Abstract
Neuroglobin is an endogenous neuroprotective protein. We determined the safety of direct delivery of Neuroglobin in the rat retina and its effects on retinal inflammatory chemokines and microglial during transient hypoxia. Exogenous Neuroglobin protein was delivered to one eye and a sham injection to the contralateral eye of six rats intravitreally. Fundus photography, Optical Coherence Topography, electroretinogram, histology and Neuroglobin, chemokines level were determined on days 7 and 30. Another 12 rats were subjected to transient hypoxia to assess the effect of Neuroglobin in hypoxia exposed retina by immunohistochemistry, retinal Neuroglobin concentration and inflammatory chemokines. Intravitreal injection of Neuroglobin did not incite morphology or functional changes in the retina. Retinal Neuroglobin protein was reduced by 30% at day 7 post hypoxia. It was restored to normoxic control levels with intravitreal exogenous Neuroglobin injections and sustained up to 30 days. IL-6, TNFα, IL-1B, RANTES, MCP-1 and VEGF were significantly decreased in Neuroglobin treated hypoxic retinae compared to non-treated hypoxic controls. This was associated with decreased microglial activation in the retina. Our findings provide proof of concept suggesting intravitreal Neuroglobin injection is non-toxic to the retina and can achieve the functional level to abrogate microglial and inflammatory chemokines responses during transient hypoxia.
Highlights
Neuroglobin (Ngb) is an endogenous heme protein found abundantly in the retina[1,2,3,4]
In a comparison of the retinal inflammatory chemokines, we found a significant reduction (p < 0.05) of TNFα (Tumour Necrosis Factor alpha), IL-6 (Interleukin 6), IL-1B (Interleukin 1 Beta), RANTES (Regulated on Activation Normal T Cell Expressed and Secreted), MCP-1 (Monocyte Chemotactic Protein 1) and VEGF (Vascular Endothelial Growth Factor) in IVT Ngb treated retinae, at 30 days post exposure to transient hypoxia compared to the non-treated hypoxic control (Fig. 2)
Intravitreal protein delivery of anti-VEGF has become the mainstay of choroidal neovascularisation in age related macular degeneration and macular edema treatment[11]
Summary
Neuroglobin (Ngb) is an endogenous heme protein found abundantly in the retina[1,2,3,4]. The small size of Ngb (17 kDa) suggests that direct intra-retinal penetration may be possible[6,7]. This pilot study aimed to demonstrate that a simple exogenous Ngb protein delivery via intravitreal (IVT) injections is safe and able to elevate retinal Ngb protein levels. Our secondary aim was to determine the retinal effects of exogenous IVT Ngb on inflammatory cytokines and microglial activation in rats exposed to transient hypoxia in order to establish proof of concept that direct Ngb protein injections may be a potential delivery modality for the study of its neuroprotective effects
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