult. Other animals will undergo MR imaging at specific intervals following cerebral hypoxia-ischemia. Other experiments will elucidate the neuroprotective effect of dexamethasone, magnesium sulfate, and L-NAME on hypoxic-ischemic brain damage in the developing rat. Analytic procedures will include sequential measures with NMR spectroscopy as well as brain tissue analysis of high-energy phosphate reserves and other metabolites using enzymatic, fluorometric techniques.