In the JournalsPerspective

Nrf2 pathway may be key in eye disease prevention, treatment

The Keap1-Nrf2-ARE pathway plays an important role in the regulation of a comprehensive and protective antioxidant response in the cells.

It could, therefore, be a key target of new approaches for treating major eye diseases, according to a recently published paper.

Starting from the assumption that “the eye is a prominent target of oxidative stress” and “is continuously exposed to various oxidative conditions,” the authors clarified the complex mechanisms through which oxidative stress contributes to pathologies such as AMD, cataract, diabetic retinopathy and glaucoma, as well as the involvement of the Nrf2 pathway in their pathophysiology.

They also gave an overview of current research on compounds that increase Nrf2 activity, such as quercetin analog, escin, salvianolic acyd and curcumin for AMD and rosa laevigata extract for cataract.

Gene therapy, leading to overexpression of Nrf2 in selected cells, was also presented as another promising research focus.

Nrf2-targeted approaches could also be useful for disease prevention, according to the authors. “By directly stimulating phase 2 enzyme expression, thereby making cells more resistant to oxidative stress-induced cell injury ... Nrf2 activators may be a novel approach for the prevention of a wide variety of oxidative stress-related human diseases and should be used in early or presymptomatic stages of diseases when restoring homeostasis is critical,” they wrote. – by Michela Cimberle

Disclosure: The authors reported no conflict of interest

The Keap1-Nrf2-ARE pathway plays an important role in the regulation of a comprehensive and protective antioxidant response in the cells.

It could, therefore, be a key target of new approaches for treating major eye diseases, according to a recently published paper.

Starting from the assumption that “the eye is a prominent target of oxidative stress” and “is continuously exposed to various oxidative conditions,” the authors clarified the complex mechanisms through which oxidative stress contributes to pathologies such as AMD, cataract, diabetic retinopathy and glaucoma, as well as the involvement of the Nrf2 pathway in their pathophysiology.

They also gave an overview of current research on compounds that increase Nrf2 activity, such as quercetin analog, escin, salvianolic acyd and curcumin for AMD and rosa laevigata extract for cataract.

Gene therapy, leading to overexpression of Nrf2 in selected cells, was also presented as another promising research focus.

Nrf2-targeted approaches could also be useful for disease prevention, according to the authors. “By directly stimulating phase 2 enzyme expression, thereby making cells more resistant to oxidative stress-induced cell injury ... Nrf2 activators may be a novel approach for the prevention of a wide variety of oxidative stress-related human diseases and should be used in early or presymptomatic stages of diseases when restoring homeostasis is critical,” they wrote. – by Michela Cimberle

Disclosure: The authors reported no conflict of interest

    Perspective
    Matt Dixon, OD

    Matt Dixon

    An online search on PubMed.gov for “oxidative stress” yields more than 250,000 articles. Most practitioners know that oxidative stress is the chief cause of the majority of human diseases, yet few of us spend much time trying to lower it.

    Add the word “eye” to the above search and you will find some 18,000 articles. The authors of this study, supported by the National Eye Institute, have reviewed 175 of these articles.

    So, what exactly is oxidative stress? It’s “... when reactive oxygen species (ROS) cellular overproduction overwhelms intrinsic antioxidant capacity [and] damage to the biomolecules of normal cells and tissues ... occurs” (Dröge). ROS include superoxide, hydrogen peroxide, single oxygen and lipid peroxides. The most common blinding conditions we treat each day are a result of ROS.

    One way the body fights harmful prooxidants is to respond through endogenous production of enzymatic antioxidants. The Nrf2 pathway is the key to upregulation of gene signaling and leads to robust antioxidant production.

    Compounds, both natural and synthetic, that can activate Nrf2 and lead to production of superoxide dismutase, catalase, glutathione peroxidase and glutathione reductase are being intensely studied. Synthetic Nrf2 activators such as Tecfidera (dimethyl fumarate, Biogen) are used to prevent relapse in multiple sclerosis. Natural compounds such as curcumin, green tea and sulforaphane show safe and promising results.

    Batliwala and colleagues have offered a valuable review of this important topic showing the vital role of Nrf2 in managing specific diseases such as age-related macular degeneration. Unfortunately, they omitted a key article implicating OS in the pathogenesis of Fuchs dystrophy and keratoconus (Wojcik et al.).

    Optometrists and ophthalmologists with an interest in epigenetics and functional medicine will integrate Nrf2 strategies as we seek to prevent and manage eye disease.

    References:

    Dröge W. Physiol Rev. 2002;82(1):47-95;doi: 10.1152/physrev.00018.2001.

    Wojcik KA, et al. Int J Mol Sci. 2013;14(9):19294-308;doi: 10.3390/ijms140919294.

    • Matt Dixon, OD
    • Advanced Eyecare Center
      Perry, Ga.
      drmattdixon@gmail.com

    Disclosures: Dixon maintains a distributorship with LifeVantage Corp. but is not a stock holder.