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

Abstract

PURPOSE. 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). METHODS.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-a, MCP-1, and iNOS.RESULTS. The density of Tuj-1-stained cells in the control was 2010 6 81.5/mm 2 and 1842 6 80.4/mm 2 on days 7 and 14 after the sham operation. These levels were lower at 995 6 122/ mm 2 and 450 6 52.4/mm 2 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 þ cells that were immunoreactive to TNF-a 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.CONCLUSIONS. P7C3-A20 can inhibit mTOR phosphorylation in the crushed optic nerve, which may suppress neuroinflammation and preserve the RGCs.

Tau Is Involved in Death of Retinal Ganglion Cells of Rats From Optic Nerve Crush

“…In this regard, we have previously shown that levels of phosphorylated mTOR (mammalian target of rapamycin) were increased in the retina on day 7 after ONC in rats. 32 Mammalian TOR is a protein kinase that regulates protein synthesis and autophagy, 33 and its FIGURE 5. Representative confocal images of flat-mounted retinas double labeled with P62 and tau antibodies as well as the nuclear stain by 4 0 ,6diamidino-2-phenylindole (DAPI).…”

Implications of NAD+ Metabolism in the Aging Retina and Retinal Degeneration

“…Supportive of this, it has been shown that P7C3, a member of the aminopropyl carbazole class, activates NAMPT contributing to increased NAD + generation [104]. This is supported by a study from the research group of Dr. Hidehiro Oku that evaluated the protective effects of P7C3 on optic nerve injury and found that 5 mg/kg/day of P7C3-A20 for 3 days had a neuroprotective effect on RGCs after the optic nerve crush in rats [103].…”

“…Diseases. In addition, to the major sight-threatening retinal diseases mentioned previously, alterations in NAD + metabolism have been reported to occur also in association with other retinal and nonretinal ocular diseases including diabetic retinopathy [101], retinal vein occlusion [23], neurotrophic keratopathy [102], and traumatic optic neuropathy [103]. A brief mention of current information available relevant to these ocular disorders is provided below.…”

mTORC2 activation protects retinal ganglion cells via Akt signaling after autophagy induction in traumatic optic nerve injury

“…Research has reported that pretreatment of rapamycin by intraperitoneal injections can inhibit mTOR phosphorylation and preserve RGCs 8,39 . This slight preservation of RGCs is different from our observations.…”