Preclinical Studies Suggest Complex Nutraceutical Strategies May Have Potential for Preventing and Managing Sepsis

An analysis of signaling mechanisms triggered by toll receptor 4 (TLR4) in macrophages, as well as of pertinent cell-culture and rodent studies, suggests that various nutraceuticals may have clinical potential for preventing and treating Gram-negative sepsis. Endotoxin activation of TLR4 results in induction of nitric oxide synthase (iNOS); cyclooxygenase 2 (COX-2); tissue factor (TF); and a range of proinflammatory cytokines, such as tumor necrosis factor α (TNF-α), interleukin-1 β (IL-1β), and interleukin 6 (IL-6), that collaborate to generate the clinical picture of sepsis. Upstream activation of nicotinamide adenine dinucleotide phosphate (NADPH) oxidase contributes importantly to those effects by inducing superoxide production that promotes activation of p38 mitogen-activated protein (MAP) kinase and nuclear factor (NF) κΒ. Bilirubin generated intracellularly by activation of heme oxygenase 1 (HO-1) functions to provide feedback inhibition of NAPDH-oxidase complexes. Exogenous bilirubin, or its precursor, biliverdin, is protective in rodent models of sepsis. One nutraceutical, phycocyanobilin (PhyCB), is a biliverdin derivative that functions as a light-gathering chromophore in cyanobacteria such as spirulina and can be converted intracellularly to a compound structurally homologous to bilirubin that likewise inhibits NADPH-oxidase complexes. In rodent studies, administration of phycocyanin, to which PhyCB is covalently attached, has likewise been shown to be protective in rodent models of sepsis. Other nutraceuticals provide benefits in counteracting the effects of TLR4. Phase 2-inductive nutraceuticals, such as lipoic acid, have the potential to induce HO-1 activity in macrophages, promoting bilirubin production. They may also antagonize the upregulatory impact of reactive oxygen species (ROS) on macrophage signaling by boosting glutathione synthesis. Another nutraceutical, glycine, helps counter the TLR4-triggered calcium influx that occurs through voltage-sensitive calcium channels and contributes to NADPH-oxidase activation, and, via activation of Ca+2/calmodulin-dependent kinase 2, also promotes induction of proinflammatory cytokines and cyclo-oxygenase 2 (COX-2). Elevations of serum glycine that are achievable through supplementation can block that calcium influx by activating membrane chloride channels in macrophages, inducing membrane hyperpolarization. Use of high-dose folate, another nutraceutical, has been shown to antagonize activation of endotoxin-mediated macrophages in cell cultures and in rodents. That result likely reflects the versatile, radical-scavenging activity of reduced intracellular folates, which in particular scavenge radicals derived from peroxynitrite, a key mediator of tissue damage in sepsis. Activators of adenosine monophosphate (AMP)-activated kinase (AMPK), such as the drug metformin or the nutraceutical berberine, have been shown to antagonize TLR4-mediated activation of extracellular-signal-regulated kinase1/2 (ERK1/2), which contributes to the induction of TF and TNF-α. In rodent models of sepsis, lipoic acid, glycine, high-dose folate, metformin, berberine, and phycocyanin have all shown protective utility, yet none of those substances has been evaluated clinically in that regard. Because those agents are all well tolerated individually, complex nutraceuticals featuring several of those agents can be envisioned as possibly aiding prevention and control of sepsis. Clinical evaluation of such a strategy should be a high priority. That approach may also have the potential for aiding survival in Ebola infection, the lethality of which is mediated by mechanisms quite analogous to those involved in sepsis.