Schwann Cell Autocrine and Paracrine Regulatory Mechanisms, Mediated by Allopregnanolone and BDNF, Modulate PKCε in Peripheral Sensory Neurons

Protein kinase type C-ε (PKCε) plays important roles in the sensitization of primary afferent nociceptors, such as ion channel phosphorylation, that in turn promotes mechanical hyperalgesia and pain chronification. In these neurons, PKCε is modulated through the local release of mediators by the surrounding Schwann cells (SCs). The progesterone metabolite allopregnanolone (ALLO) is endogenously synthesized by SCs, whereas it has proven to be a crucial mediator of neuron-glia interaction in peripheral nerve fibers. Biomolecular and pharmacological studies on rat primary SCs and dorsal root ganglia (DRG) neuronal cultures were aimed at investigating the hypothesis that ALLO modulates neuronal PKCε, playing a role in peripheral nociception. We found that SCs tonically release ALLO, which, in turn, autocrinally upregulated the synthesis of the growth factor brain-derived neurotrophic factor (BDNF). Subsequently, glial BDNF paracrinally activates PKCε via trkB in DRG sensory neurons. Herein, we report a novel mechanism of SCs-neuron cross-talk in the peripheral nervous system, highlighting a key role of ALLO and BDNF in nociceptor sensitization. These findings emphasize promising targets for inhibiting the development and chronification of neuropathic pain.

MONITORING OF PROGESTERONE AND ESTRONE FECAL METABOLITES THROUGHOUT GESTATION IN EWES

The aim of this study was to monitor the progesterone and fecal estrone metabolites throughout gestation in ewes correlating with the serum levels of these steroid hormones. Therefore, fecal and serum samples were collected from 5 weeks before mating and gestation until two weeks postparturition. Serum levels of progesterone and estrone and their fecal metabolites were measured by enzyme immunoassay. Serum and fecal hormonal patterns showed a significant correlation for both hormones (R = 0.8572, P < 0.001 for progesterone and R = 0.5893, P < 0.001 for estrone). The fecal progesterone metabolite levels showed significant increasing values among the three thirds of pregnancies, consistent with the serum levels and with the literature. Additionally, the prepartum peak of estrone in the fecal matrix was identified but without observation in the serum matrix due to the blood collection interval used. Therefore, this study demonstrated the viability of progesterone and estrone monitoring throughout gestation using fecal samples, making noninvasive longitudinal endocrine monitoring throughout gestation possible in this species.

5α-dihydroprogesterone concentrations and synthesis in non-pregnant mares

In vivo and in vitro evidence indicates that the bioactive, 5α-reduced progesterone metabolite, 5α-dihydroprogesterone (DHP) is synthesized in the placenta, supporting equine pregnancy, but its appearance in early pregnancy argues for other sites of synthesis also. It remains unknown if DHP circulates at relevant concentrations in cyclic mares and, if so, does synthesis involve the non-pregnant uterus? Jugular blood was drawn daily from cyclic mares (n = 5). Additionally, ovariectomized mares (OVX) and geldings were administered progesterone (300 mg) intramuscularly. Blood was drawn before and after treatment. Incubations of whole equine blood and hepatic microsomes with progesterone were also investigated for evidence of DHP synthesis. Sample analysis for progesterone, DHP and other steroids employed validated liquid chromatography–tandem mass spectrometry methods. Progesterone and DHP appeared a day (d) after ovulation in cyclic mares, was increased significantly by d3, peaking from d5 to 10 and decreased from d13 to 17. DHP was 55.5 ± 3.2% of progesterone concentrations throughout the cycle and was highly correlated with it. DHP was detected immediately after progesterone administration to OVX mares and geldings, maintaining a relatively constant ratio with progesterone (47.2 ± 2.9 and 51.2 ± 2.7%, respectively). DHP was barely detectable in whole blood and hepatic microsome incubations. We conclude that DHP is a physiologically relevant progestogen in cyclic, non-pregnant mares, likely stimulating the uterus, and that it is synthesized peripherally from luteal progesterone but not in the liver or blood. The presence of DHP in pregnant perissodactyla as well as proboscidean species suggests horses may be a valuable model for reproductive endocrinology in other exotic taxa.

The relationship between weight gain during pregnancy and allopregnanolone levels: a longitudinal study

Objective Large weight gain during pregnancy is a risk factor for complications for mother and fetus. Hunger and satiety are regulated in the hypothalamus, where the gamma-amino-butyric acid system (GABA) has an important role. Allopregnanolone, a progesterone metabolite, increases during pregnancy and is a potent GABA-A receptor modulating steroid. Allopregnanolone has been shown to induce overeating in rodents. The aim was to investigate whether there is a relationship between weight gain and allopregnanolone concentrations during pregnancy in humans. Design A longitudinal, cohort study. Methods Pregnant women (n = 56) were recruited in primary care in northern Sweden. Allopregnanolone concentrations in plasma were measured using radioimmunoassay and weight was measured in gestational weeks 12 and 35. Results Weight increase correlated significantly to allopregnanolone in late pregnancy increase (rs = 0.320; P = 0.016), indicating a positive relationship between weight increase and allopregnanolone increase. A positive relationship was also noted between allopregnanolone in the 35th gestational week and weight increase. Women who gained ≥11 kg during pregnancy showed higher allopregnanolone concentrations in week 35 and higher increase compared to women who increased <11 kg (P = 0.006 and P = 0.009 resp.). There was no difference in weight or allopregnanolone concentrations at the onset of pregnancy. Conclusions The results show a relationship between weight gain during pregnancy and increase in allopregnanolone concentrations.