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Alfaxalone Activates Human Pregnane-X Receptors with Greater Efficacy Than Allopregnanolone: an In-Vitro Study with Implications for Neuroprotection During Anesthesia

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Alfaxalone Activates Human Pregnane-X Receptors with Greater Efficacy Than Allopregnanolone: an In-Vitro Study with Implications for Neuroprotection During Anesthesia bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284075; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 1 Alfaxalone activates Human Pregnane-X Receptors with greater efficacy than Allopregnanolone: an in-vitro study with implications for neuroprotection during anesthesia. Juliet.M. Serrao PhD¶, and Colin.S. Goodchild PhD*,¶, Drawbridge Pharmaceuticals Pty Ltd, Malvern, Victoria, Australia *Corresponding Author: Email: [email protected] (CSG) ¶ These authors contributed equally to this work: planning of the experiments; collating and analyzing data; writing of the manuscript. Data presented herein were submitted to the meeting of the International Research Society planned for May 2020 but then cancelled because of COVID19 pandemic Funding This project was funded by Drawbridge Pharmaceuticals Pty Ltd. Abbreviated Title: alfaxalone activates pregnane-X receptors Conflicts of Interests Juliet M Serrao and Colin S Goodchild both have equity interests in Drawbridge Pharmaceuticals. Both are cited on Phaxan™ patents as inventors and they are both Directors and owners of Drawbridge Pharmaceuticals to which the Phaxan™ patents have been assigned. Abstract Background Alfaxalone is a fast acting intravenous anesthetic with high therapeutic index. It is an analogue of the naturally-occurring neurosteroid, allopregnanolone which has been bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284075; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 2 implicated in causing neuroprotection, neurogenesis and preservation of cognition, through activation of pregnane X receptors in the central nervous system. This study investigated whether alfaxalone can activate human pregnane X receptors (h-PXR) as effectively as allopregnanolone. Methods Allopregnanolone and alfaxalone were dissolved in dimethyl sulfoxide to make allopregnanolone and alfaxalone treatment solutions (serial 3-fold dilution concentration range, 50,000 – 206 nM). Activation of h-PXR by these ligand solutions compared with vehicle control was measured by an in-vitro method using human embryonic kidney cells (HEK293) expressing h-PXR hybridised and linked to the firefly luciferase gene. Ligand binding with and activation of h-PXR in those cells caused downstream changes in luciferase activity and light emission. That activity was measured as relative light units using a plate- reading luminometer, thus quantifying the changes in h-PXR activity caused by the ligand applied to the HEK293 cells. Ligand log concentration response curves were constructed to compare efficacy and potency of allopregnanolone and alfaxalone. Results Allopregnanolone and alfaxalone both activated the h-PXR to cause dose-related light emission by the linked firefly luciferase. Control solutions (0.1% dimethyl sulfoxide) produced low level light emissions. Equimolar concentrations of alfaxalone were more efficacious in activation of h-PXR: 50,000 nM, p = 0.0019; 16,700 nM, p = 0.0472; 5,600 nM, p = 0.0031 [Brown-Forsythe and Welch ANOVA]. bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284075; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 3 Conclusions Alfaxalone activates human-pregnane X receptors with greater efficacy compared with the endogenous ligand allopregnanolone. These results suggest that alfaxalone sedation and anesthesia may be accompanied by beneficial effects normally caused by the physiological effects of allopregnanolone, namely neuroprotection, neurogenesis, and preservation of cognition. bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284075; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 4 Introduction Pregnane X Receptor (PXR; NR112) is a nuclear receptor that binds with, and is activated by, a variety of xenobiotic and endogenous compounds, including naturally occurring steroids, pregnenolone, progesterone and allopregnanolone 1;2. Allopregnanolone is a metabolite of progesterone synthesized in the central nervous system where it promotes neurogenesis and neuroplasticity 3;4. PXR activation by allopregnanolone has also been linked to neuroprotection 5. Further, these properties are due to PXR activation by allopregnanolone stimulating the production of brain-derived neurotrophic factor (BDNF) 5-8. The most important functions of BDNF include: regulation of neuro-, glio-, and synapto-genesis; neuroprotection; and control of short- and long- lasting synaptic interactions responsible for memory and cognition 9. Alfaxalone, (3α-hydroxy-5α-pregnane-11,20-dione ) is a pregnane steroid which has potent anesthetic and sedative properties by actions at gamma aminobutyric acid type A (GABAA) receptors 10. It is an allopregnanolone and progesterone analogue (Figure 1), but it is devoid of conventional progestogen or endocrine hormonal activity 11. An aqueous formulation of alfaxalone (Phaxan™) has been developed for use as an intravenous sedative and anesthetic 12;13. This development occurs at a time when most commonly-used anesthetics are under investigation for neurotoxic effects 14-16. Alfaxalone differs from those commonly used anesthetics in that it is a structural analogue of a naturally occurring neuroprotective hormone, allopregnanolone. It is unknown whether alfaxalone can activate human pregnane X receptors (h-PXR) although its structural similarity to allopregnanolone suggests that it may do so. If it is found that alfaxalone can activate mechanisms utilized by allopregnanolone to cause neuroprotection, e.g., PXR, there would be implications for the use bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284075; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 5 of alfaxalone in clinical anesthetic practice. This study set out to compare the activation of h- PXR in-vitro by equimolar concentrations of allopregnanolone and alfaxalone. Figure 1: Allopregnanolone and alfaxalone: molecular structures compared bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284075; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 6 Materials and methods Assay Platform The activation of h-PXR by allopregnanolone and alfaxalone was measured using an in-vitro preparation by INDIGO Biosciences, Inc., 1981 Pine Hall Road, State College, PA, USA. This consisted of suspensions of “reporter cells” in multi well plates; human cells (HEK293) expressing the nuclear receptor, h-PXR (NR1I2). These cells were engineered to express a hybrid h-PXR, in which the N-terminal sequence encoding the binding domain was substituted with yeast GAL4-binding domain. The rest of the native h-PXR, i.e., the ligand binding and C-terminal domains, remained intact and functional. Ligand (e.g., allopregnanolone) interaction with the receptor, caused it to bind to the GAL4 DNA binding sequence. The latter was functionally linked to firefly luciferase reporter gene. Binding with, and activation of the h-PXR, caused downstream changes in luciferase activity and light emission from the treated reporter cells. That luminescence was measured as relative light units (RLU) using a plate-reading luminometer, thus measuring the changes in h-PXR activity caused by the ligand applied to the HEK293 cells in each well plate. Test Compounds The test compounds alfaxalone and allopregnanolone were obtained from Sigma-Aldrich (400 Summit Drive, Burlington, MA 0180). Assay Methods A suspension of reporter cells was prepared in cell recovery medium. Stock solutions of allopregnanolone and alfaxalone were diluted in dimethyl sulfoxide (DMSO) to generate concentrated stock solutions (1000 x the highest test concentration). These intermediate bioRxiv preprint doi: https://doi.org/10.1101/2020.09.05.284075; this version posted September 6, 2020. The copyright holder for this preprint (which was not certified by peer review) is the author/funder, who has granted bioRxiv a license to display the preprint in perpetuity. It is made available under aCC-BY-NC-ND 4.0 International license. 7 stocks were diluted directly into compound screening medium containing 10% charcoal- stripped foetal bovine serum to generate allopregnanolone and alfaxalone treatment solutions with concentrations at double the final planned testing levels:
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