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The Effects of Prenatal Dexamethasone Exposure on Brain Metabolic Homeostasis in Adulthood: Implications for Depression - PubMed

  • ️Sun Jan 01 2023

The Effects of Prenatal Dexamethasone Exposure on Brain Metabolic Homeostasis in Adulthood: Implications for Depression

Katarzyna Głombik et al. Int J Mol Sci. 2023.

Abstract

Since depression produces a long-term negative impact on quality of life, understanding the pathophysiological changes implicated in this disorder is urgent. There is growing evidence that demonstrates a key role for dysfunctional energy metabolism in driving the onset of depression; thus, bioenergetic alterations should be extensively studied. Brain metabolism is known to be a glucocorticoid-sensitive process, but the long-lasting consequences in adulthood following high levels of glucocorticoids at the early stages of life are unclear. We examined a possible association between brain energetic changes induced by synthetic glucocorticoid-dexamethasone treatment in the prenatal period and depressive-like behavior. The results show a reduction in the oxidative phosphorylation process, Krebs cycle impairment, and a weakening of the connection between the Krebs cycle and glycolysis in the frontal cortex of animals receiving dexamethasone, which leads to ATP reduction. These changes appear to be mainly due to decreased expression of pyruvate dehydrogenase, impairment of lactate transport to neurons, and pyruvate to the mitochondria. Acute stress in adulthood only slightly modified the observed alterations in the frontal cortex, while in the case of the hippocampus, prenatal exposure to dexamethasone made this structure more sensitive to future adverse factors.

Keywords: animal model; bioenergetics; brain; depression; dexamethasone.

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Conflict of interest statement

The authors declare no conflict of interest. The funders had no role in the design of the study; in the collection, analyses, or interpretation of data; in the writing of the manuscript; or in the decision to publish the results.

Figures

Figure 1
Figure 1

Schematic diagram of the experiment.

Figure 2
Figure 2

The effects of prenatal dexamethasone treatment on the immobility time (A) measured in the FST, % of open arm entries (B) and % of time spent in the open arms (C) of the EPM; * p < 0.05, n = 10. The results are expressed as the mean ± SEM. Statistics: one-way ANOVA.

Figure 3
Figure 3

The effects of DEX treatment on OXPHOS levels, mitochondrial respiration capacity, and ATP levels in the mitochondria-enriched fraction/homogenates of the frontal cortex (A,C,E) and the hippocampus (B,D,F); OXPHOS levels were determined with Western blotting analysis, mitochondrial respiration capacity was determined via respirometry, and ATP level via luminescent measurements; * p < 0.05, n = 7–9 for OXPHOS determination, n = 6–7 for O2K study and for ATP level assessment. The results are expressed as the average fold change ± SEM (A,B) or as the mean ± SEM (C–F). Statistics: one-way ANOVA.

Figure 4
Figure 4

The effects of DEX treatment and acute stress on the levels of enzymes hexokinase, phosphofructokinase, and pyruvate kinase in tissue homogenates of the frontal cortex (A,C,E) and the hippocampus (B,D,F); enzyme levels were determined with ELISA assays; * p < 0.05, n = 7–8. The results are expressed as the mean ± SEM. Statistics: two-way ANOVA, followed by the Duncan test.

Figure 5
Figure 5

The effects of DEX treatment and acute stress on pyruvate and lactate levels in the mitochondria-enriched and cytosolic fractions of the frontal cortex (A,C) and the hippocampus (B,D); lactate and pyruvate levels were determined via colorimetric and fluorometric measurements, respectively; * p < 0.05, n = 7–9. The results are expressed as the mean ± SEM. Statistics: two-way ANOVA, followed by the Duncan test.

Figure 6
Figure 6

The effects of DEX treatment and acute stress on pyruvate dehydrogenase (PDH) level and activity in the mitochondria-enriched fraction of the frontal cortex (A,C) and the hippocampus (B,D); PDH level was determined with ELISA assay, while activity with colorimetric assay; * p < 0.05, n = 8–9. The results are expressed as the mean ± SEM. Statistics: two-way ANOVA, followed by the Duncan test.

Figure 7
Figure 7

The effects of DEX treatment and acute stress on the levels of hexokinase-1 (HK1) and voltage-dependent anion-selective channel 1 (VDAC1) in the mitochondria-enriched fraction of the frontal cortex (A,C) and the hippocampus (B,D); HK1 level was determined with Western blotting analysis, and VDAC1 with ELISA assay; * p < 0.05, n = 8–9. The results are expressed as the average fold change ± SEM (A,B) or as the mean ± SEM (C,D). Statistics: two-way ANOVA, followed by the Duncan test.

Figure 8
Figure 8

The effects of DEX treatment and acute stress on the levels of MCT2, MCT4, MPC1, and MPC2 in the tissue homogenates of the frontal cortex (A,C,E,G) and the hippocampus (B,D,F,H); all proteins levels were determined with Western blotting analysis; * p < 0.05, n = 8–10. The results are expressed as the average fold change ± SEM. Statistics: two-way ANOVA, followed by the Duncan test.

Figure 9
Figure 9

The effects of DEX treatment and acute stress on the level of GPR81 in tissue homogenates of the frontal cortex and (A) the hippocampus (B); protein level was determined with Western blotting analysis; * p < 0.05, n = 9–10. The results are expressed as the average fold change ± SEM. Statistics: two-way ANOVA, followed by the Duncan test.

Figure 10
Figure 10

The effects of DEX treatment and acute stress on the levels of insulin, phospho-insulin receptor (pIR/IR), IRS1 in the tissue homogenates of the frontal cortex (A,C,E) and the hippocampus (B,D,F) and insulin in the plasma (G); proteins levels were determined with ELISA assays; * p < 0.05, n = 7–9 The results are expressed as the mean ± SEM. Statistics: two-way ANOVA, followed by the Duncan test.

Figure 11
Figure 11

The effects of DEX treatment and acute stress on the levels of phospho-Akt (pAkt/Akt) and total Akt in the tissue homogenates of the frontal cortex (A,C) and the hippocampus (B,D); proteins levels were determined with Western blotting analysis; * p < 0.05, n = 9–10. The results are expressed as the average fold change ± SEM. Statistics: two-way ANOVA, followed by the Duncan test.

Figure 12
Figure 12

Scheme summarizing the effect of DEX and DEX stress on the dysregulation of energy production in the frontal cortex (A) and hippocampus (B).

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