Cholinergic Agonists Improve Survival in Experimental Sepsis: Link to Arthritis

The Durk Pearson & Sandy Shaw®
Life Extension NewsTM
Volume 8 No. 3 • July 2005


Cholinergic Agonists Improve Survival in Experimental Sepsis: Link to Arthritis

We have written previously on protective strategies against out-of-control bacterial infections (sepsis), an increasing risk due to antibiotic-resistant bacteria. We have also written about the cholinergic vagus-nerve anti-inflammatory pathway. Here, a recent study1,2 reports that cholinergic agonists protected mice against sepsis induced by lipopolysaccharide and by cecal (part of the large intestine) ligation and puncture.

The authors of the study note that they recently identified high-mobility-group box 1 (HMGB1) protein as a late mediator of lethal systemic inflammation in sepsis. In another paper,3 the researchers identify HMGB1 as a “mediator of interest” in human and experimental arthritis; they note that HMGB1 can be either actively secreted by macrophages or passively released by necrotic cells of all kinds and that macrophages and unprogrammed cell death caused by ischemia or activated complement are prominent features of the persistent synovial inflammation of chronic arthritis. The authors3 also note that elevated levels of HMGB1 are present in synovial fluid samples from rheumatoid arthritis patients. Inhibition of HMGB1 (with either neutralizing antibodies or the antagonistic A box domain of HMGB1) was reported to ameliorate collagen-induced arthritis in both mice and rats and to inhibit local overexpression of the inflammatory cytokine IL-1beta in the joints.

The researchers3 note that serum HMGB1 levels are below 5 ng/mL in the serum of healthy animals and normal humans, but that much higher circulating levels (up to 150 ng/mL) were observed in human patients with severe sepsis, with the highest levels in those who died.

The researchers of paper 1 report that they discovered that acetylcholine release through the vagus nerve can modulate circulating tumor necrosis factor-alpha (TNF-alpha) levels induced by endotoxin. In this paper, they find that acetylcholine suppresses HMGB1 release from macrophages through a nicotinic cholinergic receptor. Nicotinic cholinergic receptors are stimulated by acetylcholine (which also stimulates muscarinic cholinergic receptors); selective nicotinic cholinergic receptor stimulators include nicotine, but unfortunately, for many reasons nicotine is not recommended. However, nicotine was used to treat the experimental mice in this study. Their results indicated that nicotine could rescue animals from established severe sepsis.

Our choline supplement includes choline and vitamin B5, as well as other nutrients. Vitamin B5 is required to convert choline to acetylcholine. We take it daily for its cognition-enhancing effects, but would take more if we became infected with an antibiotic-resistant strain of bacteria. It may also help with arthritis, though it is hard to separate the effects from everything else we take.

References

  1. Wang et al. Cholinergic agonists inhibit HMGB1 release and improve survival in experimental sepsis. Nature Med 10(11):1216-21 (2004).
  2. Matrthay and Ware. Can nicotine treat sepsis? Nature Med 10(11):1161-2 (2004).
  3. Andersson and Erlandsson-Harris. HMGB1 is a potent trigger of arthritis. J Int Med 255:344-50 (2004).

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