Biomedical Fast Takes


Can Galantamine Treat Sepsis?

The nervous system, through the vagus nerve* and its neurotransmitter acetylcholine, has been shown to down-regulate systemic inflammation in vivo. Recently, it has been deduced that there is a role for brain cholinergic mechanisms to activate this cholinergic anti-inflammatory pathway. Galantamine is a natural cholinesterase inhibitor and one of several centrally acting cholinergics widely in use. In a new rat study designed to evaluate the effect of galantamine on circulating tumor necrosis factor alpha (TNF-α)—a cytokine that promotes inflammation and is implicated in cancer—peritonitis was induced in order to investigate the role of the vagus nerve in the action of galantamine.1


* The vagus is one of the cranial nerves that runs from the medulla of the brain down to the neck, chest, and abdomen, where it contributes to the nerve connections of the viscera, the internal organs. Besides its output to the various organs in the body, the vagus nerve conveys sensory information about the state of the body’s organs to the central nervous system.

† Peritonitis is an inflammation of the peritoneum, the membrane that lines part of the abdominal cavity and viscera.


Rat models of induced peritonitis and vagotomy—the severing of part of the vagus nerve—were employed in two experiments. In the first, the rats were randomly divided into a control group, a peritonitis group, and a peritonitis group treated with three dosages of galantamine. In the second, the rats were randomly divided into five groups: 1) sham-operated,** 2) sham-operated plus peritonitis, 3) sham-operated plus peritonitis treated with galantamine, 4) vagotomy plus peritonitis, and 5) vagotomy plus peritonitis treated with galantamine. The levels of TNF-α were determined in every group. When the results came in, galantamine was shown to have an inhibitory effect on TNF-α release in rats with induced peritonitis, and the vagus nerve played a role in the process by which galantamine operated.


** Also known as placebo surgery, sham surgery is a faked operation that omits the step thought to be therapeutically necessary.


Sepsis is the most common complication of trauma, shock, burns, infection, and major surgery. When severe, sepsis can transform into septic shock and multiple organ dysfunction syndrome. In fact, sepsis has become one of the most important causes of death in critically ill patients. It remains a challenge problem in critical care. Also, it has been established that the nervous system, through the vagus nerve, can down-regulate systemic inflammation, and this effect is mediated by an interaction of the principle vagus nerve neurotransmitter acetylcholine, along with the alpha 7 nicotinic acetylcholine receptor located on macrophages, and other cytokine expressing cells.

Understanding the “cholinergic anti-inflammatory pathway” mechanism has led researchers to a new idea for sepsis treatment. This entails a role for brain cholinergic mechanisms in activating the cholinergic anti-inflammatory pathway. Stimulating the central cholinergic system can increase the activities of the vagus nerve and inhibit systemic inflammation. This shows something new: it is possible to activate the cholinergic anti-inflammatory pathway through the use of agents that increase the activities of the central cholinergic system.

According to the researchers, their study shows that galantamine possesses the ability to regulate inflammatory response, a new use for the acetylcholinesterase inhibitor and one that may prove effective in the treatment of inflammatory disease, including sepsis.

Of the three doses used in the study, the 3 mg/kg dosage of galantamine had the most significant inhibition on TNF-α. Such a dose is similar to the dose of galantamine use for inhibiting central cholinesterase.

References

  1. Liu ZH, Ma YF, Wu JS, Gan JX, Xu SW, Jiang GY. Effect of cholinesterase inhibitor galanthamine on circulating tumor necrosis factor alpha in rats with lipopolysaccharide-induced peritonitis. Chin Med J (Engl). 2010 Jul;123(13):1727-30.

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