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Section 7. Medical science
References:
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Sokolova Mariia Georgievna, candidate of Medical Sciences, North-West State Medical University named after 1.1. Mechnikov, Russia, Saint-Petersburg E-mail: [email protected]
High level of neurotrophins in blood of patients with spinal muscular atrophy of the 2 type as a result of compensatory-adaptive process
Abstract: Adaptation is a broad biological concept, including all forms of regulation of the body functions under normal and pathological conditions. A study of neurotrophic regulation in patients with spinal muscular atrophy of the 2 type with identification of neurotrophins (BDNF and NGF) in blood was carried out. High concentration of neurotrophins in serum may be related to the activity of compensatory and adaptive processes aimed at partial recovery of lost motor function in patients with the SMA of the 2 type. The obtained data shall be taken into account when treating patients with the SMA of the 2 type.
Keywords: spinal muscle atrophy of type 2 (SMA), compensatory and adaptive mechanisms, blood serum, neurotrophins, BDNF, NGF, immunoenzyme method.
Compensatory and adaptive mechanisms are triggered both under physiological and pathological conditions. Any form of life envisages adaptive reactions aimed at its survival, preservation of its condition or properties when exposed to environmental factors or shifts within the system itself [1, 173]. Compensation is one of the most important forms of adaptation, which develops under pathological conditions, so it is distinctive, as a specific human has a specific disease. Thus, compensation is a set of body reactions, occurring during injuries or diseases and aiming to restore disturbed functions. Human has individual reactions, but at the same time, as a representative of biologic species, he is also given some species-specific adaptive reactions. Both reactions are difficult to separate, that is why they are normally referred to in clinics as compensatory and adaptive processes. The biological matter of compensatory reactions is to restore disturbed functions of organs and systems, and the degree of their recovery is the main criterion for the adequacy of these reactions. The physiological goal of the neurotrophic regulation is maintenance ofviable populations of neurons to perform a genetically-programmed function. The study of neurotrophic regulation in
patients with neurodegenerative diseases may open up new therapeutic directions for the doctors.
The objective of the study: to evaluate the activity of compensatory and adaptive processes in patients with spinal muscular atrophy of the 2 type, exploring the neurotrophic regulation by determining neurotrophins (BDNF, NGF) in blood.
Materials and methods. Clinical-neurologic and neu-rophysiological examination of 10 patients with 2 type SMA was carried out. Level Beta-NGF and BDNF in 10 patients (SMA 2 type) was determined in serum using Beta-NGF ELISA Kit and BDNF ELISA Kit (RayBiotech, Inc). The studies were carried out according to standard protocol. The work was based on the following methods of statistical analysis: determination of numerical characteristics of variables; estimation of conformity of empirical law of distribution of quantitative variables to theoretical law of Gaussian distribution according to Shapiro-Wilk test; an estimation of influence of qualitative factor on a dispersion of quantity indicator using ANOVA dispersion method, an estimation of a force and direction of linear relationship between the quantity indicators
High level of neurotrophins in blood of patients with spinal muscular atrophy of the 2 type as a result.
using parametrical Pearson correlation coefficient, nonlinear relationship — using Spearman's correlation coefficient. Description of quantitative signs was carried out using arithmetic mean value and standard deviation. Zero statistical hypothesis was rejected at significance value p <0,05. The statistical analysis was carried out using STATISTICA 8.0 package (StatSoft®, Inc., USA).
Results and discussions: Spinal muscular atrophy is autosomal recessive disorder, characterized by progressive degeneration of alfa-motor neurons of spinal cord. With an incidence of 1 in 6000-10 OOO live births and a carrier frequency of 1 in 40-50. The disease manifests itself as a weakness of proximal muscles, pareses, respiratory insufficiency and early mortality [2, 358]. 10 patients with 2 type spinal muscular atrophy were examined, among them: 4 girls and 6 boys at the age from 8 up to 12 years old. All patients with 2 type SMA have been under medical observation for 3 years, during this period of time the disease was progressing. Motor defect was manifested since birth. Genetic defect was identified at the long arm of 5th chromosome (within the interval between D5S629 and D5S557). Clinical-neurologic picture includes flaccid pareses of hands and feet with prevalence of the process in the proximal parts, active movements were only in distal parts of the hands, neck muscles, mimic and respiratory muscles. There were generalized fibrillations and fasciculations of the muscles, intense diffuse hypomyotonia. 85% of children had intense atrophies of intercostal muscles with respiratory insufficiency and minor bulbar disorders. Changes of osteoarticular system were manifested as intense contractures of large joints of extremities and kyphoscoliosis. Functions of pelvic bodies were normal. There were no sensitivity and cognitive disorders.
Results of enzyme immunoassay testify that blood serum concentration of NGF (3899±1058 pg/ml) in patients with 2 type SMA is significantly (p<0,001) higher, than in control group (782±582 pg/ml). Estimated values of NGF blood serum concentration in control group are within the range from 110 pg/ml to 2237 pg/ml. Whereas in 2 type SMA patients- within the range from 1387 pg/ml to 5411 pg/ml. BDNF (36653±3606 pg/ml) concentration in blood serum of patients with 2 type SMA is significantly (p<0,05) higher, than in control group (27313±7260 pg/ml). Analysis of the parameter dispersion has shown, that BDNF blood serum concentration in the control group is within the range from 16040 pg/ml to 41960 pg/ml, in patients with 2 type SMA — from 22523 pg/ml to 63700 pg/ml. The research performed by us has shown that children patients with 2 type SMA have elevated level of neurotrophins: BDNF and NGF.
The study carried out by us showed that patients with SMA of the 2 type had an increased level of neurotrophins in contrast to other neurodegenerative diseases of the CNS, which are followed by a shortage of neurotrophic support [5, 231-243; 11, 27-29]. Neurotrophins are synthesized by neu-
rons, glial cells and target cells, interact with tyrosine kinase receptors (Trk-A, Trk-B, Trk-C) on the surface of neurons [8, 677-736]. This triggers the activation of protein kinases cascade known as mitogenactivatedproteinkinas — MAP kinase pathway, further phosphorylated MAP kinase). MAP kinase passes through a nuclear membrane and phosphorylates various gene transcription factors within a nucleus [7, 145-156]. Resulting changes in gene transcription initiate the processes of proliferation, differentiation and maintenance of neuronal survival [6, 1134-1148]. High concentration of NGF may be associated with age of the patients, because regardless of pathology a child's body is growing. The processes of growth and differentiation of neural tissue, synaptogenesis are intensive in children [4, 117-123]. The activity of these processes depends on the concentration of growth peptides. But hyperexpression of neurotrophins can not be explained simply by ontogenesis peculiarity, as a control group was represented by children of this age. Perhaps the increased synthesis of neurotrophins (BDNF, NGF) is due to development of compensatory and adaptive processes aimed at strengthening of the reparative function of the nervous tissue.
Progressive loss of motor neurons in the SMA of the 2 type leads to increased neurotrophic regulation, but part of the neurons population has already died and is not capable to interact with growth factors. These phenomena can hypo-thetically explain the elevated level of neurotrophins (BDNF, NGF) in the SMA of the 2 type. However, a very high concentration of neurotrophins according to our research does not lead to restoration or partial compensation for lost motor function in patients with SMA of the 2 type [3, 45-52]. In the experiment on organotypic tissue culture, we have demonstrated that the serum of the patients with SMA of the 2 type inhibits outgrowth of sensory ganglia neurites [10, 112-117]. We found a strong correlation between the fact of neurite growth inhibition of sensory ganglia neurons and concentration of neurotrophins in serum of the patients with SMA of the 2 type [9, 148-150]. Thus it has been shown that the process of sprouting in patients with SMA of the 2 type is not triggered due to very high concentration of neurotrophins that promotes further progression of the disease.
Conclusion. Patients with SMA of the 2 type have increased concentration of neurotrophins (BDNF, NGF) in blood. Most probably hyperexpression of neurotrophins (BDNF, NGf) in patients with SMA of the 2 type is caused as a result of the activity of compensatory and adaptive mechanisms aimed at strengthening of neurotrophic regulation for a partial compensation for lost motor function. These data shall be taken into account when treating patients with SMA of the 2 type. Neuroimmunology success opens new perspectives for clinicians in study of neurotrophic regulation of the nervous system, which in future may come into daily practice and will be used for diagnostics and creation of individual treatment programs for the patients with neurodegenerative diseases.
