Axonal degeneration, regeneration and ganglion cell death in a rodent model of anterior ischemic optic neuropathy (rAION)

Abstract

Using laser-induced photoactivation of intravenously administered rose Bengal in rats, we generated an ischemic infarction of the intrascleral portion of the optic nerve (ON) comparable to that which occurs in humans to investigate optic nerve axon degenerative events following optic nerve infarct and the potential for axon re-growth. Animals were euthanized at different times post infarct. Axon degeneration was evaluated with SMI312 immunolabeling, and GAP-43 immunostaining was used to identify axon regeneration. Terminal dUTP nick end labeling (TUNEL) was used to evaluate retinal ganglion cell (RGC) death. There was significant axon structural disruptinot ion at the anterior intrascleral portion of the ON by 3d post-infarct, extending to the posterior ON by 7d post-stroke. Destruction of normal axon structure and massive loss of axon fibers occurred by 2 weeks. GAP-43 immunoreactivity occurred in the anterior ON by 7d post-infarct, lasting 3-4 weeks, without extension past the primary ischemic lesion. TUNEL-positive cells in the RGC layer appeared by 7d post-insult. These results indicate that following induction of ischemic optic neuropathy, significant axon damage occurs by 3d post-infarct, with later neuronal death. Post-stroke adult rat retinal ganglion cells attempt to regenerate their axons, but this effort is restricted to the unmyelinated region of the anterior ON. These responses are important in understanding pathologic process that underlies human non-arteritic anterior ischemic optic neuropathy (NAION) and may guide both the appropriate treatment of NAION and the window of opportunity for such treatment.

Early macular ganglion cell–inner plexiform layer analysis in non-arteritic anterior ischemic optic neuropathy

“…Thinning was first observed in the minimum mGCIPL thickness (32.5±12.1 days), followed by the average mGCIPL thickness (46.1±23.2 days), and lastly, the average pRNFL (79.2±19.7 days). These results were in accordance with the results of SD-OCT imaging in experimental NAION models and histological measurements of retinal ganglion cell and axonal loss occurring early after gradual thinning induced by ischemia [22,23]. Our results suggest that SD-OCT is a suitable method for ophthalmologists to more easily diagnose NAION 1 to 2 months after the visual disturbance.…”

Difference in the posterior pole profiles associated with the initial location of visual field defect in early‐stage normal tension glaucoma

“…In contrast to the typical VF defects below or above the horizontal meridian, paracentral VF loss frequently occurs in glaucoma patients with abnormal ocular blood flow (Anctil & Anderson 1984;Lee et al 2012;Hood et al 2013). Moreover, papillomacular fibres that correspond to central VFs have increased vulnerability to ischaemic insult (Quigley et al 1985;Zhang et al 2010). Taken together, these results suggest that abnormal ocular blood flow may play a role in the pathogenesis of NTG, particularly with paracentral VF loss.…”

Optical Coherence Tomography Study of Experimental Anterior Ischemic Optic Neuropathy and Histologic Confirmation

“…Increased SD-OCT thickness can also be partly due to early and persistent inflammatory response, increased glial activation, and recruitment of macrophages to the ischemic optic nerve from day 3 to day 35 postinjury. 58,59 Chronically, thinning on SD-OCT measurements correlated better with histology and loss of RGC layer neurons, although thickness measurement alone does not tell the whole story. In patient eyes with no light perception from various optic neuropathies for at least 1 year, the retinal nerve fiber layer thinning is only approximately 50%.…”