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C. J. Lieven, B. R. Schwechter, M. J. Hoegger, L. A. Levin; Effectiveness of Novel Borane-Protected Phosphines as Neuroprotectants in a Rat Optic Nerve Crush Model. Invest. Ophthalmol. Vis. Sci. 2008;49(13):2072.
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Previous work in our laboratory has shown the sulfhydryl reducing compound tris(2-carboxyethyl)phosphine (TCEP) is neuroprotective for retinal ganglion cells (RGCs) after optic nerve crush. We have also developed a novel class of borane-protected substituted phosphines that are reducing agents, and are neuroprotective of RGCs in primary cultures at much lower doses than TCEP (Exp Eye Res 83:1252, 2006). We tested if these compounds would have a similar protective effect after optic nerve crush at lower doses than TCEP.
RGCs of 6-10 week old Long-Evans rats were retrogradely labeled with the fluorescent tracer DiI. Seven to 10 days after labeling, the left optic nerve of each rat was crushed with forceps, followed by a 4 µL intravitreal injection of bis(3-propionic acid methyl ester)phenylphosphine borane complex (PB1), (3-propionic acid methyl ester)diphenylphosphine borane complex (PB2), or vehicle alone to final concentrations of 1 nM, 100 nM, or 10 µM. The right eye was used as the control. Nine days after the crush injury, the animals were sacrificed, retinas whole-mounted, and photographed for automated counting with NIH ImageJ software.
PB2 exhibited significant neuroprotection at a concentration of 10 µM (82.7 ± 4.1% of control eye with PB2 injection vs 63.8 ± 1.5% for vehicle; p = 0.001), corresponding to a rescue of 40 ± 9% of RGCs compared to vehicle alone. PB2 also showed an overall protective effect across treatments by ANOVA (p = 0.007).
PB2 is neuroprotective of RGCs in an optic nerve crush model at lower concentrations than TCEP. It is unclear if this increase in potency is due to improved cell permeability, better retention within the cell, targeting to an intracellular site, or a combination of these factors.
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