Department of Pediatrics, Division of Neonatology and Developmental Biology, Neonatal Research Center, David Geffen School of Medicine UCLA, Los Angeles, CA 90095-1752, USA.
Brain Res. 2013 Feb 7;1495:61-75. doi: 10.1016/j.brainres.2012.11.050. Epub 2012 Dec 7.
Prenatal nutrient restriction (NR) culminating in intra-uterine growth restriction (IUGR) with postnatal catch up growth leads to diabesity. In contrast, postnatal NR with growth restriction (PNGR) superimposed on IUGR (IPGR) protects young and aging adults from this phenotype. We hypothesized that PNGR/IPGR will compromise the blood-brain metabolic profile impairing neurobehavior and predisposing to Alzheimer's disease (AD). NR (50%) in late gestation followed by cross-fostering of rat pups to either ad lib fed (CON) or NR (50%) lactating mothers generated CON, IUGR, PNGR and IPGR male (M) and female (F) offspring that were examined through the life span. In PNGR/IPGR plasma/CSF glucose and lactate decreased while ketones increased in (M) and (F) (PN21, PN50). In addition increased brain glucose transporters, Glut1 & Glut3, greater brain derived neurotrophic factor (BDNF), reduced Glut4, with unchanged serotonin transporter concentrations were noted in (F) (PN50-60). While (F) displayed more hyperactivity, both (F) and (M) exhibited anxiety although socially and cognitively unimpaired (PN25-28&50). Aging (15-17 m) (F) not (M), expressed low plasma insulin, reduced brain IRS-2, pAkt, and pGSK-3β(Ser9), unchanged pPDK1, pTau or lipoprotein receptor related protein 1 (LRP1), higher glial fibrillary acidic protein (GFAP) and spinophilin but a 10-fold increased amyloid-β42. We conclude that therapeutically superimposing PNGR on IUGR (IPGR) should be carefully weighed in light of unintended consequences related to perturbed neurobehavior and potential predilection for AD.
产前营养限制（NR）导致宫内生长受限（IUGR），随后出现追赶性生长，导致糖尿病肥胖症。相比之下，在 IUGR 上叠加出生后 NR（PNGR）可保护年轻和老年成年人免受这种表型影响。我们假设 PNGR/IPGR 将损害血脑代谢谱，损害神经行为，并易患阿尔茨海默病（AD）。在妊娠晚期进行 NR（50%），然后将大鼠幼崽交叉寄养给自由进食（CON）或 NR（50%）哺乳期母亲，生成 CON、IUGR、PNGR 和 IPGR 雄性（M）和雌性（F）后代，通过寿命进行检查。在 PNGR/IPGR 中，血浆/CSF 葡萄糖和乳酸降低，而酮体在雄性（M）和雌性（F）中增加（PN21、PN50）。此外，还观察到大脑葡萄糖转运蛋白 Glut1 和 Glut3 增加，脑源性神经营养因子（BDNF）增加，Glut4 减少，而 50 至 60 天的雌性（F）中 5-羟色胺转运体浓度不变。虽然（F）表现出更多的多动，但（F）和（M）都表现出焦虑，尽管社交和认知能力不受影响（PN25-28 和 50）。衰老（15-17 个月）（F）而非（M），表现出低血浆胰岛素、减少大脑 IRS-2、pAkt 和 pGSK-3β（Ser9）、不变的 pPDK1、pTau 或脂蛋白受体相关蛋白 1（LRP1），更高的神经胶质纤维酸性蛋白（GFAP）和螺旋蛋白，但淀粉样蛋白-β42 增加了 10 倍。我们得出结论，在考虑到与神经行为紊乱和潜在 AD 倾向相关的意外后果的情况下，在 IUGR 上叠加出生后 NR（IPGR）的治疗应该慎重权衡。
