Effects of Exogenous Neuroglobin (Ngb) on retinal inflammatory chemokines and microglia in a rat model of transient hypoxia

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.

Role of Neuroglobin in the Neuroprotective Actions of Estradiol and Estrogenic Compounds

“…This is in agreement with the fact that neuroglobin expression is enhanced in astrocytes and microglia after brain injury [53,[56][57][58][59]. Furthermore, it has been shown that exogenous intravitreal injection of neuroglobin reduces the activation of microglia, the expression of inflammatory cytokines and the apoptosis of retinal ganglion cells in hypoxic retina [60]. Therefore, the control of neuroinflammation by astrocytes and microglia may participate in the neuroprotective response mediated by neuroglobin.…”

Extracellular Neuroglobin as a Stress-Induced Factor Activating Pre-Adaptation Mechanisms against Oxidative Stress and Chemotherapy-Induced Cell Death in Breast Cancer

“…Indeed, during the last years, the idea that NGB localization may provide some clues about its function and that stimuli able to change NGB level/localization might also affect such function, has earned growing interest [ 8 , 33 , 36 , 37 , 38 ]. Other independent studies further complicate this scenario, indicating that NGB may be released from astrocytes [ 11 ] and exogenous NGB can exert cytoprotective functions in astroglial cells [ 12 ] and retinal neurons [ 39 ].…”

Neuroglobin in Retinal Neurodegeneration: A Potential Target in Therapeutic Approaches

“…In this context, it has been reported that retinal NGB is modulated in terms of expression, protein levels, and distribution under stressing and pathological conditions. NGB is rapidly overexpressed under hypoxia/ischemia insults in rats [59] and mice [37], after optic nerve injury in mice [47] and zebrafish [42], elevated intraocular pressure (IOP) [36] and blue (453 nm) light exposure [60] in rodent models, although the expression of the globin decrease to the normal levels [36,43,59,60] or at lower levels at longer time of the insult [37,47,61], at least in part due to the stress-induced retinal cell death (Table 2). Indeed, the expression of NGB has been demonstrated to significantly drop in parallel with retinal cell death after chemical-induced degeneration of photoreceptors [62,63] or in the mouse Harlequin (Hq) strain which shows defects of mitochondrial respiratory chain complex I and RGCs loss [35].…”

“…In addition to the transgenic-induced overexpression of NGB, an alternative approach using the injection in the mouse eyes of a chimeric human-zebrafish NGB with the ability to cross the plasma membrane, demonstrated that high levels of intracellular NGB led to a threefold increase in survival of RGCs accompanied with a significant axon-regenerating outgrowth after optic nerve injury [47]. Similarly, the intravitreal injections of mammalian exogenous NGB have been described to restore the long-time decrease in endogenous NGB after 7 days of hypoxia injury and to functionally prevent the stress-induced ganglion cell death and microglial activation, proposing the NGB injection as a potential therapy for retinal disease [61]. Of note, the latter results have been correlated with the intra-retinal penetration of exogenous mammalian NGB due to the small size of the globin and they could not exclude the possibility of a direct extracellular effect of NGB in the retinal tissue.…”