September 2016
Volume 57, Issue 12
Open Access
ARVO Annual Meeting Abstract  |   September 2016
Source of Optic Nerve Metabolic Vulnerability in DBA/2J Model of Glaucoma
Author Affiliations & Notes
  • Denise M Inman
    Pharmaceutical Sciences, Northeast Ohio Medical University, Rootstown, Ohio, United States
  • Peter G Palmer
    Bio-Med Science Academy, Rootstown, Ohio, United States
  • Footnotes
    Commercial Relationships   Denise Inman, None; Peter Palmer, None
  • Footnotes
    Support  None
Investigative Ophthalmology & Visual Science September 2016, Vol.57, 3016. doi:
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      Denise M Inman, Peter G Palmer; Source of Optic Nerve Metabolic Vulnerability in DBA/2J Model of Glaucoma. Invest. Ophthalmol. Vis. Sci. 2016;57(12):3016.

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

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Abstract

Purpose : Optic nerve from pre-glaucomatous DBA/2J mouse demonstrates lack of resilience to oxygen-glucose deprivation to a degree that correlates with magnitude of intraocular pressure exposure. These experiments investigate the source of energy vulnerability by examining energy storage (glycogen and creatine kinase activity), energy exchange (monocarboxylate transporters (MCT), glucose transporters), and metabolic substrate utilization (lactate dehydrogenase) in the optic nerve.

Methods : DBA/2J (D2) and age-matched DBA/2Jwt-gpnmb (D2G) eyes were injected with cholera toxin B to assess axon transport status. Mice were grouped by age (3 and 10 months) and extent of transport deficit, mRNA was isolated, and gene expression analyzed in optic nerve by qPCR. Optic nerves were also isolated and analyzed for glycogen levels and creatine kinase activity.

Results : Significant increases in MCT-2 and -4 gene expression levels were observed in 10m D2 optic nerve compared to age-matched control D2G (t-test, p=0.0036, p=0.0376, respectively); MCT-2 is preferentially expressed in axons, and MCT-4 in astrocytes. Energy storage analysis indicated significant decreases in glycogen (10m D2 versus D2G, p=0.027) and creatine kinase activity (10m D2 with axon transport deficit versus D2G, p=0.0288). Upregulation of Glut3, a glucose transporter specific to axons, was observed in 3m D2 versus D2G (p=0.0007), in 10m D2 with normal transport versus D2G (p=0.0017), and in 10m D2 with transport deficit versus D2G (p=0.0081). Astrocyte-specific lactate dehydrogenase-A (LDH-A) was significantly upregulated in 10m D2 with axon transport deficit compared to 10m D2 with normal transport (p=0.0439). Axon-specific LDH-B was significantly upregulated in 3m D2 versus D2G (p=0.0052), and in 3m D2G versus 10m D2 with (p<0.0001) or without axon transport (p=0.0147).

Conclusions : Decreased glial-specific expression of MCT-1 in the context of axon transport deficit accompanied increased LDH-A expression, suggesting that glial cells are utilizing the lactate that is no longer transported to the dysfunctional axons. In functional 10m D2 axons, increased MCT-2 and -4 expression suggests a drive to obtain lactate. The energy vulnerability observed in D2 optic nerve may be traced to the significant decrease in glycogen storage and creatine kinase activity, despite increased opportunity for lactate exchange through MCT upregulation in functional axons.

This is an abstract that was submitted for the 2016 ARVO Annual Meeting, held in Seattle, Wash., May 1-5, 2016.

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