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James D Lindsey, Karen Duong-Polk, Dustin Hammond, Christopher Kai-Shun Leung, Robert N Weinreb; Long Term Alternate Day Fasting Differentially Protects Injured Retinal Ganglion Cell Dendrites and Induces BiP and XBP-1. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2595.
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© ARVO (1962-2015); The Authors (2016-present)
Alternate day fasting (ADF) protects against cardiovascular disease, metabolic decline, and exitotoxic neuronal injury. This study determined whether long term ADF protects retinal ganglion cell (RGC) dendrites after optic nerve injury and whether it alters expression of binding immunoglobulin protein (BiP) or X-box binding protein-1 (XBP-1).
Thy1-YFP mice were fed ad libitum (AL, N=19) or with ADF (N=20) from 2 months until 18 months old. Fluorescent RGCs were imaged at 17 months old using a modified confocal scanning laser ophthalmoscope. The mice then received unilateral optic nerve crush (ONC) and the RGCs were re-imaged weekly for 4 weeks. RGCs were assigned to 6 RGC groups according to Leung et al. (IOVS 2011;52:1539). Total dendrite length (TDL) and dendritic branching complexity (DBC) were determined using Imaris and evaluated using the Mann-Whitney-U test. In a parallel study, 16 month-old C57BL/6 mice received unilateral ONC. Three weeks later, the eyes were collected and ganglion cell layer (GCL) neurons were analyzed by quantitative immunohistochemistry using the Steel-Dwass-Critchlow-Fligner test.
ADF protected TDL in all RGCs considered together at 1, 2, and 3 weeks after ONC (P=0.006, 0.00002 and 0.002, respectively; N=79 [AL] and 133 [ADF] RGCs). DBC also was protected in all RGCs (P=0.007, 0.000002 and 0.03, respectively). When the RGC groups were analyzed separately, ADF protected TDL in Group 5 RGCs (P<0.0005 at weeks 1, 2, and 3 after ONC; N=56 and 54) and Group 6 RGCs (P=0.03 at 2 weeks after ONC, N=10 and 34). ADF protected DBC in Group 5 RGCs (P<0.01 at 1, 2, and 3 weeks after ONC; N=44 and 55) and Group 6 RGCs (P=0.02 and 0.03 at 1 and 2 weeks after ONC; N=10 and 35). ADF did not protect TDL or DBC in RGCs from Groups 1, 2, or 3 (P>0.05). ADF increased cytoplasmic BiP staining intensity by 78±23% (SD, P<0.001, N=50 [AL] and 50 [ADF] GCL neurons). ONC increased BiP by 23±27% in AL mice (P<0.001, N=50 and 50) but not in ADF mice (P>0.05). ADF increased nuclear XBP-1 by 70±24% in uncrushed eyes (P<0.01, N=40 and 52). XBP-1 was the same at 3 weeks after ONC in both AL and ADF mice (P>0.05).
Long term ADF selectively protects RGC dendrites following optic nerve crush. This protective effect is associated with ADF induction of increased cytoplasmic BiP and nuclear XBP-1.
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