Female Steroid Hormones Modulate Receptors for Nerve Growth Factor in Rat Dorsal Root Ganglia1

Abstract

Calcitonin gene-related peptide (CGRP) is a vasodilatory peptide, and it is primarily synthesized in dorsal root ganglia (DRG). Plasma CGRP levels increase during pregnancy and with steroid hormones, and nerve growth factor (NGF) stimulates calcitonin/CGRP promoter and CGRP synthesis in DRG. We previously showed that CGRP levels in DRG were stimulated with steroid hormone treatments in vivo but not in vitro. Thus, the stimulation of CGRP by these hormones may be indirect through the upregulation of NGF effects. We hypothesized that the female sex steroid hormones upregulate NGF receptors, trkA and p75(NTR), in DRG. We examined the effects of 17 beta-estradiol (E(2)) and progesterone (P(4)) on NGF receptors in DRG obtained from ovariectomized (ovx) rats. Groups of 4 ovx rats were injected s.c. with 5 microg E(2), 4 mg P(4), or 5 microg E(2) + 4 mg P(4) in 0.2 ml sesame oil or injected with oil only and were killed at 6, 24, and 48 h. In addition, ovx rats were also injected s.c. with varying doses (0.2, 1.0, 5.0, 25 microg) of E(2) (0.5, 1.5, 4, 10 mg) P(4), and (5 microg) E(2) + (0.5, 1.5, 4.0, 10 mg) P(4) in 0.2 ml sesame oil, or vehicle, and killed at 6 (for E(2)) or 24 (for P(4) and E(2) + P(4)) h. Furthermore, groups of ovx rats were also killed at 12 and 24 h; 3 and 7 days; 2, 4, and 6 wk after ovariectomy. The DRGs were collected from all groups and then processed for Western immunoblotting to examine both trkA and p75(NTR) levels. Estradiol increased trkA at 6 h but not p75(NTR). Progesterone caused upregulation of trkA and p75(NTR) at 6 and 24 h. 17 beta-Estradiol + P(4) increased trkA at 6 and 24 h and p75(NTR) at all time points examined. One microgram of E(2) increased trkA but did not affect p75(NTR) levels. Progesterone at 4 and 10 mg upregulated trkA but only 10 mg P(4) increased p75(NTR). Five micrograms of E(2) coinjected with P(4) at 1.5 and 4 mg increased trkA, while p75(NTR) receptor was upregulated when coinjected with P(4) at 1.5 to 10 mg. The ovariectomy caused a decrease in trkA receptors compared to proestrus rats, and these decreases were significant by 6 wk, but surprisingly p75(NTR) increased at 2 wk after ovariectomy. 17 beta-Estradiol increased trkA but not p75(NTR) receptors in DRG, whereas P(4) caused increases in both trkA and p75(NTR) in DRG. In addition, the combination of these steroid hormones had more effect on both receptors than either hormone alone. Thus, we concluded that high levels of female steroid hormones such as those due to pregnancy or hormonal replacement therapy could increase NGF receptor expression in DRG that carry more NGF to elevate the CGRP synthesis in these groups. We suggested that the regulation of NGF receptors by ovarian steroids may underlie steroidal regulation of other factors such as CGRP.

The organizational and activational effects of sex hormones on tactile and thermal hypersensitivity following lumbar nerve root injury in male and female rats

“…The first mechanism is via binding of the sex steroid molecules to associated receptors (estrogen receptor α/β, androgen receptor, progesterone receptor) which then bind to discrete response elements on DNA and mediate transcription or repression of target genes (Truss and Beato, 1993) including, but not limited to: neurotransmitter receptor sub-units (Cyr et al, 2000;D'Souza et al, 2003), trkA and p75 NTR receptors (Lanlua et al, 2001), and peripheral myelin proteins (Melcangi et al, 2000). The second mechanism of action of gonadal hormones is via binding of the steroid molecules to membrane-associated receptors which signal through a variety of intracellular signaling cascades (Moggs and Orphanides, 2001;Simoncini and Genazzani, 2003).…”

Regulation of the immunoexpression of aquaporin 9 by ovarian hormones in the rat oviductal epithelium

“…Because the ratio of the maximal plasma levels of estrogen with respect to that of P4 during proestrus is ϳ1:1,000 (44), we used 5 mg P 4. Furthermore, these doses have been previously reported to produce estrogenic and progestogenic responses in the reproductive tract (20) and other organs (29).…”

Aging of the brain, neurotrophin signaling, and Alzheimer's disease: Is IGF1-R the common culprit?

“…Animal studies have also shown that surgical ovariectomy increases the expression of p75 NTR , while decreasing TrkA, at both mRNA and protein levels. These effects are completely abrogated by exogenous estrogens [51,80,89,123]. Therefore, the loss of ovarian function after menopause would only aggravate the age-associated changes in neurotrophin receptors, further increasing the risk for AD in normally aging women.…”