Brain cholesterol biosynthesis, a separate and distinct process from whole-body cholesterol homeostasis, starts during embryonic development. To gain a better understanding of the neuronal and glial contributions to the brain cholesterol pool, we studied this process in control, Dhcr7 −/− , and Dhcr24 −/− cell cultures. Our LC-MS/MS method allowed us to measure several different sterol intermediates and cholesterol during neuronal differentiation. We found that developing cortical neurons rely on endogenous cholesterol synthesis and utilize ApoE-complexed cholesterol and sterol precursors from their surroundings. Both developing neurons and astrocytes release cholesterol into their local environment. Our studies also uncovered that developing neurons produced significantly higher amounts of cholesterol per cell than the astrocytes. Finally, we established that both neurons and astroglia preferentially use the Bloch sterol biosynthesis pathway, where desmosterol is the immediate precursor to cholesterol. Overall, our studies suggest that endogenous sterol synthesis in developing neurons is a critical and complexly regulated homeostatic process during brain development.

The clinical course of 87 infants with bronchopulmonary dysplasia (BPD) on home oxygen therapy was reviewed to determine the occurrence of systemic hypertension (HTN) and to evaluate associated clinical features. Eleven of 87 (13%) infants developed systemic HTN either in the neonatal intensive care unit or following discharge. Clinical features that distinguished the hypertensive from the normotensive group were as follows: greater use of bronchodilators, 91% vs 37% (p < 0.001), and diuretics, 91% vs 55% (p < 0.05), longer duration of home oxygen therapy 21.6 +/- 9.9 vs 9.2 +/- 5.8 months (p < 0.05), and greater mortality, 36% vs 1% (p < 0.001). The course of systemic HTN in the surviving patients (7 of 11) was benign and resolved in all patients prior to weaning from home oxygen therapy. Systemic HTN is frequently present in infants with severe BPD and appears to be related to the clinical severity of lung disease.

While antipsychotic medications provide important relief from debilitating psychotic symptoms, they also have significant adverse side effects, which might have relevant impact on human health. Several research studies, including ours, have shown that commonly used antipsychotics such as haloperidol and aripiprazole affect cholesterol biosynthesis at the conversion of 7-dehydrocholesterol (7-DHC) to cholesterol. This transformation is promoted by the enzyme DHCR7 and its inhibition causes increases in plasma and tissue levels of 7-DHC. The inhibition of this enzymatic step by mutations in the Dhcr7 gene leads to Smith-Lemli-Opitz syndrome, a devastating human condition that can be replicated in rats by small molecule inhibitors of DHCR7. The fact that two compounds, brexpiprazole and cariprazine, that were recently approved by the FDA have substructural elements in common with the DHCR7 inhibitor aripiprazole, prompted us to evaluate the effect of brexpiprazole and cariprazine on cholesterol biosynthesis. We report that cariprazine affects levels of 7-DHC and cholesterol in cell culture incubations at concentrations as low as 5 nM. Furthermore, a common metabolite of cariprazine and aripiprazole, 2,3-(dichlorophenyl) piperazine, inhibits DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944. The cell culture experiments were corroborated in mice in studies showing that treatment with cariprazine elevated 7-DHC in brain and serum. The consequences of sterol inhibition by antipsychotics in the developing nervous system and the safety of their use during pregnancy remains to be established.

Cariprazine (CAR) is a strong inhibitor of the Dhcr7 enzyme, the last enzyme in the cholesterol biosynthesis pathway. We assessed the effects of CAR on maternally exposed Dhcr7+/− and wild-type mouse offspring, and tested the biochemical effects of CAR in human serum samples. Dhcr7+/− and wild-type time-pregnant mice were exposed to vehicle or 0.2 mg/kg CAR from E12 to E19. Levels of CAR, CAR metabolites, sterols, and oxysterols were measured in the brain of maternally exposed offspring at various time points using LC-MS/MS. Embryonic exposure to CAR significantly increased levels of 7-DHC in all organs of exposed embryos, with a particularly strong effect in the brain. Detectable levels of CAR and elevated 7-DHC were observed in the brain of newborn pups 14 days after drug exposure. In addition, CAR altered sterol metabolism in all animals analyzed, with the strongest effect on the brain of Dhcr7+/− pups born to Dhcr7+/− dams. Furthermore, CAR elevated toxic oxysterols in the brain of maternally exposed Dhcr7+/− offspring to levels approaching those seen in a mouse model of Smith–Lemli–Opitz syndrome. Finally, we observed that patients taking CAR have elevated 7-DHC in their serum. In summary, maternal DHCR7 heterozygosity, combined with offspring DHCR7 heterozygosity might represent a vulnerability factor to medications that interfere with sterol biosynthesis. Due to the conserved sterol biosynthesis between mice and humans, we suggest that the 1–3% of patient population with single-allele DHCR7 mutations might not be ideal candidates for CAR use, especially if they are nursing, pregnant or plan to become pregnant.