Expression of ABC Efflux Transporters in Placenta from Women with Insulin-Managed Diabetes

Drug efflux transporters in the placenta can significantly influence the materno-fetal transfer of a diverse array of drugs and other xenobiotics. To determine if clinically important drug efflux transporter expression is altered in pregnancies complicated by gestational diabetes mellitus (GDM-I) or type 1 diabetes mellitus (T1DM-I), we compared the expression of multidrug resistance protein 1 (MDR1), multidrug resistance-associated protein 2 (MRP2) and the breast cancer resistance protein (BCRP) via western blotting and quantitative real-time polymerase chain reaction in samples obtained from insulin-managed diabetic pregnancies to healthy term-matched controls. At the level of mRNA, we found significantly increased expression of MDR1 in the GDM-I group compared to both the T1DM-I (p<0.01) and control groups (p<0.05). Significant changes in the placental protein expression of MDR1, MRP2, and BCRP were not detected (p>0.05). Interestingly, there was a significant, positive correlation observed between plasma hemoglobin A1c levels (a retrospective marker of glycemic control) and both BCRP protein expression (r = 0.45, p<0.05) and BCRP mRNA expression (r = 0.58, p<0.01) in the insulin-managed DM groups. Collectively, the data suggest that the expression of placental efflux transporters is not altered in pregnancies complicated by diabetes when hyperglycemia is managed; however, given the relationship between BCRP expression and plasma hemoglobin A1c levels it is plausible that their expression could change in poorly managed diabetes

Placental ABC efflux transporter expression in pregnancies complicated by insulin-managed diabetes.

<p><b>A</b>, MDR1 (ABCB1). <b>B</b>, MRP2 (ABCC2). <b>C</b>, BCRP (ABCG2). Boxes represent quartiles enclosing 50% of the data and the whiskers at either end extend to the 25^th and 75^th quartiles. The median is marked by a line, the mean is marked by an “+” and outliers are marked by a “•” outside the 25^th and 75^th quartiles. The “Combined” group presents data from all patients (n = 33) and was not included in statistical analyses. <b>D</b>, Spearman correlation analysis of the relationship between HbA1c levels (%) and BCRP protein expression in diabetic pregnancies (p<0.05).</p

Localization of MDR1, MRP2, and BCRP in placenta.

<p>The syncytiotrophoblast (S) layer of the placenta is comprised of multinucleated (N) cells that contain a number of apically-localized transport proteins that contribute to the function of the placental barrier, including MDR1, MRP2, and BCRP.</p

Inclusion/exclusion criteria.

<p>Inclusion/exclusion criteria.</p

Placental ABC efflux transporter expression in pregnancies complicated by insulin-managed diabetes.

<p><b>A</b>, MDR1 (ABCB1). <b>B</b>, MRP2 (ABCC2). <b>C</b>, BCRP (ABCG2). Boxes represent quartiles enclosing 50% of the data and the whiskers at either end extend to the 25^th and 75^th quartiles. The median is marked by a line, the mean is marked by an “+” and outliers are marked by a “•” outside the 25^th and 75^th quartiles. The “Combined” group presents data from all patients (n = 33) and was not included in statistical analyses. <b>D</b>, Spearman correlation analysis of the relationship between HbA1c levels (%) and BCRP mRNA expression in diabetic pregnancies (p<0.01).</p

Sculpting Neural Circuits by Axon and Dendrite Pruning

The assembly of functional neural circuits requires the combined action of progressive and regressive events. Regressive events encompass a variety of inhibitory developmental processes, including axon and dendrite pruning, which facilitate the removal of exuberant neuronal connections. Most axon pruning involves the removal of axons that had already made synaptic connections, thus, axon pruning is tightly associated with synapse elimination. In many instances these developmental processes are regulated by the interplay between neurons and glial cells that act instructively during neural remodeling. Owing to the importance of axon and dendritic pruning, these remodeling events require precise spatial and temporal control, and this is achieved by a range of distinct molecular mechanisms. Disruption of these mechanisms results in abnormal pruning, which has been linked to brain dysfunction. Therefore, understanding the mechanisms of axon and dendritic pruning will be instrumental in advancing our knowledge of neural disease and mental disorders