Abstract
Injury to retinal ganglion cell (RGC) axons leads to selective loss of RGCs and vision. Previous studies have shown that exogenous neurotrophic factors promote RGC survival. We investigated the neuroprotective effects of oncostatin M (OSM), a member of the IL-6 family of cytokines, on pattern electroretinogram (PERG) and RGC survival after optic nerve crush (ON-crush) in the mouse. BALB/C mice received ON-crush in the left eyes for either 4-second or 1-second duration (4-s or 1-s). Fluoro-gold retrograde labeling was used to identify RGCs. RGC function was assessed by PERG measurement. OSM or CNTF protein was injected intravitreally immediately after ON-crush. OSM responsive cells were identified by localization of increased STAT3 phosphorylation. Significant higher RGC survival (46% of untreated control) was seen in OSM-treated eyes when assessed 2 weeks after 4-s ON-crush as compared to that (14% of untreated control) of the PBS-treated eyes (P<0.001). In addition, PERG amplitude was significantly higher in eyes treated with OSM or CNTF 1 week after 1-s ON-crush (36% of baseline) as compared with the amplitude of PBS-treated eyes (19% of the baseline, P = 0.003). An increase in STAT3 phosphorylation was localized in Müller layer after OSM treatment, suggesting that Müller cells mediate the effect of OSM. Our results demonstrate that one single injection of either OSM or CNTF after ON-crush improves RGC survival together with their electrophysiological activity. These data provide proof-of-concept for using neurotrophic factors OSM and CNTF for RGC degenerative diseases, including glaucoma and acute optic nerve trauma.
Highlights
Retinal ganglion cells (RGCs) send neuronal output of the retina to the brain targets through long axons, which form the optic nerve
Intravitreal administration of neurotrophic factors, including BDNF, NT-4, and CNTF, protects RGCs from optic nerve crush induced cell death [9]. These studies support the notion that injury to RGC axons reduces target-derived neurotrophic factors, which in turn leads to RGC death [10]
In eyes treated with ON-crush+oncostatin M (OSM), RGC densities were significantly higher than eyes treated with ON-crush+phosphate buffered saline (PBS) (42.0% of normal at 0.5 mm, 47.2% at 1.0 mm, and 48.1% at 1.5 mm; two-way ANOVA: effect of treatment, P,0.001)
Summary
Retinal ganglion cells (RGCs) send neuronal output of the retina to the brain targets through long axons, which form the optic nerve. Studies have shown that retrograde axonal transport of targetderived neurotrophic factors, such as BDNF (brain derived neurotrophic factor), is important for RGC survival [5,6], whereas deprivation of target-derived BDNF by impairment of retrograde axonal transport leading to RGC death [7,8]. Intravitreal administration of neurotrophic factors, including BDNF, NT-4 (neurotrophin-4), and CNTF (ciliary neurotrophic factor), protects RGCs from optic nerve crush induced cell death [9]. These studies support the notion that injury to RGC axons reduces target-derived neurotrophic factors, which in turn leads to RGC death [10]. A clinical trial of CNTF via CNTF-secreting implants [14] is currently underway (clinicaltrials.gov NCT01408472)
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