Luteinizing hormone receptor mediates neuronal pregnenolone production via up‐regulation of steroidogenic acute regulatory protein expression

Abstract

The functional consequences of luteinizing hormone/human chorionic gonadotropin signaling via neuronal luteinizing hormone/human chorionic gonadotropin receptors expressed throughout the brain remain unclear. A primary function of luteinizing hormone (LH) in the gonads is the stimulation of sex steroid production. As LH can cross the blood-brain barrier, present in cerebrospinal fluid and is expressed by neuronal cells, we tested whether LH might also modulate steroid synthesis in the brain. Treatment of differentiated rat primary hippocampal neurons and human M17 neuroblastoma cells with LH (100 mIU/mL) resulted in a twofold increase in pregnenolone secretion in both cell types, suggesting an increase in P450scc-mediated cleavage of cholesterol to pregnenolone and its secretion from neurons. To explore how LH might regulate the synthesis of pregnenolone, the precursor for steroid synthesis, we treated rat primary hippocampal neurons with LH (0, 10 and 100 mIU/mL) and measured changes in the expression of LH receptor and steroidogenic acute regulatory protein (StAR). LH induced a rapid (within 30 min) increase in the expression of StAR, but induced a dose-dependent decrease in LH receptor expression. Consistent with these results, the suppression of serum LH in young rats treated with leuprolide acetate for 4 months down-regulated StAR expression, but increased LH receptor expression in the brain. Taken together, these results indicate that LH induces neuronal pregnenolone production by modulating the expression of the LH receptor, increasing mitochondrial cholesterol transport and increasing P450scc-mediated cleavage of cholesterol for pregnenolone synthesis and secretion. Keywords: brain, estrogen, human, leuprolide acetate, luteinizing hormone, luteinizing hormone receptor, neuron, pregnenolone, rat, steroidogenic acute regulatory protein. Neurosteroids are synthesized by both neurons and glia, and a number of different functions have been attributed to specific neurosteroids. These include the modulation of memory and behavior, neuroprotection, and neurotrophic activities, such as the regulation of myelinization, microtubule assembly, and the growth of axons and dendrites (e.g. Abbreviations used: CSF, cerebrospinal fluid; EIA, enzyme immunoassay; FBS, fetal bovine serum; LH/hCG, luteinizing hormone/human chorionic gonadotropin; LRBP, LH receptor mRNA binding protein; PBS, phosphate-buffered saline; SDS, sodium dodecyl sulfate; StAR, steroidogenic acute regulatory protein.

Human neurons express type I GnRH receptor and respond to GnRH I by increasing luteinizing hormone expression

“…Irrespective, these data support the use of leuprolide acetate in the treatment of AD; leuprolide acetate has been shown in clinical trials to stabilize cognition in women with mild-to-moderate AD over a 1 year period (LaPlante et al 2006). Thirdly, neuronal LH might impact neurosteroid production, since we have recently demonstrated that LH promotes neurosteroid production in human neuroblastoma cells and in differentiated rat primary neurons (Liu et al 2006). Future studies will therefore be important in determining the exact role of neuronal LH.…”

Gonadotropin-releasing hormone modulates cholesterol synthesis and steroidogenesis in SH-SY5Y cells

“…GnRH receptors (GnRHRs) have been localized in many regions of the brain such as the hippocampus and cortex and detected in human neuronal cell models like the neuroblastoma SH-SY5Y and M17 cells [16,17]. In M17 cells GnRH induces an up-regulation of the LH␤ subunit [17] and LH mediates neuronal pregnenolone production increasing Steroidogenic Acute Regulatory protein (StAR) expression [18]. Moreover, GnRH regulates estrogen synthesis and spine synapse density in rat primary hippocampal cultures [19].…”

Degradation of the electrospun silica nanofiber in a biological medium for primary hippocampal neuron – effect of surface modification

“…38,39 The live cells were counted using trypan blue exclusion assay in a hemocytometer. The SNF substrates on the coverslips were placed under the ultraviolet radiation overnight before use.…”