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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 evolved from an intracellular messenger to an intercellular signaler, giving it the status of a hormone.  Hundreds more millennia passed as serotonin become an important neurotransmitter in vertebrates, while preserving its old evolutionary functions.

Increasing serotonin profoundly impacts animals. Did we mention that in protozoa models serotonin decreases cellular activity and just one exposure can last up to thirty 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. These effects can last a long time.

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.  Super-potent.

Our investigations tie soluble IL6, a proinflammatory cytokine, to clinical signs of inflammation in horses.  Serotonin and IL6 are inversely related: increase the serotonin and the IL6 levels will drop, they are a dynamic duo.  The cytokine IL6 is very short lived in the serum and it binds cell bound receptors (cell bound receptors are called cognate receptors) making IL6 unprofitable as a measure of disease.  However, the initial effect of IL6 (stimulated by infections) includes production of C-reactive protein (CRP) by the liver.

As an active enzyme, CRP splits IL6 and its receptor from peripheral cells allowing the now soluble pair to migrate across the blood brain barrier and set up inflammation.  The result is clinical signs that look like "EPM".  CRP is profitable as a measure of active infections and inflammation.  An elevated serum CRP concentration indicates an active infectious process from parasites, virus, or bacteria, C-reactive protein can't distinguish the etiology of the stimulus. Another important cytokine is TNF-alpha.

Tumor Necrosis Factors (alpha-mediated inflammatory pathways) have been strongly implicated in myesthenia gravis, neurodegenerative diseases 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.  Super-potent.

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, receptors can change their shape on one end in response to molecules that bind them on the other end. Sometimes it is the concentration of the drug that impacts a pathway. Drugs can be metabolized or, in some forms, quickly degraded. An active molecule can have the desired effect, a metabolized drug can produce multiple molecules with different actions and degradation can yield products that increase, decrease, or not effect inflammatory pathways.

Levamisole is an ionophore, a thymopoietin mimic, a cholinergic agent, and an indirect serotonin agonist.  It is a known inhibitor of nuclear pathways that express cytokine cell receptors. Our research investigates the action of molecules on protozoan parasites and their hosts, where they diferentially activate  multiple effector pathways.

 

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