Reproductive hormones regulate the selective permeability of the blood-brain barrier

Abstract

Reproductive hormones have been demonstrated to modulate both gap and tight junction protein expression in the ovary and other reproductive tissues, however the effects of changes in reproductive hormones on the selective permeability of the blood-brain barrier (BBB) remain unclear. Age-related declines in BBB integrity correlate with the loss of serum sex steroids and increase in gonadotropins with menopause/andropause. To examine the effect of reproductive senescence on BBB permeability and gap and tight junction protein expression/localization, female mice at 3 months of age were either sham operated (normal serum E2 and gonadotropins), ovariectomized (low serum E2 and high serum gonadotropins) or ovariectomized and treated with the GnRH agonist leuprolide acetate (low serum E2 and gonadotropins). Ovariectomy induced a 2.2-fold increase in Evan's blue dye extravasation into the brain. The expression and localization of the cytoplasmic membrane-associated tight junction protein zona occludens 1 (ZO-1) in microvessels was not altered among groups indicating that the increased paracellular permeability was not due to changes in this tight junction protein. However, ovariectomy induced a redistribution of the gap junction protein connexin-43 (Cx43) such that immunoreactivity relocalized from along the extracellular microvascular endothelium to become associated with endothelial cells. An increase in Cx43 expression in the mouse brain following ovariectomy was suppressed in ovariectomized animals treated with leuprolide acetate, indicating that serum gonadotropins rather than sex steroids were modulating Cx43 expression. These results suggest that elevated serum gonadotropins following reproductive senescence may be one possible cause of the loss of selective permeability of the BBB at this time. Furthermore, these findings implicate Cx43 in mediating changes in BBB permeability, and serum gonadotropins in the cerebropathophysiology of age-related neurodegenerative diseases such as stroke and Alzheimer's disease.

Pre- and post-estrogen administration in global cerebral ischemia reduces blood-brain barrier breakdown in ovariectomized rats

“…Age-related increases in the blood-brain barrier permeability were attributed to the loss of sex hormones in the serum (22). It was reported that ovariectomy caused an almost 2.2-fold increase in the Evans Blue permeability of the blood-brain barrier (22). In our study, BBB permeability significantly increased in all brain areas after ovariectomy, relative to the control group, and this result is parallel to the result of the abovecited studies.…”

“…Similarly, estrogen was reported to perform a protective action against brain injuries inflicted in different conditions and the resulting impairments to the bloodbrain barrier (5,6). Age-related increases in the blood-brain barrier permeability were attributed to the loss of sex hormones in the serum (22). It was reported that ovariectomy caused an almost 2.2-fold increase in the Evans Blue permeability of the blood-brain barrier (22).…”

“…The integrated function of the cerebral microvasculature, tight junction proteins, brain microvascular endothelial cells, cellular transport pathways, and enzymatic machinery jointly contribute to normal BBB integrity. Aging, systemic diseases, and ischemic injury can disrupt these processes, resulting in a decline in overall BBB function and integrity (22). Alterations to hormone levels at the onset of menopause and as a result of estrogen treatment may cause further changes in BBB functions (17).…”

Immune stress up regulates <i>TLR4</i> and <i>Tollip</i> gene expression in the hypothalamus of ewes

“…It is worth mentioning, however, that BBB permeability is not constant, but depends on the physiological state of animals. It was previously found that BBB permeability could be affected by the level of gonadal steroids (Wilson et al, 2008), melatonin (Turgut et al, 2007), and stress (Esposito et al, 2001). So it can be speculated that the varied results on the ability of LPS to cross the BBB could be, at least partially, caused by the different physiological states of the animals used in those studies.…”

Lactate dyscrasia: a novel explanation for amyotrophic lateral sclerosis

“…Dysregulation of the hypothalamicpituitary-gonadal (HPG) axis with aging has been postulated to drive aging-related diseases via alterations in cell signaling throughout the body Vadakkadath Meethal and Atwood, 2005). This altered cell cycle signaling, resulting from the decline in sex steroid and inhibin production and elevation in gonadotropin-releasing hormone, gonadotropin, and activin signaling, has been shown to drive postreproductive degenerative mechanisms involved in Alzheimer's disease Casadesus et al, 2006), osteoporosis (Sun et al, 2006), and blood-brain barrier integrity and associated diseases such as stroke (Wilson et al, 2008).…”