Optic nerve inflammation and demyelination in a rodent model of nonarteritic anterior ischemic optic neuropathy.
OBJECTIVE
Optic nerve (ON) ischemia associated with nonarteric anterior ischemic optic neuropathy (NAION) results in axon and myelin damage. Myelin damage activates the intraneural Ras homolog A (RhoA), contributing to axonal regeneration failure. We hypothesized that increasing extrinsic macrophage activity after ON infarct would scavenge degenerate myelin and improve postischemic ON recovery. We used the cytokine granulocyte-macrophage colony-stimulating factor (GM-CSF) to upregulate ON macrophage activity, and evaluated GM-CSF's effects after ON ischemia in the NAION rodent model (rAION).


METHODS
Following rAION induction, GM-CSF was administered via intraventricular injection. Retinal ganglion cell (RGC) stereologic analysis was performed 1 month postinduction. The retinae and optic nerve laminae of vehicle- and GM-CSF-treated animals were examined immunohistochemically and ultrastructurally using transmission electron microscopy (TEM). RhoA activity was analyzed using a rhotekin affinity immunoanalysis and densitometry. Isolated ONs were analyzed functionally ex vivo by compound action potential (CAP) analysis.


RESULTS
Rodent NAION produces ON postinfarct demyelination and myelin damage, functionally demonstrable by CAP analysis and ultrastructurally by TEM. Granulocyte-macrophage colony-stimulating factor increased intraneural inflammation, activating and recruiting endogenous microglia, with only a moderate amount of exogenous macrophage recruitment. Treatment with GM-CSF reduced postinfarct intraneural RhoA activity, but did not neuroprotect RGCs after rAION.


CONCLUSIONS
Sudden ON ischemia results in previously unrecognized axonal demyelination, which may have a clinically important role in NAION-related functional defects and recovery. Granulocyte-macrophage colony-stimulating factor is not neuroprotective when administered directly to the optic nerve following ON ischemia, and does not improve axonal regeneration. It dramatically increases ON-microglial activation and recruitment.
Department of Ophthalmology and Visual Sciences, University of Maryland-Baltimore, Baltimore, Maryland.
Bernard J
BJ
Slater
Fernandino L
FL
Vilson
Yan
Y
Guo
Daniel
D
Weinreich
Shelly
S
Hwang
Steven L
SL
Bernstein
D000818:Animals; D003711:Demyelinating Diseases / Q000209:etiology* / Q000378:metabolism / Q000473:pathology; D003720:Densitometry; D004195:Disease Models, Animal; D016178:Granulocyte-Macrophage Colony-Stimulating Factor / Q000096:biosynthesis; D008297:Male; D017628:Microglia / Q000378:metabolism / Q000648:ultrastructure; D046529:Microscopy, Electron, Transmission; D009900:Optic Nerve / Q000378:metabolism / Q000473:pathology*; D009902:Optic Neuritis / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D018917:Optic Neuropathy, Ischemic / Q000150:complications / Q000378:metabolism / Q000473:pathology*; D051381:Rats; D017207:Rats, Sprague-Dawley; D012165:Retinal Ganglion Cells / Q000378:metabolism / Q000648:ultrastructure; D015854:Up-Regulation
D016178:Granulocyte-Macrophage Colony-Stimulating Factor
GM-CSF; immune regulation; macrophages; microglia; naion; optic nerve ischemia; postinfarct demyelination; rodent models