Estrogen-IGF-1 interactions in neuroprotection: ischemic stroke as a case study

Abstract

The steroid hormone 17b-estradiol and the peptide hormone insulin-like growth factor (IGF)-1 independently exert neuroprotective actions in neurologic diseases such as stroke. Only a few studies have directly addressed the interaction between the two hormone systems, however, there is a large literature that indicates potentially greater interactions between the 17b-estradiol and IGF-1 systems. The present review focuses on key issues related to this interaction including IGF-1 and sex differences and common activation of second messenger systems. Using ischemic stroke as a case study, this review also focuses on independent and cooperative actions of estrogen and IGF-1 on neuroprotection, blood brain barrier integrity, angiogenesis, inflammation and post-stroke epilepsy. Finally, the review also focuses on the astrocyte, a key mediator of post stroke repair, as a local source of 17b-estradiol and IGF-1. This review thus highlights areas where significant new research is needed to clarify the interactions between these two neuroprotectants.

Keywords: Astrocytes; Blood brain barrier; Estrogen; IGF-1; Inflammation; Neuroprotection; Sex differences.

Figure 1

Schematic representation of the estrogen and IGF-1 receptor interaction with second messenger systems. Homodimers of ER-a and IGFR can activate the MAPK pathway and the PI3K/AKT pathway. Co-treatment with estrogen and IGF-1, which can result in ER-a/IGFR heterodimers, have been shown to inhibit ERK activation.

Figure 2

Schematic representation of the blood brain barrier: The blood brain barrier consists of closely arranged endothelial cells surrounded by basement membrane.Circulating immune cells are shown in the lumen of microvessels, while microglia are located in the brain parenchyma. Astrocytic endfeet contact the endothelial layer and provide physical and growth factor-mediated support to the barrier. Estrogen receptors and the IGF-1 receptor are located on endothelial cells, astrocytes and microglia. Astrocytes also synthesize IGF-1 and neurosteroids including estrogen. Activated microglia can also synthesize IGF-1. In cerebral ischemia, this morphological arrangement ensures steroid and growth factor support for endothelial cells.