SIRT1 and NRF2 Gene Transfer Mediate Distinct Neuroprotective Effects Upon Retinal Ganglion Cell Survival and Function in Experimental Optic Neuritis

Abstract

PurposeOptic neuritis is a condition defined by autoimmune-mediated demyelination of the optic nerve and death of retinal ganglion cells. SIRT1 and NRF2 stimulate anti-inflammatory mechanisms and have previously demonstrated therapeutic value in preclinical models of neurodegenerative disease. Here we investigated the neuroprotective potential of SIRT1 or NRF2 gene transfer using adeno-associated virus (AAV) vectors in the experimental autoimmune encephalomyelitis (EAE) model of multiple sclerosis.MethodsC57Bl/6J mice were administered intravitreal doses of AAV2 vectors and immunized to induce EAE symptoms. Visual function was examined by recording the optokinetic response (OKR) just prior to EAE induction and once every 7 days postinduction for 7 weeks. Retina and optic nerves were harvested to investigate retinal ganglion cell survival (immunolabeling with Brn3a antibodies); inflammation (hematoxylin and eosin staining); and demyelination (luxol fast blue staining).ResultsAnimals modeling EAE demonstrate reduced visual acuity compared to sham-induced controls. Intravitreal delivery of AAV2-NRF2 did not preserve visual function. However, AAV2-SIRT1 mediated significant preservation of the OKR compared to AAV2-eGFP controls. Treatment with AAV2-NRF2 promoted RGC survival while AAV2-SIRT1 mediated an upward trend in protection compared to vehicle and AAV2-eGFP controls. Neither NRF2 nor SIRT1 gene augmentation was able to suppress optic nerve inflammation or demyelination.ConclusionsAAV-mediated overexpression of NRF2 or SIRT1 within RGCs mediates distinct neuroprotective effects upon visual function and RGC survival. This study expands our understanding of SIRT1 and NRF2-mediated neuroprotection in the context of MS pathogenesis and optic neuropathies.

Sirtuins in Multiple Sclerosis: The crossroad of neurodegeneration, autoimmunity and metabolism

“…As neuroprotective agents, simultaneous overexpression of NRF2 or SIRT1 within RGCs could prevent impairment of visual function and induced RGCs survival in EAE mice (McDougald et al, 2018). Also, similar protective effects were reported in chronic EAE in C57BL/6 mice and in a virus-induced CNS demyelination model (Fonseca-Kelly et al, 2012;Khan et al, 2014).…”

“…The elevated level in the generation of oligodendrocyte progenitor cells (OPCs) was also reported in NPC-specific knockout of SIRT1 in mice (Rafalski et al, 2013). Furthermore, several studies have shown that SIRT1 inhibition leads to improvement of Table 2 The role of sirtuins in human pathologies or animal models of MS. (Shindler et al, 2007) EAE mouse SRT501 Preservation of axonal density in the spinal cord (Shindler et al, 2010) EAE mouse Genetically SIRT1 overexpression Suppression of EAE symptoms (Nimmagadda et al, 2013) EAE mouse Intravitreal overexpression of SIRT1 Neuroprotection of visual function and RGC survival (McDougald et al, 2018) EAE mouse Increase of SIRT1 expression in GFAP-positive cells around inflammatory lesions (Prozorovski et al, 2008) C57BL/6 mice Resveratrol (SIRT1 activator) Suppression of proliferation in NPCs-differentiation toward astrocyte (Prozorovski et al, 2008) C57BL/6 mice Knockout of SIRT1 Elevated level in OPCs generation (Rafalski et al, 2013) EAE mouse Ex-527 (SIRT1 inhibitor) Induction of remyelination, delay in paralysis onset, inhibition of pro-inflammatory Th17 cells and reduction of infiltration of immune cells into the spinal cord (Lim et al, 2015) EAE mouse Increase in level of transcription of SIRT1 in the CNS during chronic disease stages (Prozorovski et al, 2019) Upregulated level of SIRT1 in nuclei of NG2+ or PDGFRα+ OPCs in demyelinated brain lesions.…”

Potential Protective and Therapeutic Roles of the Nrf2 Pathway in Ocular Diseases: An Update

“…When the role of Nrf2 was examined, Nrf2 KO EAE mice showed more severe visual impairment, optic nerve inflammation, and RGC degeneration, indicating that Nrf2 had a neuroprotective effect in EAE-related optic neuritis. The overexpression of Nrf2 increased RGC survival in an EAE model of optic neuritis [161]. Dimethyl fumarate (DMF) has been used in the treatment of MS [162], experimental Parkinson's diseases [163], long-term memory deficits [164], and other diseases of the nervous system.…”

AKT3 Gene Transfer Promotes Anabolic Reprogramming and Photoreceptor Neuroprotection in a Pre-clinical Model of Retinitis Pigmentosa

“…Visual acuity was assessed by measuring the OKR using the OptoMotry software and apparatus (Cerebral Mechanics, Medicine Hat, AB, Canada) as previously described. 48 Recordings were performed by an investigator masked to the experimental treatments.…”