By our mind, the most logic are concepts that connect the MS pathogenesis with the dialogue disturbance between the nervous and immune systems, particularly due to imbalance of neurotransmitters. We try here to point out some issues connected to this problem.
It is known by the moment that imbalance of neurotransmitters is an obligate condition in the MS patients as well as in people with other somatic and psychiatric disorders. For example, alterations in the serotonin content were described in details for MS patients both with relapsing-remitting, primary and secondary progressive forms15-18. Also, neurochemical disturbances were detected in patients with schizophrenia15, 19, cystic fibrosis20, pulmonary hipertension21, pancreatitis22, gallbladder muscle dysfunction23 and in many other cases. Moreover, some research groups showed evidently that reversibility of normal signalization within the CNS might result in normalization of functioning of various organs and systems15 and leading to improvement in people with neuroendocrine carcinoid syndrome24, bronchial asthma25, acute pancreatitis26 and during many other conditions.
Currently, neurological manifestations of MS are generally associated with the axon demyeliniation, which is considered also as an examination criterion27. However, clinical data suggest that a strong correlation between brain lesions and clinical presentation is absent. For example, as far back as last sixties researchers showed that the vision recovery after the optic neuritis episode cannot be explained by remyelination28. Moreover, it is known that sometimes people with intensive demyeliniation events may have no neurological deficit29. Also, brain lesions and spinal cord lesions may be observed accidentally in people long before development of the first clinical signs of MS30-33. The accumulated data suggest that the MS challenges cannot be considered as the direct manifestation of demyeliniation and that other possible factors, particularly imbalance of neurotransmitters, should be taken into account.
Over thirty years ago, the level of 5-hydroxyindoleacetic acid (5-HIAA) was shown to be decreased in the cerebral spinal fluid of patients with MS16, 17. Additionally, the level of the above-mentioned metabolite of serotonin was more decreased in the most severely disabled MS patients18. So, the presented data confirm a correlation between the level of cerebral serotonin and the disease course.
Since the beginning of sixties of the last century, intensive investigations of neurotransmitters and their metabolites are carried out in the Institute of Experimental Medicine (Caracas, Venezuela). Over 30000 healthy and diseased individuals were analyzed and some general conclusions were made. In particular, the investigators showed that patients with Th-1 immune profile (increased cellular immunity) display neurochemical features similar to those observed in major depression15. Namely, in patients with MS, Grave's ophthalmopathy, Crohn's disease, rheumatic arthritis, psoriasis and many others, a similar neurochemical disturbances are observed: increased norepinephrine to epinephrine ratio plus decreased level of tryptophan in the blood plasma. Alternatively, in Th-2 diseases (increased humoral immunity) - myasthenia, thrombocytopenic purpura, hemolytic anemia and others - the opposite neurochemical defects are detected (profile of maladaptation to stress)15. Numerous works by these authors have demonstrated that redressement of the observed neurotransmitter imbalance may result in improvement of patients. Moreover, one therapeutical scheme may work efficiently in patients with different disorders but incoming into one group (Th-1 or Th-2 diseases)15, 34-36.
It should be noted here that many studies have confirmed an entwinement between activity of immune and nervous systems37-38. Immunological changes observed in the MS patients are similar to those detected in the major depressed patients39. It is also known that depletion of the serotonin neurotransmission may be mediated by activation of indoleamine-2,3-dioxygenase (IDO) by inflammatory cytokines39. Some reseachers showed that the tryptophan derivates (3-hydroxy-kynurenine (3OH-KYN) and quinolinic acid (QUIN) arisen in the kynurenine cycle have neurotoxic effect40-41. Increased level of the above-mentioned metabolites is detected in neurodegenerative diseases and major depression40, 42. In turn, 3OH-KYN is able to induce the reactive oxygen species formation whose cytopathogenic effect is well documented43. Thus, the accumulated scientific data suggest neurochemical disturbances are obligate in any neurological disease and, as some investigators stated15, psychosomatic disorder. Therefore, prescription of some appropriate neurotrophic drugs able to restore neurotransmitter balance may be useful in many autoimmune diseases including MS.
In 1987, the selective serotonin reuptake inhibitors (SSRI) were introduced into clinical practice. Initially, this type of antidepressants was used entirely in psychiatric practice. However, during the last decade, some immunological activities of these drugs were described. At present, it is know that SSRI can cause significant decrease in synthesis of inflammatory cytokines and increase in the production of anti-inflammatory ones48-51 as well as mediate reduction of the interferon- to interleukin 10 (INF- /IL-10) ratio whose importance for T-cell activation was shown previously52.
The presence of the increased levels of inflammatory cytokines in the MS patients was confirmed by many studies53-55. Therefore, we consider that application of SSRI and other serotonin promoting substances with the immune downregulation properties should be studied. Moreover, there were some positive results: administration of L-tryptophan to the MS patients resulted in improvement of autonomic, motor and sensory functions56. Expediency of the SSRI administration in the MS patients is under discussion now57. This type of antidepressant was shown to cause anti-inflammatory and anti-asthenia effects58-59 as well as have analgesic action60-61 that is very important for the MS sufferers.
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