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Dynamic Duo

Adapt or perish is a basic biological truth.  When given enough time to change, the possibilities are endless—a common molecule can gain prominence in almost every aspect of every being.  Given a couple of billion years, that is what serotonin did.

Serotonin is a biogenic amine that regulates cellular activity, an important modulator of long-lasting changes in the functional state of cells.  Over the eons, serotonin’s role morphed from an intracellular messenger to intercellular signaling, giving it the status of a hormone.  Hundreds more millennia saw serotonin become an important neurotransmitter in vertebrates while preserving its old evolutionary functions.  Did we mention that in protozoa models serotonin decreases cellular activity and just one exposure can last up to 30 generations?

Known as a brain chemical, an astounding 90% of serotonin is actually produced in the gut enterochromaffin cells.  Serotonin works it’s magic by an active process that employs SERT, the serotonin transporter protein.  Chemicals that are serotonin agonists will lengthen serotonin’s actions on a cell and can prevent recycling of the molecule by blocking SERT.

Serotonin is intricately involved in innate immune systems, turning cell activities on and off via different biochemical (effector) pathways.  The power afforded by this molecule is such that a very small amount can set many paths in motion at the same time cascading the overall effect.  Superpotent.

Our investigations tie soluble IL6, a proinflammatory cytokine, to clinical signs of EPM.  Serotonin and IL6 are inversely related: increase the serotonin and IL6 levels will drop.  The cytokine IL6 is very short lived in the serum and it binds cell bound receptors (cognate), making it unprofitable as a measure of disease.  The initial effect of IL6 (stimulated by infections) includes production of C-reactive protein (CRP) by the liver.  An active enzyme, CRP splits IL6 and its receptor from the peripheral cells allowing the now soluble pair to migrate across the blood brain barrier and set up inflammation that results in clinical signs of EPM.  CRP is profitable as a measure of active infection.  CRP indicates an active infectious process. Another important EPM cytokine is TNF-alpha.

Tumor Necrosis Factor alpha-mediated inflammatory pathways have been strongly implicated in a number of diseases, including myesthenia gravis, neurodegenerative disease and malaria.  Human researchers found that activation of serotonin receptors by serotonin receptor agonists are extremely potent therapeutic agents for TNF-alpha-mediated disease.  They found targeting these receptors was 300 times more effective than current anti-inflammatory agents.  Superpotent.

The superpotentiality of these therapies may lie in the concept of functional selectivity.  Different drugs can act at the same receptor and have the ability to differentially activate individual effector pathways.  Sometimes the ability to activate or deactivate a pathway is simply to change the shape of the receptor.

Levamisole is an indirect serotonin agonist.  Increasing serotonin profoundly impacts animals.  Our research also investigates the action of serotonin on the protozoan parasite, S. neurona.  Levamisole is cholinergic, meaning it acts on a receptor to deferentially activate additional effector pathways, giving levamisole the ability to differentially activate multiple effector pathways in the parasite and the host.

 

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