The mechanism of neurovascular damage in neonatal rat with hypoxic-ischemic brain injury

  • 許 宜菁

Student thesis: Doctoral Thesis


Brain cells are extremely sensitive to oxygen deprivation Some brain cells actually start dying just under five minutes after their oxygen supply is cut As a result brain hypoxia can kill brain cells and rapidly cause severe brain damage This is an emergency and the sooner medical attention is given and the oxygen supply restored the lower the chances of severe brain damage or death Neonatal hypoxic-ischemic (HI) stress can lead to HI encephalopathy There is still no effective drug against neonatal HI brain injury Most neuroprotective agents have not benefitted patients with stroke Because researchers have reported that neurovascular units can be the targets of hypoxic stress and that both neurons and microvessels respond equally rapidly to the insult it has been hypothesized that vascular protection would be more effective than neuroprotection against HI brain damage To clarify the function of neurovascular unit in neonatal HI brain injury a major cause of neonatal mortality and long-term disability we used 7-day-old rat pups with an animal model of HI injury: one side carotid artery was permanently ligated and each rat pup was subjected to systemic hypoxia (8% O for 2 h) to induce ipsilateral cerebral HI injury This study investigated whether neurovascular unit damage is an early event in HI neonatal brain damage and how nitric oxide contributes to HI-induced brain injury The data show that IgG leakage and microvascular change were observed with transmission electron microscopy (TEM) as early as 1 h after HI insult Nitrotyrosine was overexpressed immediately after reoxygenation The hypothesis that “microvascular damage occurs soon after hypoxic-ischemia: neuronal nitric oxide synthase (nNOS) is activated and contributes to brain injury” was tested Treating the rat pups with 7-nitroindazole (7-NI) an nNOS inhibitor and aminoguanidine (AG) an inducible NOS (iNOS) inhibitor before hypoxia provided complete and partial neuroprotection respectively I also use ischemic preconditioning (IP) as a complete brain protection model for comparison Pretreatment with 7-NI and IP protected cerebral blood flow (CBF) from hypoxia-induced hypoperfusion that reduced the brain infarct area In summary nNOS-mediated vascular damage is an early event caused by hypoxic-ischemia and that vascular protection might be better than neuroprotection However how the IP is related to endothelial cells requires additional investigation
Date of Award2014 Jul 21
Original languageEnglish
SupervisorChao-Ching Huang (Supervisor)

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