P7C3 Suppresses Neuroinflammation and Protects Retinal Ganglion Cells of Rats from Optic Nerve Crush

• Published in: Investigative ophthalmology & visual science 2017-09, Vol.58 (11), p.4877-4888
• Main Authors: Oku, Hidehiro, Morishita, Seita, Horie, Taeko, Kida, Teruyo, Mimura, Masashi, Kojima, Shota, Ikeda, Tsunehiko
• Format: Article
• Language: English
• Subjects: Animals; Anti-Inflammatory Agents - therapeutic use; Biomarkers - metabolism; Carbazoles - pharmacology; Disease Models, Animal; Male; Nerve Crush; Neuroprotective Agents - pharmacology; Optic Nerve - pathology; Optic Nerve Injuries - drug therapy; Optic Nerve Injuries - metabolism; Optic Nerve Injuries - pathology; Phosphorylation - drug effects; Rats; Rats, Wistar; Retinal Ganglion Cells - drug effects; Retinal Ganglion Cells - metabolism; Retinal Ganglion Cells - pathology; Sirolimus - pharmacology; TOR Serine-Threonine Kinases - metabolism; Tumor Necrosis Factor-alpha - metabolism
• ISSN: 1552-5783; 1552-5783
• DOI: 10.1167/iovs.17-22179

To determine whether P7C3-A20 can inhibit the phosphorylation of the mammalian target of rapamycin (mTOR), depress neuroinflammation, and protect retinal ganglion cells (RGCs) of rats from optic nerve crush (ONC). The left optic nerve was crushed, and 5.0 mg/kg/d of P7C3-A20, 1.0 mg/kg/d of rapamycin, or their vehicle was injected intraperitoneally for 3 consecutive days beginning 1 day before the ONC. The protective effects on the RGCs were determined by immunohistochemical staining for Tuj-1. The level of phosphorylated mTOR was determined by immunoblotting. The neuroinflammation in the optic nerve was determined by changes in the expression of CD68, TNF-α, MCP-1, and iNOS. The density of Tuj-1-stained cells in the control was 2010 ± 81.5/mm2 and 1842 ± 80.4/mm2 on days 7 and 14 after the sham operation. These levels were lower at 995 ± 122/mm2 and 450 ± 52.4/mm2 on days 7 and 14 after the ONC, respectively. Rapamycin and P7C3-A20 preserved the density at significantly higher levels on both days (P < 0.05, Scheffe test). The level of phosphorylated mTOR increased by 1.56-fold above the control level on day 7. Rapamycin and P7C3 significantly lowered the level of phosphorylated mTOR to 0.89-fold and 0.67-fold of the control, respectively. There was an accumulation of CD68+ cells that were immunoreactive to TNF-α at the crush site. The expression of MCP-1 and iNOS was increased chiefly in the astrocytes around the lesion. These inflammatory events were suppressed by both rapamycin and P7C3. P7C3-A20 can inhibit mTOR phosphorylation in the crushed optic nerve, which may suppress neuroinflammation and preserve the RGCs.