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2,3‐Dichlorophenylpiperazine (DCPP)‐derived Antipsychotics Obstruct Cholesterol Biosynthesis in hiPSC‐derived Neural Precursors and Early Postmitotic Neurons
Author(s) -
Kim John,
Neely M. Diana,
Kim Hye-Young,
Tallman Keri,
Porter Ned
Publication year - 2020
Publication title -
the faseb journal
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.709
H-Index - 277
eISSN - 1530-6860
pISSN - 0892-6638
DOI - 10.1096/fasebj.2020.34.s1.03215
Subject(s) - aripiprazole , glutamatergic , smith–lemli–opitz syndrome , dopaminergic , neural stem cell , chemistry , endocrinology , medicine , pharmacology , biology , dopamine , biochemistry , reductase , microbiology and biotechnology , receptor , enzyme , schizophrenia (object oriented programming) , 7 dehydrocholesterol reductase , psychiatry , stem cell , glutamate receptor
Antipsychotic prescriptions have steadily expanded in recent years as have their uses for “off‐label” indications such as bipolar affective disorder and major depressive disorder. Aripiprazole (Abilify) and cariprazine (Vraylar) are atypical antipsychotics which share a 2,3‐dichlorophenylpiperazine (2,3‐DCPP) moiety in their chemical structure. Preclinical and clinical studies have shown these small molecules have off‐target inhibitory effects on 7‐dehydrocholesterol reductase (DHCR7) which converts the highly oxidizable lipid 7‐dehydrocholesterol (7‐DHC) to cholesterol. Recent studies have also demonstrated that 2,3‐DCPP alone can potently inhibit DHCR7. The grave consequences of impaired DHCR7 function are demonstrated in Smith‐Lemli‐Opitz syndrome (SLOS), a rare neurodevelopmental disorder in which genetic defects in the enzyme result in the abnormal accumulation of 7‐DHC. Given the developmental deficits seen in SLOS, the use of DHCR7 inhibitors during the first trimester of pregnancy has been suggested to have deleterious outcomes in fetal development. Recognizing the dynamic nature of cellular biochemistry in neural development, we examined the impact of two structurally similar antipsychotics on cholesterol biosynthesis precursor profiles in highly proliferative NPCs and early post‐mitotic neurons differentiated from human‐induced pluripotent stem cells (hiPSCs). We exposed cortical glutamatergic and mesencephalic dopaminergic NPCs and early postmitotic neurons to increasing concentrations (1–1000 nM) of aripiprazole and cariprazine for 48 hours after which we quantified lipid extracts via liquid chromatography‐tandem mass spectrometry (LC‐MS‐MS). Cortical glutamatergic and mesencephalic dopaminergic lineages of both developmental stages exhibited dose‐dependent increases in DHCR7 substrates and corresponding decreases in DHCR7 products. While in early postmitotic neurons both compounds showed similar potency with observable changes in sterol profile at >10 nM exposures, proliferative NPCs demonstrated a particularly high sensitivity to cariprazine with significant effects at 1 nM. These findings are highly significant as patients on cariprazine retain plasma levels of cariprazine and its metabolites above 100 nM for many months. Despite the substantial alterations in sterol profile, no significant cytotoxicity was observed at any dosage. Overall, these observations illustrate the importance of assaying DHCR7 activity as it relates to teratogenicity of novel pharmaceuticals, especially those bearing the 2,3‐DCPP structural unit. Support or Funding Information This work was supported by the SyBBURE Searle Program and NIH R01HD064727‐01 (NAP). Cell counts were obtained via the ImageXPress instrument of the Vanderbilt High Throughput Screening (HTS) facility.