Birth insults involving hypoxia produce long-term increases in hippocampal [ 125I]insulin-like growth factor-I and -II receptor binding in the rat

Abstract

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.