Abstract
Nordihydroguaiaretic acid (NDGA) is a phenolic lignan obtained from Larrea tridentata, the creosote bush found in Mexico and USA deserts, that has been used in traditional medicine for the treatment of numerous diseases such as cancer, renal, cardiovascular, immunological, and neurological disorders, and even aging. NDGA presents two catechol rings that confer a very potent antioxidant activity by scavenging oxygen free radicals and this may explain part of its therapeutic action. Additional effects include inhibition of lipoxygenases (LOXs) and activation of signaling pathways that impinge on the transcription factor Nuclear Factor Erythroid 2-related Factor (NRF2). On the other hand, the oxidation of the catechols to the corresponding quinones my elicit alterations in proteins and DNA that raise safety concerns. This review describes the current knowledge on NDGA, its targets and side effects, and its synthetic analogs as promising therapeutic agents, highlighting their mechanism of action and clinical projection towards therapy of neurodegenerative, liver, and kidney disease, as well as cancer.
Highlights
Nordihydroguaiaretic acid (NDGA), called masoprocol {IUPAC name: 4-[4-(3,4dihydroxyphenyl)-2,3-dimethylbutyl]benzene-1,2-diol}, is a phenolic lignan mainly extracted from the five plant species that constitute the genus Larrea (Arteaga et al, 2005; Peralta et al, 2018)
Despite the existence of many preclinical studies that highlight the therapeutic potential of NDGA, the fact is that most of its beneficial effects are not supported by clinical studies, as it usually happens with parapharmaceutical products (AbouGazar et al, 2004; Arteaga et al, 2005)
Two other 5-LOX inhibitors (Rev5901 and AA861) did not mimic the effect of NDGA, and addition of 5-LOX metabolites did not reverse the NDGA-driven suppression of STAT. These results suggest that NDGA regulates IFNg-mediated inflammation through mechanisms that are not related to LOX inhibition and might be the result of combined mechanisms, possibly related to Nuclear Factor Erythroid 2-related Factor (NRF2) activation (Cuadrado et al, 2018)
Summary
Nordihydroguaiaretic acid (NDGA), called masoprocol {IUPAC name: 4-[4-(3,4dihydroxyphenyl)-2,3-dimethylbutyl]benzene-1,2-diol}, is a phenolic lignan mainly extracted from the five plant species that constitute the genus Larrea (Arteaga et al, 2005; Peralta et al, 2018). Despite the existence of many preclinical studies that highlight the therapeutic potential of NDGA, the fact is that most of its beneficial effects are not supported by clinical studies, as it usually happens with parapharmaceutical products (AbouGazar et al, 2004; Arteaga et al, 2005). This review will critically discuss the best characterized mechanisms and targets attributed to NDGA, safety concerns and the potential of NDAG analogs for clinical translation
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