Abstract
The rodent model of nonarteritic anterior ischemic optic neuropathy (rNAION) is similar in many of its pathophysiological responses to clinical NAION. Like human NAION, there is significant variability in the severity of the lesion produced, and little is known of the parameters associated with rNAION induction severity or if pre- or early post-induction biomarkers can be identified that enable prediction of lesion severity and ultimate loss of retinal ganglion cells (RGCs). Adult male Sprague-Dawley outbred rats were evaluated for various parameters including physiological characteristics (heart rate, respiratory rate, temperature, hematocrit [Hct]), optic nerve head (ONH) appearance, pre- and post-induction mean diameter, and intravenous fluorescein and indocyanine green angiographic patterns of vascular leakage at 5 hours post-induction, performed using a spectral domain-optical coherence tomography (SD-OCT) instrument. Early changes were correlated with ultimate RGC loss by Brn3a (+) immunohistology. RGC loss also was correlated with the relative level of laser exposure. The severity of ONH edema 2d, but not 5hr, post induction was most closely associated with the degree of RGC loss, revealing a threshold effect, and consistent with a compartment syndrome where a minimum level of capillary compression within a tight space is responsible for damage. RGC loss increased dramatically as the degree of laser exposure increased. Neither physiological parameters nor the degree of capillary leakage 5hr post induction were informative as to the ultimate degree of RGC loss. Similar to human NAION, the rNAION model exhibits marked variability in lesion severity. Unlike clinical NAION, pre-induction ONH diameter likely does not contribute to ultimate lesion severity; however, cross-sectional ONH edema can be used as a biomarker 2d post-induction to determine randomization of subjects prior to inclusion in specific neuroprotection or neuroregeneration studies.
Highlights
Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve-related vision loss in individuals over the age of 50 in the developed world [1]
We found no evidence of an association between lesion severity and Hct, core temperature, heart rate, or respiratory rate during induction
The finding that retinal ganglion cells (RGCs) loss in the rNAION model is associated with a threshold expansion of the optic nerve head (ONH) is consistent with the ‘compartment syndrome’ theory of the pathophysiology of clinical NAION; ie, there is a threshold level of ONH edema that results in compression of the ONH capillaries in both human NAION and rNAION
Summary
Nonarteritic anterior ischemic optic neuropathy (NAION) is the most common cause of sudden optic nerve-related vision loss in individuals over the age of 50 in the developed world [1]. To circumvent the problems inherent in NAION clinical research, we developed rodent and primate nonarteritic anterior ischemic optic neuropathy (rNAION and pNAION, respectively) [5,6,7] These models are pathophysiologically similar in many ways to the clinical disease in terms of presentation with ONH edema, acellular and cellular inflammatory responses, ON-axon loss, isolated retinal ganglion cell (RGC) loss and visual debilitation [8]. In these models, laser-induced superoxide radicals from a photosensitive dye induce anterior ON capillary decompensation and leakage, resulting in ON edema, a compartment syndrome, and a lesion resembling the clinical one [9]. We previously documented fluorescein leakage in rNAION [6]
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