TSPO activation modulates the effects of high pressure in a rat ex vivo glaucoma model.
We previously reported that elevated pressure induces axonal swelling and facilitates the synthesis of the neurosteroid, allopregnanolone (AlloP), in the ex vivo rat retina. Exogenously applied AlloP attenuates the axonal swelling, suggesting that the neurosteroid plays a neuroprotective role against glaucomatous pressure-induced injuries, although mechanisms underlying neurosteroidogenesis have not been clarified. The aim of this study was to determine whether AlloP synthesis involves activation of translocator protein 18 kD (TSPO) and whether TSPO modulates pressure-induced retinal injury. Ex vivo rat retinas were exposed to various pressures (10, 35, or 75 mmHg) for 24 h. Expression of TSPO, 5α-reductase (5aRD), and AlloP was examined by quantitative real-time RT-PCR, ELISA, immunohistochemistry, and LC-MS/MS. We also examined the effects of TSPO ligands on AlloP synthesis and retinal damage. In this acute model, quantitative real-time RT-PCR and ELISA analyses revealed that elevated pressure facilitated TSPO expression. Similarly, these methods also detected enhanced 5aRD (mostly type II), which was observed in retinal ganglion cells (RGC) and the inner nuclear layer (INL). Atriol, a TSPO antagonist, suppressed pressure mediated AlloP synthesis and induced more severe histological changes in the inner retina when combined with elevated pressure. PK11195, a TSPO ligand that facilitates AlloP synthesis by itself, remarkably diminished pressure-mediated retinal degeneration. These results suggest that AlloP synthesis is induced by sequential activation of TSPO and 5aRD in an ex vivo glaucoma model, and that TSPO agonists may serve as potential therapeutic agents for the prevention of pressure-induced retinal damage.
Department of Ophthalmology, Akita Graduate University School of Medicine, Akita, Japan. Electronic address: mako@med.akita-u.ac.jp.
Makoto
M
Ishikawa
Department of Ophthalmology, Akita Graduate University School of Medicine, Akita, Japan.
Takeshi
T
Yoshitomi
Department of Developmental Biology, Washington University School of Medicine, St. Louis, M.O, USA; The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, M.O, USA.
Douglas F
DF
Covey
The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, M.O, USA; Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, M.O, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, M.O, USA.
Charles F
CF
Zorumski
The Taylor Family Institute for Innovative Psychiatric Research, Washington University School of Medicine, St. Louis, M.O, USA; Center for Brain Research in Mood Disorders, Washington University School of Medicine, St. Louis, M.O, USA; Department of Psychiatry, Washington University School of Medicine, St. Louis, M.O, USA.
Yukitoshi
Y
Izumi
D058891:5-alpha Reductase Inhibitors / Q000008:administration & dosage; D000818:Animals; D002352:Carrier Proteins / Q000378:metabolism*; D042944:Cholestenone 5 alpha-Reductase / Q000378:metabolism*; D004195:Disease Models, Animal; D000068538:Dutasteride / Q000008:administration & dosage; D005901:Glaucoma / Q000378:metabolism* / Q000473:pathology; D066298:In Vitro Techniques; D007546:Isoquinolines / Q000008:administration & dosage; D008297:Male; D011280:Pregnanolone / Q000096:biosynthesis*; D011312:Pressure; D051381:Rats; D017207:Rats, Sprague-Dawley; D011963:Receptors, GABA-A / Q000378:metabolism*; D012160:Retina / Q000473:pathology / Q000648:ultrastructure; D012165:Retinal Ganglion Cells / Q000187:drug effects / Q000473:pathology; D015854:Up-Regulation
D058891:5-alpha Reductase Inhibitors; D002352:Carrier Proteins; D007546:Isoquinolines; D011963:Receptors, GABA-A; C069997:Tspo protein, rat; D011280:Pregnanolone; D042944:Cholestenone 5 alpha-Reductase; D000068538:Dutasteride; C037850:PK 11195
5α-reductase; Allopregnanolone; Glaucoma; Neuroprotection; Neurosteroid; TSPO