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Free serotonin in plasma  role in triggering myasthenic crisis

 

It has long been known that NA (noradrenaline) facilitates neuromuscular transmission and muscle contraction . The sudden (acute) clinical improvement registered in all our MG patients during neuropharmacological therapy should be attributed to the effect of NA released at spinal motoneuron levels. At this level, NA excites alpha-1 post-synaptic receptors which facilitate muscular activity. As is implied , the CNS controls posture and movements through the activation of spinal motoneurons which receive noradrenergic excitatory and serotonergic modulatory axons from medullary and pontine nuclei. Spinal motoneurons receive thousands of presynaptic excitatory (NA) and inhibitory (5HT) axons which distribute throughout their dendritic trees. Noradrenaline excites alpha-1 receptors whereas serotonin, acting at 5HT-1a receptors, modulates NA effects at the spinal motoneurons level. In addition, NA synchronizes the evoked quantal release at neuromuscular junctions . Noradrenergic axons innervating spinal motoneurons arise from the locus coeruleus (LC) also called A6-NA and A5-NA cell groups . Serotonergic axons innervating spinal motoneurons arise from the medullary raphe pallidus and raphe obscurus nuclei.

Alpha-2 antagonist drugs excite motoneurons by increasing the firing activity of NA neurons which release noradrenaline from axons innervating spinal motoneurons. Similar effects are displayed by buspirone. This drug at low doses (similar to those employed in anxiety patients) may exert a dual effect on spinal motoneurons: an excitatory effect by increasing the release of NA from noradrenergic axons, and an indirect polysynaptic effect secondary to the reduction of activity of the medullary raphe nuclei which possess 5HT-1a inhibitory autoreceptors. The short-lived effect of the alpha2antagonists-induced release of noradrenaline can be prolonged by the addition of an inhibitor of NA re-uptake at synaptic level (desipramine, nortryptiline, protryptiline, doxepin,. According to all the above, it becomes clear why neuropharmacological therapy addressed to enhancing central NA neural transmission triggers an acute and sudden improvement of muscular strength in MG patients. This phenomenon has been known since the 1980s decade to neurophysiologists familiar with the findings obtained in spinal cats. Adrafinil and modafinil (two alpha1 agonists) trigger acetylcholine release from motor nerves and facilitate neuromuscular transmission by a selective action at presynpatic alpha1 receptors located at that level .

The late and sustained improvement registered in our study would reflect the role played by the excitatory effect of noradrenergic innervation at lymphoid organs and the immunosuppressant effects displayed by plasma serotonin (f-5HT). 

It has been exhaustively demonstrated that the regions in which lymphocytes T cells reside, and through which they recirculate, receive direct sympathetic neural input. Therefore, the immune system can be considered “hard-wired” to the brain. Chemical sympathectomy of adult mice resulted in reduced antibody responses to T-dependent antigens.  These and other findings demonstrate that the noradrenergic innervation of bone marrow is functionally dynamic and is responsive to central activation. Furthermore, these results lend credence to the premise that neural mechanisms participate in regulating lymphopoietic cellular events.

 Finally, it has been known for several years that pharmacological enhancement of 5HT metabolism suppresses the immune response in vivo. This immunosuppression occurs peripherally, not centrally .

Free serotonin in plasma should also play some important role in triggering myasthenic crisis since we were able to accelerate the recovery of several MG patients affected by this severe complication by administering tianeptine to them. This finding is consistent with the bronchial constriction effect exerted by f-5HT in asthmatic patients who were also dramatically improved by this serotonin-enhancing uptaker drug.

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