TY - JOUR
T1 - Additive neuroprotective effects of 24(S)-hydroxycholesterol and allopregnanolone in an ex vivo rat glaucoma model
AU - Ishikawa, Makoto
AU - Yoshitomi, Takeshi
AU - Covey, Douglas F.
AU - Zorumski, Charles F.
AU - Izumi, Yukitoshi
N1 - Funding Information:
Authors thank Sanae Takaseki for technical supports. This work was supported in part by JSPS KAKENHI Grant No. 15K10888 and No. 18K09438 to M.I., and National Institute of Health grants MH077791 and MH101874, and the Bantly Foundation to C.F.Z. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript.
Publisher Copyright:
© 2018, The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - In a rat ex vivo acute glaucoma model, high pressure (75 mmHg) causes swelling of ganglion cell axons and elevates levels of the endogenous steroids 24(S)-hydroxycholesterol (24SH) and allopregnanolone (AlloP). Furthermore, 24SH (0.1 µM) alone elevates AlloP levels via NMDA receptors. With this model, we now investigate possible interactions between 24SH and AlloP. We found that inhibition of AlloP synthesis with dutasteride under high pressure results in severe excitotoxicity in addition to axonal swelling. The excitotoxicity is prevented by exogenous AlloP but not 24SH, indicating that endogenous AlloP is crucial for protection. However, inhibition of 24SH synthesis with voriconazole induces severe excitotoxicity under normal pressure. Paradoxically, the excitotoxicity by voriconazole is better prevented by AlloP than 24SH. These findings suggest that inhibition of 24SH synthesis becomes excitotoxic in the absence of AlloP. We also observed that co-administration of sub-micromolar 24SH (0.1 µM) and AlloP (0.1 µM), concentrations that are only partially effective when administered alone, prevents axonal swelling under high pressure. This apparent enhanced protection indicates strong interaction between the two neurosteroids to preserve neuronal integrity, with 24SH contributing to AlloP synthesis via NMDA receptors and with AlloP playing an essential role in neuroprotection via GABAA receptors.
AB - In a rat ex vivo acute glaucoma model, high pressure (75 mmHg) causes swelling of ganglion cell axons and elevates levels of the endogenous steroids 24(S)-hydroxycholesterol (24SH) and allopregnanolone (AlloP). Furthermore, 24SH (0.1 µM) alone elevates AlloP levels via NMDA receptors. With this model, we now investigate possible interactions between 24SH and AlloP. We found that inhibition of AlloP synthesis with dutasteride under high pressure results in severe excitotoxicity in addition to axonal swelling. The excitotoxicity is prevented by exogenous AlloP but not 24SH, indicating that endogenous AlloP is crucial for protection. However, inhibition of 24SH synthesis with voriconazole induces severe excitotoxicity under normal pressure. Paradoxically, the excitotoxicity by voriconazole is better prevented by AlloP than 24SH. These findings suggest that inhibition of 24SH synthesis becomes excitotoxic in the absence of AlloP. We also observed that co-administration of sub-micromolar 24SH (0.1 µM) and AlloP (0.1 µM), concentrations that are only partially effective when administered alone, prevents axonal swelling under high pressure. This apparent enhanced protection indicates strong interaction between the two neurosteroids to preserve neuronal integrity, with 24SH contributing to AlloP synthesis via NMDA receptors and with AlloP playing an essential role in neuroprotection via GABAA receptors.
UR - http://www.scopus.com/inward/record.url?scp=85052291435&partnerID=8YFLogxK
U2 - 10.1038/s41598-018-31239-2
DO - 10.1038/s41598-018-31239-2
M3 - Article
C2 - 30150786
AN - SCOPUS:85052291435
VL - 8
JO - Scientific Reports
JF - Scientific Reports
SN - 2045-2322
IS - 1
M1 - 12851
ER -