Title:Creation of Retinal Vein Occlusion Model in Cynomolgus Monkeys and Determination of its Pathological Features
Volume: 18
Issue: 1
Author(s): Satoshi Inagaki, Masamitsu Shimazawa*, Wataru Otsu, Tomoaki Araki, Yosuke Numata, Shinsuke Nakamura, Hideshi Tsusaki and Hideaki Hara
Affiliation:
- Department of Biofunctional Evaluation, Gifu Pharmaceutical University, Gifu,Japan
Keywords:
Ranibizumab, retinal vein occlusion (RVO), Non-human primate RVO model, retinal vascular disorder, VEGF,
edema.
Abstract:
Objective: A retinal vein occlusion (RVO) is a relatively common retinal vascular disorder,
especially in the elderly. Many experiments have been performed on patients with an RVO but
performing any type of experiments and especially longitudinal experiments on humans is difficult,
if not impossible, on ethical grounds. Therefore, we have created a retinal vein occlusion (RVO)
model by laser irradiation of cynomolgus monkeys after intravenous injection of rose bengal. We
evaluated the pathological changes of the retina, and the effects of ranibizumab, an anti-vascular endothelial
growth factor (VEGF) antibody, on the characteristics of the RVO.
Methods: The integrity of the vascular system was evaluated by fluorescein angiography (FA), and
the retinal thickness and volume were determined by optical coherence tomography (OCT). The cytokines
and growth factors in the aqueous humour were identified by multiplex profiling.
Results: Our results showed that ranibizumab decreased the degree of vascular leakage and retinal
edema at 1-3 days (acute phase) and 3-7 days (subacute phase), and suppressed foveal thinning at
28-42 days (chronic phase) after the laser irradiation. Ranibizumab also decreased the area of the
foveal avascular zone, and the area was negatively and significantly correlated with the thickness
of the ganglion cell layer (GCL) complex. Furthermore, ranibizumab reduced the increased expression
of VEGF in the aqueous humor, but did not affect the expressions of interleukin-6 (IL-6),
monocyte chemotactic protein-1 (MCP-1), angiopoietin-1 (ANG-1), or angiopoietin-2 (ANG-2).
These findings suggest that ranibizumab attenuates the retinal edema and subsequent retinal atrophy
in part by neutralizing VEGF. However, other cytokines and growth factors were also affected
by the ranibizumab, which suggests that not only VEGF but also other unidentified agents might
play a role in the pathogenesis of the RVO.
Conclusion: We have created a non-human primate RVO model, which resembles the clinical
RVO pathology. In this model, an injection of ranibizumab leads to a reduction in vascular leakage
and the retinal thickness and volume by blocking the expression of VEGF. Our model might be useful
for investigating the pathological mechanisms of RVOs and explore new therapeutic agents for
RVO.
