From the Departments of Basic Science (A.M., T.L., J.H.Z.), Neurosurgery (J.H.Z.), Anesthesiology (M.B., J.H.Z.), and Psychology (R.H.), Loma Linda University, CA.
Stroke. 2014 Mar;45(3):828-34. doi: 10.1161/STROKEAHA.113.003754. Epub 2014 Jan 14.
Transforming growth factor-β (TGF-β) overproduction and activation of the TGF-β pathway are associated with the development of brain injury following germinal matrix hemorrhage (GMH) in premature infants. We examined the effects of GMH on the level of TGF-β1 in a novel rat collagenase-induced GMH model and determined the effect of inhibition of the TGF receptor I.
In total, 92 seven-day old (P7) rats were used. Time-dependent effects of GMH on the level of TGF-β1 and TGF receptor I were evaluated by Western blot. A TGF receptor I inhibitor (SD208) was administered daily for 3 days, starting either 1 hour or 3 days after GMH induction. The effects of GMH and SD208 on the TGF-β pathway were evaluated by Western blot at day 3. The effects of GMH and SD208 on cognitive and motor function were also assessed. The effects of TGF receptor I inhibition by SD208 on GMH-induced brain injury and underlying molecular pathways were investigated by Western blot, immunofluorescence, and morphology studies 24 days after GMH.
GMH induced significant delay in development, caused impairment in both cognitive and motor functions, and resulted in brain atrophy in rat subjects. GMH also caused deposition of both vitronectin (an extracellular matrix protein) and glial fibrillary acidic protein in perilesion areas, associated with development of hydrocephalus. SD208 ameliorated GMH-induced developmental delay, improved cognitive and motor functions, and attenuated body weight loss. SD208 also decreased vitronectin and glial fibrillary acidic protein deposition and decreased GMH-induced brain injury.
Increased level of TGF-β1 and activation of the TGF-β pathway associate with the development of brain injury after GMH. SD208 inhibits GMH-induced activation of the TGF-β pathway and leads to an improved developmental profile, partial recovery of cognitive and motor functions, and attenuation of GMH-induced brain atrophy and hydrocephalus.
转化生长因子-β（TGF-β）的过度产生和 TGF-β 途径的激活与早产儿脑室内出血（GMH）后脑损伤的发展有关。我们在一种新型胶原酶诱导的 GMH 大鼠模型中研究了 GMH 对 TGF-β1 水平的影响，并确定了抑制 TGF 受体 I 的效果。
共使用了 92 只 7 天大（P7）的大鼠。通过 Western blot 评估 GMH 对 TGF-β1 和 TGF 受体 I 水平的时间依赖性影响。在 GMH 诱导后 1 小时或 3 天时，每天给予 TGF 受体 I 抑制剂（SD208），持续 3 天。在第 3 天，通过 Western blot 评估 GMH 和 SD208 对 TGF-β 途径的影响。还评估了 GMH 和 SD208 对认知和运动功能的影响。通过 Western blot、免疫荧光和形态学研究，在 GMH 后 24 天，研究了 SD208 通过抑制 TGF 受体 I 对 GMH 诱导的脑损伤及其潜在分子途径的影响。
GMH 导致发育迟缓，认知和运动功能受损，并导致大鼠脑萎缩。GMH 还导致细胞外基质蛋白 vitronectin 和神经胶质纤维酸性蛋白在损伤周围区域沉积，与脑积水的发展有关。SD208 改善了 GMH 诱导的发育迟缓，改善了认知和运动功能，并减轻了体重减轻。SD208 还减少了 vitronectin 和神经胶质纤维酸性蛋白的沉积，并减轻了 GMH 诱导的脑损伤。
TGF-β1 水平升高和 TGF-β 途径的激活与 GMH 后脑损伤的发展有关。SD208 抑制 GMH 诱导的 TGF-β 途径激活，导致发育谱改善，认知和运动功能部分恢复，并减轻 GMH 诱导的脑萎缩和脑积水。
