Rao Raghavendra, Nashawaty Motaz, Fatima Saher, Ennis Kathleen, Tkac Ivan
Division of Neonatology, Department of Pediatrics, University of Minnesota, Minneapolis, MN, USA.
Center for Neurobehavioral Development, University of Minnesota, Minneapolis, MN, USA.
NMR Biomed. 2018 May;31(5):e3910. doi: 10.1002/nbm.3910. Epub 2018 Mar 13.
Hyperglycemia (blood glucose concentration >150 mg/dL) is common in extremely low gestational age newborns (ELGANs; birth at <28 week gestation). Hyperglycemia increases the risk of brain injury in the neonatal period. The long-term effects are not well understood. In adult rats, hyperglycemia alters hippocampal energy metabolism. The effects of hyperglycemia on the developing hippocampus were studied in rat pups. In Experiment 1, recurrent hyperglycemia of graded severity (moderate hyperglycemia (moderate-HG), mean blood glucose 214.6 ± 11.6 mg/dL; severe hyperglycemia (severe-HG), 338.9 ± 21.7 mg/dL; control, 137.7 ± 2.6 mg/dL) was induced from postnatal day (P) 3 to P12. On P30, the hippocampal neurochemical profile was determined using in vivo H MR spectroscopy. Dendritic arborization in the hippocampal CA1 region was determined using microtubule-associated protein (MAP)-2 immunohistochemistry. In Experiment 2, continuous hyperglycemia (mean blood glucose 275.3 ± 25.8 mg/dL; control, 142.3 ± 2.6 mg/dL) was induced from P2 to P6 by injecting streptozotocin (STZ) on P2. The mRNA expression of glycogen synthase 1 (Gys1), lactate dehydrogenase (Ldh), glucose transporters 1 (Glut1) and 3 (Glut3) and monocarboxylate transporters 1 (Mct1), 2 (Mct2) and 4 (Mct4) in the hippocampus was determined on P6. In Experiment 1, MRS demonstrated lower lactate concentration and glutamate/glutamine (Glu/Gln) ratio in the severe-HG group, compared with the control group (p < 0.05). Phosphocreatine/creatine ratio was higher in both hyperglycemia groups (p < 0.05). MAP-2 histochemistry demonstrated longer apical segment length, indicating abnormal synaptic efficacy in both hyperglycemia groups (p < 0.05). Experiment 2 showed lower Glut1, Gys1 and Mct4 expression and higher Mct1 expression in the hyperglycemia group, relative to the control group (p < 0.05). These results suggest that hyperglycemia alters substrate transport, lactate homeostasis, dendritogenesis and Glu-Gln cycling in the developing hippocampus. Abnormal neurochemical profile and dendritic structure due to hyperglycemia may partially explain the long-term hippocampus-mediated cognitive deficits in human ELGANs.
高血糖症（血糖浓度>150mg/dL）在极早早产儿（ELGANs；妊娠<28周出生）中很常见。高血糖症会增加新生儿期脑损伤的风险。其长期影响尚不清楚。在成年大鼠中，高血糖会改变海马体的能量代谢。在新生大鼠幼崽中研究了高血糖对发育中海马体的影响。在实验1中，从出生后第3天（P3）至P12诱导出不同严重程度的复发性高血糖症（中度高血糖（中度-HG），平均血糖214.6±11.6mg/dL；重度高血糖（重度-HG），338.9±21.7mg/dL；对照组，137.7±2.6mg/dL）。在P30时，使用体内氢磁共振波谱法测定海马体神经化学特征。使用微管相关蛋白（MAP）-2免疫组织化学法测定海马体CA1区的树突分支。在实验2中，通过在P2注射链脲佐菌素（STZ），从P2至P6诱导出持续性高血糖症（平均血糖275.3±25.8mg/dL；对照组，142.3±2.6mg/dL）。在P6时测定海马体中糖原合酶1（Gys1）、乳酸脱氢酶（Ldh）、葡萄糖转运蛋白1（Glut1）和3（Glut3）以及单羧酸转运蛋白1（Mct1）、2（Mct2）和4（Mct4）的mRNA表达。在实验1中，磁共振波谱显示，与对照组相比，重度-HG组的乳酸浓度和谷氨酸/谷氨酰胺（Glu/Gln）比值较低（p<0.05）。两个高血糖组的磷酸肌酸/肌酸比值均较高（p<0.05）。MAP-2组织化学显示顶端节段长度更长，表明两个高血糖组的突触效能异常（p<0.05）。实验2表明，与对照组相比，高血糖组的Glut1、Gys1和Mct4表达较低，而Mct1表达较高（p<0.05）。这些结果表明，高血糖会改变发育中海马体的底物转运、乳酸内稳态、树突形成和Glu-Gln循环。高血糖导致的异常神经化学特征和树突结构可能部分解释了人类ELGANs中由海马体介导的长期认知缺陷。
