Sárközy Gergely, Griesmaier Elke, He Xiangying, Kapelari Klaus, Urbanek Martina, Simbruner Georg, Gressens Pierre, Keller Matthias
Department of Paediatrics IV, Neonatology, Neuropediatrics and Metabolic Diseases, Medical University Innsbruck, Anichstrasse 35, Innsbruck, Austria.
Eur J Paediatr Neurol. 2007 May;11(3):129-35. doi: 10.1016/j.ejpn.2006.11.009. Epub 2007 Jan 11.
Periventricular leukomalacia (PVL) is a major cause of neurological handicap in pre-term infants. At present, there are no effective or causal therapies available. Thyroid hormones play an essential role in brain development and are reported to be decreased in pre-terms and following brain injury in adults.
Excitotoxic brain damage of newborn mice decreases thyroid hormone concentrations. Exogenous T3 administration restores thyroid hormone levels and reduces perinatal brain damage in an animal model of PVL.
To create white and gray matter (WM/GM) lesion mimicking several key aspects of PVL, we injected ibotenic acid (Ibo), a glutamate analog, into the right hemisphere (intracranially (i.c.)) of 5-day-old mice. T3 (10 microg/kg body weight (bw)) was injected intraperitoneally (i.p.) 1 h or repeatedly 1/24/48/72/96 h post-insult. We determined lesion size, number of apoptotic cells in WM/GM and serum T3/T4 concentration at 24 and 120 h after injury. Serum T3/T4 concentration was also determined before and 1 and 2h after T3 administration.
Excitotoxic brain damage did not alter serum T3/T4 concentrations within 120 h of injury. Serum T3 levels were distinctly elevated within 1 h of T3 injection; however, this elevation was relatively short-lived (half-life estimated to be less than 12 h). Neither single nor repetitive T3 treatment regimen reduced excitotoxic lesion size, but it did reduce apoptosis.
T3 replacement does not prevent excitotoxic cell death, but it does reduce developmental neuronal apoptosis, which could participate to the beneficial neuropsychological effects of hormone therapy. Further study is therefore warranted.
脑室周围白质软化（PVL）是早产儿神经功能障碍的主要原因。目前，尚无有效的治疗方法或病因疗法。甲状腺激素在大脑发育中起重要作用，据报道，早产儿和成人脑损伤后甲状腺激素水平会降低。
新生小鼠的兴奋性毒性脑损伤会降低甲状腺激素浓度。在PVL动物模型中，外源性给予T3可恢复甲状腺激素水平并减少围产期脑损伤。
为了制造模仿PVL几个关键方面的白质和灰质（WM/GM）损伤，我们将谷氨酸类似物鹅膏蕈氨酸（Ibo）注射到5日龄小鼠的右半球（颅内（i.c.））。在损伤后1小时或反复在损伤后1/24/48/72/96小时腹腔内（i.p.）注射T3（10微克/千克体重（bw））。我们在损伤后24小时和120小时测定损伤大小、WM/GM中的凋亡细胞数量以及血清T3/T4浓度。在给予T3之前以及给予T3后1小时和2小时也测定血清T3/T4浓度。
兴奋性毒性脑损伤在损伤后120小时内未改变血清T3/T4浓度。注射T3后1小时内血清T3水平明显升高；然而，这种升高持续时间相对较短（半衰期估计小于12小时）。单次或重复的T3治疗方案均未减少兴奋性毒性损伤大小，但确实减少了细胞凋亡。
T3替代不能预防兴奋性毒性细胞死亡，但确实减少了发育性神经元凋亡，这可能参与了激素治疗的有益神经心理学效应。因此，有必要进行进一步研究。
