June 2015
Volume 56, Issue 7
ARVO Annual Meeting Abstract  |   June 2015
RGC Survival with a Selective Nicotinic Agonist and Modulator
Author Affiliations & Notes
  • David Linn
    Biomedical Sciences, Grand Valley State University, Allendale, MI
  • Jenna Fredrickson
    Biomedical Sciences, Grand Valley State University, Allendale, MI
  • Leah Lyons
    Biomedical Sciences, Grand Valley State University, Allendale, MI
  • Footnotes
    Commercial Relationships David Linn, None; Jenna Fredrickson, None; Leah Lyons, None
  • Footnotes
    Support None
Investigative Ophthalmology & Visual Science June 2015, Vol.56, 2415. doi:
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      David Linn, Jenna Fredrickson, Leah Lyons; RGC Survival with a Selective Nicotinic Agonist and Modulator. Invest. Ophthalmol. Vis. Sci. 2015;56(7 ):2415.

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      © ARVO (1962-2015); The Authors (2016-present)

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Purpose: When retinal ganglion cells (RGCs) are cultured, there is a characteristic decline in numbers over time, which approaches a plateau between 3 and 5 days. Previously, we have shown that the application of a selective α7 nicotinic agonist and modulator to isolated porcine RGCs block this naturally occurring decline. In this study, we sought to compare the intracellular mechanisms thought to be involved in neuroprotection against excess glutamate exposure and the typical RGC decline.

Methods: Panned isolated adult pig RGCs were exposed to increasing doses of a positive allosteric modulator (PNU-120596) in the presence of 100 nM of agonist (PNU-282987) to determine a dose-response relationship. In addition, specific enzyme inhibitors (10 nM) were used to test the role of specific intracellular pathways. LY 294002 was used as a PI3 kinase inhibitor, SB 203580 to block p38 MAP kinase activity and ABT 199 to block Bcl-2 activity. RGCs were cultured under control and experimental conditions for 3 days, labeled with calcein, counted and compared to control conditions. Cell counts were normalized and T-tests were calculated for statistical significance (P<0.05).

Results: No significant effect was observed on RGC survival with the α7 modulator alone (N=6). However, a significant dose-dependent increase in RGC survival was seen when the modulator was co-applied with the α7 selective agonist. 100 nM of modulator applied with 100 nM of agonist elicited a significant increase of RGC survival by 52 +/- 21% (N=9). Exposure to the PI3 kinase inhibitor increased RGC survival by an average of only 7 +/- 9% (N=4) over control values. As expected, exposure to the p38 MAP kinase inhibitor increased RGC survival compared to agonist/modulator alone by an average of 36 +/- 18% (N=4). Lastly, exposure to the Bcl-2 inhibitor resulted in no significant change in RGC survival compared to control conditions. In the presence of Bcl-2 inhibitor, RGC survival changed by 23 +/- 20% compared to controls.

Conclusions: These results support the hypothesis that an α7 agonist/modulator combination can increase RGC survival through the PI-3 - Akt - Bcl-2 cell survival mechanism with or without excess glutamate. Blockade of p38 MAPK, a known apoptotic protein, resulted in increased RGC survival comparable to agonist/modulator alone. This suggests that the interaction(s) between these pathways are involved during typical culture conditions.


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