Adeno-associated virus-mediated neuroglobin overexpression ameliorates the N-methyl-N-nitrosourea-induced retinal impairments: a novel therapeutic strategy against photoreceptor degeneration

Abstract

Retinal degeneration (RD) is a heterogeneous group of inherited dystrophies leading to blindness. The N-methyl-N-nitrosourea (MNU)-administered mouse is used as a pharmacologically induced RD animal model in various therapeutic investigations. The present study found the retinal neuroglobin (NGB) expression in the MNU-administered mice was significantly lower than in normal controls, suggesting NGB was correlated with RD. Subsequently, an adeno-associated virus (AAV)-2-mCMV-NGB vector was delivered into the subretinal space of the MNU-administered mice. The retinal NGB expression of the treated eye was upregulated significantly in both protein and mRNA levels. Further, we found NGB overexpression could alleviate visual impairments and morphological devastations in MNU-administered mice. NGB overexpression could rectify apoptotic abnormalities and ameliorate oxidative stress in MNU-administered mice, thereby promoting photoreceptor survival. The cone photoreceptors in MNU-administered mice were also sensitive to AAV-mediated NGB overexpression. Taken together, our findings suggest that manipulating NGB bioactivity via gene therapy may represent a novel therapeutic strategy against RD. Future elucidation of the exact role of NGB would advance our knowledge about the pathological mechanisms underlying RD.

Neuroglobin in Retinal Neurodegeneration: A Potential Target in Therapeutic Approaches

“…Consistently, in Hq mice, overexpressed NGB has been demonstrated to restore the mitochondrial function and improve RGCs survival, to maintain nerve fiber integrity, reduce the glial cell activation and, in turn, protect the visual functions [35]. Furthermore, similar effects were also observed in mice treated with N-Methyl-N-nitrosourea (MNU), an alkylant toxicant that causes the selective photoreceptor apoptosis in the mammalian retina, where the induction of NGB overexpression through an adeno-associated-virus vector ameliorated the oxidative stress and apoptotic cell death in photoreceptor cells alleviating the morphological alteration of the retina and the visual impairments [62].…”

“…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]. On the other side, just few human studies about the connection between NGB levels and retinal disease have been yet performed.…”

A rare natural lipid induces neuroglobin expression to prevent amyloid oligomers toxicity and retinal neurodegeneration

“…These results strongly suggest that mRNA levels of neuroglobin are regulated similarly to YHB1 in response to tripentadecanoin. To test the effect of tripentadecanoin in vivo, we chose an N‐nitroso‐N‐methylurea (NMU) induced photoreceptor degeneration model for several reasons: Yhb1 has mostly been associated with nitrosated stress (Lewinska & Bartosz, 2006) while over‐expression of neuroglobin was previously shown to rescue visual defects induced by NMU (Tao et al, 2017). Moreover, NMU causes photoreceptor degeneration within 7 days of a single‐dose injection and the induced damage mimics the photoreceptor degenerative process in progressive human retinal degenerative diseases.…”

A rare natural lipid induces neuroglobin expression to prevent amyloid oligomers toxicity and retinal neurodegeneration

“…These results strongly suggests that mRNA levels of neuroglobin are regulated similarly to YHB1 in response to tripentadecanoin. To test the effect of tripentadecanoin in vivo, we chose an N-nitroso-N-methylurea (NMU) induced photoreceptor degeneration model for several reasons: Yhb1 has mostly been associated with nitrosated stress ( 12 ) while over-expression of neuroglobin was previously shown to rescue visual defects induced by NMU ( 13 ). Moreover, NMU causes photoreceptor degeneration within 7 days of a single-dose injection and the induced damage mimics the photoreceptor degenerative process in progressive human retinal degenerative diseases.…”