Bioprotective Carnitinoids: Lipoic Acid, Butyrate, and Mitochondria‐Targeting to Treat Radiation Injury: Mitochondrial Drugs Come of Age

Abstract

Preclinical Research Given nuclear-power-plant incidents such as the 2011 Japanese Fukushima-Daiichi disaster, an urgent need for effective medicines to protect against and treat the harmful biological effects of radiation is evident. To address such a challenge, we describe potential strategies herein including mitochondrial and epigenetic-driven methods using lipoic and butyric acid ester conjugates of carnitine. The antioxidant and other therapeutically beneficial properties of this class of agents may protect against ionizing radiation and resultant mitochondrial dysfunction. Recent studies of the compounds described herein reveal the potential-although further research and development is required to prove the effectiveness of this approach-to provide field-ready radiation-protective drugs.

Epigenetic Treatment of Neurodegenerative Disorders: Alzheimer and Parkinson Diseases

“…4), are actively transported and mitochondria-localizing biomimetic CoA surrogates of SCFAs [US Patents 6,316,652 and 8,741,853;Steliou et al, 2009Steliou et al, , 2012Steliou et al, , 2015Moos et al, 2016]. Mitochondria-targeting molecules attached to a triphenylphosphonium (TPP) cation also localize (by Coulombic pressure) in mitochondria, for example, the lipoic acid derivative, MitoL (Fig.…”

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.…”

Epigenetic Treatment of Neuropsychiatric Disorders: Autism and Schizophrenia

“…Carnitinoids are a class of compounds reported to present several key features: active‐transport; mitochondria‐localizing; biomimetic coenzyme A surrogates of SCFAs [Chenault et al, ; Billhardt et al, ; Steliou, ; Steliou et al, ; Virmani et al, ]; and HDAC inhibition [van de Mark et al, ; Dashwood and Ho, ; Ahmad et al, ; Steliou et al, ]. A few representative examples include PMX‐500FI, PMX‐500DBr, PMX‐550B, and PMX‐550DBr shown in Figure ; and a western blot demonstrating hyperacetylation of histone H3 with these compounds, along with the known HDAC inhibitor butyrate for reference, is shown in Figure .…”

“…Although these conditions are effectively resistant to therapeutic modalities available to date [Gray and Roth, ; Erdmann, ; Machado‐Vieira et al, ; Smith and Ehlers, ; Silverman and Crawley, ; Hyman, ; Horváth and Mirnics, ; Neul and Sahin, ; Wagner et al, ], epigenetic‐driven methods using short‐chain fatty acid (SCFA) histone deacetylase (HDAC) inhibitors (HDACi) are surfacing as promising avenues in the treatment of neuropsychiatric diseases associated with mitochondrial dysfunction (Fig. ) [Moos and Dykens, ; Steliou et al, ]. SCFAs—by inhibiting the deacetylation of histones, increasing DNA accessibility and turning genes on—activate a number of critical biological pathways that serve as master regulators of certain antioxidant and cytoprotective genes and their products, namely, nuclear factor (erythroid‐derived 2)‐like 2/antioxidant response element (Nrf2/ARE) [Gano et al, ; Sandberg et al, ; Inglese and Petracca, ; Vasconcelos et al, ], which can stimulate mitophagy to decrease the accumulation of damaged mitochondria [Wallace, ].…”

“…The purpose of this review is to discuss emerging epigenetic‐driven approaches for the treatment of neuropsychiatric disorders associated with mitochondrial dysfunction. Having addressed other diseases elsewhere [Steliou et al, ], herein we focus on ASD and SCZ and highlight the therapeutic potential of novel acylcarnitine esters (carnitinoids) in treatment. These small molecules target mechanisms of great interest with respect to genes and pathways implicated in the pathogenesis and progression of ASD and SCZ.…”