Boksa P, Zhang Y, Amritraj A, Kar S
Department of Psychiatry, McGill University, Douglas Hospital Research Center, 6875 LaSalle Boulevard, Verdun, Quebec, Canada H4H 1R3.
Neuroscience. 2006 May 12;139(2):451-62. doi: 10.1016/j.neuroscience.2005.12.017. Epub 2006 Jan 31.
Insulin-like growth factors-I and -II and insulin are structurally related mitogenic growth factors with multiple actions in the developing nervous system and adult CNS. Previous studies have demonstrated acute induction of insulin-like growth factors and their receptors, over a time course of several days, in response to hypoxic/ischemic insult to developing or adult brain. The current study tested whether birth insults involving hypoxia may produce long term changes in brain insulin-like growth factor or insulin receptor levels, lasting into adulthood. For this, rats were born vaginally (controls), by cesarean section, or by cesarean section with 15 min of added global anoxia (cesarean section+anoxia), and brain [125I]insulin-like growth factor-I, [125I]insulin-like growth factor-II and [125I]insulin receptor binding sites were assessed autoradiographically at adulthood. [125I]Insulin-like growth factor-I receptor binding sites were increased in all hippocampal subfields (CA1-CA3, dentate gyrus) in rats born either by cesarean section or by cesarean section+anoxia, compared with vaginal birth. [125I]Insulin-like growth factor-II binding was increased in all hippocampal subfields only in rats born by cesarean section+anoxia compared with either vaginal birth or cesarean section groups. [125I]Insulin-like growth factor-I and [125I]insulin-like growth factor-II binding in frontal cortex, striatum and cerebellum were unaffected by birth group, except for increased [125I]insulin-like growth factor-I binding in the cerebellar molecular layer of cesarean-sectioned animals. Birth group had no significant effect on [125I]insulin binding in any brain region. Affinity cross-linking experiments performed with hippocampal membranes from the three birth groups showed that i) [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II recognized bands of molecular weights characteristic of insulin-like growth factor-I and insulin-like growth factor-II receptors, respectively, and ii) [125I]insulin-like growth factor-I and [125I]insulin-like growth factor-II were displaced more potently by their respective unlabeled ligands than by related molecules. It is concluded that birth insults involving hypoxia can induce lasting increases in insulin-like growth factor-I and -II receptors in the CNS. There is specificity with respect to the subtype of insulin-like growth factor receptor affected by the particular birth insult and the brain region affected. It is suggested that enduring increases in levels of insulin-like growth factor receptors consequent to hypoxic birth insult may help to maintain hippocampal function at adulthood, and could modulate responsiveness to insulin-like growth factor administration.
胰岛素样生长因子-I和-II以及胰岛素是结构相关的促有丝分裂生长因子，在发育中的神经系统和成年中枢神经系统中具有多种作用。先前的研究表明，在发育中的或成年大脑受到缺氧/缺血性损伤后的数天时间内，胰岛素样生长因子及其受体可被急性诱导。本研究测试了涉及缺氧的出生损伤是否可能导致大脑胰岛素样生长因子或胰岛素受体水平的长期变化，并持续到成年期。为此，将大鼠经阴道分娩（对照组）、剖宫产或剖宫产并额外进行15分钟全脑缺氧（剖宫产+缺氧），在成年期通过放射自显影术评估大脑中[125I]胰岛素样生长因子-I、[125I]胰岛素样生长因子-II和[125I]胰岛素受体结合位点。与经阴道分娩相比，剖宫产或剖宫产+缺氧出生的大鼠海马所有亚区（CA1-CA3、齿状回）中[125I]胰岛素样生长因子-I受体结合位点均增加。与经阴道分娩组或剖宫产组相比，仅在剖宫产+缺氧出生的大鼠海马所有亚区中[125I]胰岛素样生长因子-II结合增加。额叶皮质、纹状体和小脑中[125I]胰岛素样生长因子-I和[125I]胰岛素样生长因子-II结合不受出生组影响，但剖宫产动物小脑分子层中[125I]胰岛素样生长因子-I结合增加。出生组对任何脑区的[125I]胰岛素结合均无显著影响。对来自三个出生组的海马膜进行的亲和交联实验表明：i）[125I]胰岛素样生长因子-I和[125I]胰岛素样生长因子-II分别识别出胰岛素样生长因子-I和胰岛素样生长因子-II受体特征性分子量的条带；ii）[125I]胰岛素样生长因子-I和[125I]胰岛素样生长因子-II被各自未标记的配体取代的效力比对相关分子更强。得出的结论是，涉及缺氧的出生损伤可诱导中枢神经系统中胰岛素样生长因子-I和-II受体的持续增加。受特定出生损伤影响的胰岛素样生长因子受体亚型和受影响的脑区具有特异性。提示缺氧出生损伤导致的胰岛素样生长因子受体水平的持久增加可能有助于维持成年期海马功能，并可能调节对胰岛素样生长因子给药的反应性。
