Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

Abstract

Preclinical Research In this review, we discuss epigenetic-driven methods for treating neurodegenerative disorders associated with mitochondrial dysfunction, focusing on carnitinoid antioxidant-histone deacetylase inhibitors that show an ability to reinvigorate synaptic plasticity and protect against neuromotor decline in vivo. Aging remains a major risk factor in patients who progress to dementia, a clinical syndrome typified by decreased mental capacity, including impairments in memory, language skills, and executive function. Energy metabolism and mitochondrial dysfunction are viewed as determinants in the aging process that may afford therapeutic targets for a host of disease conditions, the brain being primary in such thinking. Mitochondrial dysfunction is a core feature in the pathophysiology of both Alzheimer and Parkinson diseases and rare mitochondrial diseases. The potential of new therapies in this area extends to glaucoma and other ophthalmic disorders, migraine, Creutzfeldt-Jakob disease, post-traumatic stress disorder, systemic exertion intolerance disease, and chemotherapy-induced cognitive impairment. An emerging and hopefully more promising approach to addressing these hard-to-treat diseases leverages their sensitivity to activation of master regulators of antioxidant and cytoprotective genes, antioxidant response elements, and mitophagy. Drug Dev Res 77 : 109-123, 2016. © 2016 Wiley Periodicals, Inc.

Epigenetic treatment of dermatologic disorders

“…Not surprisingly, there is great interest in pharmacological modulators of Nrf2 that could be developed into therapeutics for the treatment and prevention of disease (Buendia et al, ; Cuadrado et al, ; Dodson et al, ; Du et al, ; Gacesa et al, ; Kumar, Kim, More, Kim, & Choi, ; Lu, Ji, Jiang, & You, ; Rabbani, Ellison, et al, ; Sivandzade et al, ; Sklirou, Papanagnou, Fokialakis, & Trougakos, ; Sova & Saso, ; Vega, Dodson, Chapman, & Zhang, ; Yamamoto et al, ; Zhang et al, ), including skin disorders (Dodson et al, ; Ferrándiz, Nacher‐Juan, & Alcaraz, ; Gacesa et al, ; Kumar et al, ; Lu et al, ; Penta, Somashekar, & Meeran, ; Rabbani, Ellison, et al, ; Son et al, ; Yamamoto et al, ). Examples of natural products known to induce epigenetic Nrf2‐activating effects are shown in Figure (Bambouskova et al, ; Dodson et al, ; Fazzari et al, ; Fratantonio et al, ; Garaude, ; Gill, Raman, Yost, Garrett, & Vedam‐Mai, ; Gu et al, ; Iranshahy, Iranshahi, Abtahi, & Karimi, ; Irwin, Moos, Faller, Steliou, & Pinkert, ; Kumar et al, ; Li et al, ; Mathers et al, ; Matzinger, Fischhuber, & Heiss, ; Moos, Maneta, et al, ; Moos et al, ; Rigacci & Stefani, ; Rusu, Gheldiu, Mocan, Vlase, & Popa, ; Sivandzade et al, ; Steliou, Boosalis, Perrine, Sangerman, & Faller, ; Steliou, Faller, Pinkert, Irwin, & Moos, ; Tsujita et al, ). Some products are endogenously made, like the prostaglandins and l ‐carnitine as well as butyric, α‐lipoic, fumaric, itaconic, and the nitro‐fatty acids.…”

Translating HDAC inhibitors in Friedreich’s ataxia

“…The structures of some of these compounds are shown in Figure 2. While the development of HDAC inhibitors as anti-cancer therapeutics is quite advanced [57], interest in the development of HDAC inhibitors for neurodegenerative and neuromotor diseases has increased in the past few years [53, 58]. …”

The nature of the GRE influences the screening for GR-activity enhancing modulators

“…Originally HDACi were used to treat solid and haematological cancers [33–36]. Nowadays, HDACi are used far beyond the cancer field to treat, amongst others, neurodegenerative diseases [37, 38] and inflammatory disorders [39, 40] such as rheumatoid arthritis [41], lupus erythematosus [42] and type 2 diabetes [43]. So far, four HDACi, namely Vorinostat (SAHA), Romidepsin, Panobinostat and Belinostat, are approved by the United States Food and Drug Administration (FDA).…”