| Summary: | 博士 === 長庚大學 === 臨床醫學研究所 === 101 === Periventricular white matter injury (PWMI) is the major neuropathological form of brain injury in premature babies. PWMI underlines most of the neurological morbidity encountered in survivals of preterm birth. Approximately 10-15% of these patients exhibit spastic motor deficits and an additional 25-50% later manifest cognitive or behavior deficits, however, there is no effective therapeutic regimens. Several possible pre-and perinatal risk factors, such as intrauterine infection, intraventricular hemorrhage and hypoxic-ischemia have been proposed that are related to PWMI, but perinatal hypoxia-ischemia is thought to be the primary cause of PWMI. Myelin disruption and maturation-dependent vulnerability of the oligodendroglial precursor (pre-OLs) cell represents the major target in PWMI. Thyroid hormone (TH) is essential for oligodendrocyte maturation and myelination. Low levels of TH are commonly found in the first weeks after birth in preterm babies, a phenomenon called transient hypo-thyroxinemia of prematurity (THOP). THOP was a strong independent risk factor for WM injury in premature babies. We investigated whether exogenous administration of thyroxin might stimulate the repair potential of endogenous pre-OLs and protect against WM injury in the immature brain.
We established a PWMI animal model by unilateral carotid artery ligation followed by 6.5% 1 hour of hyoxia in P7 rat pups. The pups were subjected to various dose of T4 at 0 hr, 48 hrs, 96 hrs after HI. At neurofunctional levels, T4 1mg/Kg- treated group had better gait, plane climbing ability and motor coordination. At pathologic levels, T4-1 group was found reducing hypomyelination, decreasing depletion of pre-oligodendrocytes (pre-OLs), improving axonal injury and attenuating reactive astrogliosis. We also disclosed T4 decreased proliferation of pre-OLs which indicated T4might drive pre-OLs toward maturation in this model. We also demonstrated that the protect effect of T4 was through up-regulating signal pathway of brain-derived neurotrophic factor (BDNF).Intracranial stereotactically injection of BDNF receptor antagonist, TrkB-Fc, and BDNF analoge, 7,8 dihydroxyflavone supported the demonstrations.
We explored the mechanism of T4 effect in pre-OLs at molecular biological and functional levels. Our study demonstrated that T4 post-treatment in hypoxic-ischemic immature brain would yield Nkx2.2 mRNA up-regulation in the periventricular white matter. To test the Nkx2.2 gene function in vitro, we obtained N19 and N20.1 cell lines. We disclosed that N19 and N20.1 showed differently responsive to thyroid hormone. Addition of tri-iodothyronine (T3) accelerates cell maturation in N19 cells by increasing myelin production and changing cell morphological complexity into relative mature type, whereas the myelin production and cell morphology complexity kept consistent regardless of TH treatment in N20.1 cells. N19 cells were the potential candidate cell line for our future experiments.
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