Optic Nerve Degeneration after Retinal Ischemia/Reperfusion in a Rodent Model

Abstract

Retinal ischemia is a common pathomechanism in many ocular disorders such as age-related macular degeneration (AMD), diabetic retinopathy, glaucoma or retinal vascular occlusion. Several studies demonstrated that ischemia/reperfusion (I/R) leads to morphological and functional changes of different retinal cell types. However, little is known about the ischemic effects on the optic nerve. The goal of this study was to evaluate these effects. Ischemia was induced by raising the intraocular pressure (IOP) in one eye of rats to 140 mmHg for 1 h followed by natural reperfusion. After 21 days, histological as well as quantitative real-time PCR (qRT-PCR) analyses of optic nerves were performed. Ischemic optic nerves showed an infiltration of cells and also degeneration with signs of demyelination. Furthermore, a migration and an activation of microglia could be observed histologically as well as on mRNA level. In regard to macroglia, a trend toward gliosis could be noted after ischemia induction by vimentin staining. Additionally, an up-regulation of glial fibrillary acidic protein (GFAP) mRNA was found in ischemic optic nerves. Counting of oligodendrocyte transcription factor 2 positive (Olig2+) cells revealed a decrease of oligodendrocytes in the ischemic group. Also, myelin basic protein (MBP) and myelin oligodendrocyte glycoprotein (MOG) mRNA expression was down-regulated after induction of I/R. On immunohistological level, a decrease of MOG was detectable in ischemic optic nerves as well. In addition, SMI-32 stained neurofilaments of longitudinal optic nerve sections showed a strong structural damage of the ischemic optic nerves in comparison to controls. Consequently, retinal ischemia impacts optic nerve degeneration. These findings could help to better understand the course of destruction in the optic nerve after an ischemic insult. Especially for therapeutic studies, the optic nerve is important because of its susceptibility to be damaged as a result to retinal ischemic injury and also its connecting function between the eye and the brain. So, future drug screenings should target not only the retina, but also the functionality and structure of the optic nerve. In the future, these results could lead to the development of new therapeutic strategies for treatment of ischemic injury.

Increased Hydrostatic Pressure Promotes Primary M1 Reaction and Secondary M2 Polarization in Macrophages

“…In macrophages, the activation of the TLR-4 signaling pathway induces an M1 polarization and inflammatory response that leads to activation of NF-κB to produce proinflammatory cytokines (IL-1β, TNF-α, iNOS, and others), which are known to play an important role in IRI, hemorrhagic shock, and retinal injury under elevated pressure ( 25 , 46 ). Various studies reported that increased expression of TNF-α seems to be related to impaired retina in cases of acutely elevated IOP ( 47 , 48 ). Except for the damage to retinal ganglion cells and optic nerve head, the elevated production of TNF-α by M1 macrophages induces a response of T-helper cells and their differentiation to Th17, which turns the acute inflammation into a fibrotic reaction ( 49 ).…”

Fewer Functional Deficits and Reduced Cell Death after Ranibizumab Treatment in a Retinal Ischemia Model

“…To induce retinal ischemia/reperfusion we used an in our group established ischemia/reperfusion model [ 11 , 50 ]. Ischemia was induced for 60 min by elevating the IOP to 140 mmHg.…”

“…Immunohistological stainings were performed as previously described [ 11 , 38 , 50 , 51 , 52 ]. To prepare the retinal cross-sections ( n = 5–6/group) for immunohistochemistry, they were first dried and rehydrated in PBS, followed by blocking in 10–20% appropriate serum with 1% BSA in 0.1% or 0.2% Triton X-100 in PBS.…”

Optic Nerve Changes in Diabetic Retinopathy

“…There is no algorithm to define the pattern of contrast sensitivity alteration in the early stage of DR. Adachi, Jochim, and Renner. observed reduced contrast sensitivity only at single low spatial frequency in cases of non-insulin-dependent diabetes mellitus without DR [79][80][81]. Meanwhile, Joltikov et al and Safi et al reported decline in contrast sensitivity at all spatial frequencies early in the course of diabetic retinal sensory neuropathy [14,82].…”