The arachidonic acid 5‐lipoxygenase inhibitor nordihydroguaiaretic acid inhibits tumor necrosis factor α activation of microglia and extends survival of G93A‐SOD1 transgenic mice

Abstract

Familial forms of amyotrophic lateral sclerosis (ALS) can be caused by mutations in copper, zinc-superoxide dismutase (SOD1). Mice expressing SOD1 mutants demonstrate a robust neuroinflammatory reaction characterized, in part, by up-regulation of tumor necrosis factor alpha (TNFa) and its primary receptor TNF-RI. In an effort to identify small molecule inhibitors of neuroinflammation useful in treatment of ALS, a microglial culture system was established to identify TNFa antagonists. Walker EOC-20 microglia cells were stimulated with recombinant TNFa, with or without inhibitors, and the cell response was indexed by NO 2 -output. Three hundred and fifty-five rationally selected compounds were included in this bioassay. The arachidonic acid 5-lipoxygenase (5LOX) and tyrosine kinase inhibitor nordihydroguaiaretic acid (NDGA), a natural dicatechol, was one of the most potent non-cytotoxic antagonists tested (IC 50 8 ± 3 lM). Investigation of the G93A-SOD1 mouse model for ALS revealed increased message and protein levels of 5LOX at 120 days of age. Oral NDGA (2500 p.p.m.) significantly extended lifespan and slowed motor dysfunction in this mouse, when administration was begun relatively late in life (90 days). NDGA extended median total lifespan of G93A-SOD1 mice by 10%, and life expectancy following start of treatment was extended by 32%. Diseaseassociated gliosis and cleaved microtubule-associated tau protein, an indicator of axon damage, were likewise reduced by NDGA. Thus, TNFa antagonists and especially 5LOX inhibitors might offer new opportunities for treatment of ALS.

Regulation of pro-inflammatory responses by lipoxygenases via intracellular reactive oxygen species in vitro and in vivo

“…These results show that ROS may perform essential functions for both the induction of airway inflammation and for the pathogenesis of asthmatic diseases. Previous studies have revealed that NDGA exerts pleiotropic effects capable of influencing a wide variety of cellular processes, including TGF-β-induced signal transduction, leukocyte chemotaxis, myoblast cell differentiation, cancer cell proliferation, and viral proliferation in infected cells (Goetzl et al, 1980;Gnabre et al, 1995;Lee et al, 2003;West et al, 2004;Ito et al, 2005;Youngren et al, 2005;Arasaki et al, 2007). However, its anti-inflammatory effects in allergic inflammation have been investigated to a lesser degree.…”

“…To that end, we utilized Nordihydroguaiaretic acid (NDGA), LOXs inhibitor. The results of previous studies have shown that NDGA exerts pleiotropic effects capable of influencing a broad variety of cellular processes, including growth factor-and TNF-induced signal transduction, leukocyte chemotaxis, myoblast cell differentiation, cancer cell proliferation, and viral proliferation in infected cells (Goetzl et al, 1980;Gnabre et al, 1995;Lee et al, 2003;West et al, 2004;Ito et al, 2005;Youngren et al, 2005;Arasaki et al, 2007). It can also induce the expression of NOS, regulate calcium channel activity, and inhibit the growth of β-amyloid protofibrils (Ramasamy et al, 1999;Huang et al, 2004;Moss et al, 2004).…”

Nordihydroguaiaretic Acid Affects Multiple Dynein-Dynactin Functions in Interphase and Mitotic Cells

“…Nordihydroguaiaretic acid (NDGA) is a drug that affects a wide variety of cellular processes, including growth factorand tumor necrosis factor-induced signal transduction (Domin et al, 1994;Lee et al, 2003;West et al, 2004), leukocyte chemotaxis (Goetzl, 1980), myoblast cell differentiation (Ito et al, 2005), cancer cell proliferation (Avis et al, 1996;McDonald et al, 2001;Seufferlein et al, 2002;Youngren et al, 2005), and viral proliferation in infected cells (Gnabre et al, 1995). It can also induce nitric-oxide synthase expression (Ramasamy et al, 1999), regulate calcium channel activity (Korn and Horn, 1990;Huang et al, 2004), and inhibit growth of ␤-amyloid (1-40) protofibril (Moss et al, 2004).…”

The Neuroinflammation in the Physiopathology of Amyotrophic Lateral Sclerosis

“…mice on an NDGA-diet from presymptomatic stage to end-point have a 32% increase in median lifespan as well as a reduced motoneuron loss and astrocytosis [197].…”