Maternal cariprazine exposure inhibits embryonic and postnatal brain cholesterol biosynthesis

Thiago C Genaro-Mattos,Luke B Allen,Zeljka Korade,Keri A Tallman,Allison Anderson,Ned A Porter,Károly Mirnics

doi:10.1038/s41380-020-0801-x

Thiago C Genaro-Mattos, Luke B Allen + Show 5 more

Open Access

https://doi.org/10.1038/s41380-020-0801-x

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Abstract

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.

Highlights

Cariprazine (CAR) is a novel antipsychotic, approved in 2015 for the treatment of adults with schizophrenia and manic or mixed episodes
These results suggest that CAR is distributed to multiple organs, systemically inhibits the Dhcr7 enzyme and increases 7-DHC across all tissues
(5) CAR alters sterol metabolism in all animals analyzed, but maternally exposed pups with Dhcr7+/− genotype are more vulnerable than their WT littermates

Summary

1234567890();,: 1234567890();,: Introduction

Cariprazine (CAR) (marketed under the name of Vraylar®) is a novel antipsychotic, approved in 2015 for the treatment of adults with schizophrenia and manic or mixed episodes. Its complete mechanism of action is still not fully understood, the primary effect of CAR is mediated through a combination of activity at D2 and D3 receptors and 5-HT1A receptors [5, 6]. CAR and aripiprazole (ARI), another atypical antipsychotic with a similar mechanism of action, are both metabolized to 2,3-(dichlorophenyl) piperazine (2,3-DCPP), which is an active and stable metabolite (Supplementary Fig. 1) [9,10,11]. The common metabolite of CAR and ARI, 2,3-DCPP, inhibits the DHCR7 activity at concentrations comparable to those of the potent teratogen AY9944 [10]. We undertook a series of experiments in Dhcr7+/+ (WT) and heterozygous Dhcr7+/− (Het) mice, analyzing levels of CAR and its metabolites in the brain of maternally exposed offspring. The complete study design is outlined in Supplementary Fig. 2

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Discussion

Compliance with ethical standards