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Nazarova Janna, scientific applicant Tashkent Postgraduate Medical Institute E-mail: nilu74@list.ru
BIOLOGICAL MARKERS IN THE DIAGNOSIS OF CEREBRAL ISCHEMIA
Abstract: In recent years, a new line of scientific inquiry-proteomics, which is defined as the study of the "pro-teome", is all the proteins synthesized in a single cell or in an organism as a whole.
Definition of a set of biomarkers of acute and chronic brain ischemia can personalize organizational approaches when planning volume medical and diagnostic care for patients.
Thus, a simple and rapid analysis of blood biomarkers can reveal acute cerebral ischemia, cerebral ischemia differentiate from "mimic" a stroke or predict the short-term risk of recurrent TIA or stroke.
Keywords: Biomarkers, ischemia, stroke, diagnosis.
Relevance. Development of new methods for early diagnosis and prevention of cerebrovascular diseases, which are a major cause of morbidity, disability and mortality of adult population has a greater medical and social importance. Thus, the mortality from cerebrovascular diseases in developed countries is 11-12% of total mortality, taking place after 3 deaths from heart disease and tumors. In Russian mortality from stroke per 1000 population of 1.0-1.41 [2; 6].
Percentage of initial manifestations of cerebrovascular insufficiency and chronic cerebral circulatory disorders in the structure of cerebrovascular diseases according outpatient service is respectively 52% and 17%. This situation raises a number of topical issues in diagnosing the problem early an-gioneurology doinsultnyh forms of vascular pathology of the brain, including the laboratory in which the preventive and therapeutic measures can be most effective [7; 10].
In the past decade has been notable success in discovering and understanding the mechanisms of cerebral ischemia: there were also actively developed new aspects angioneurol-ogy - theory heterogeneity of ischemic stroke, risk factors and antirisk, hemodynamic cerebral reserve, ischemic penumbra [penumbra], the concept of the therapeutic window. The most promising areas of research are the primary prevention of ischemic brain damage, and determination of risk factors antiriska, identification of initial manifestations of the disease, the study subtle biochemical processes occurring in ischemic brain tissue [7; 9].
In recent years, a new line of scientific inquiry - pro-teomics, which is defined as the study of the "proteome", i.e. all the proteins synthesized in a single cell or in an organism as a whole [12].
Proteomics has an impressive arsenal of methodic, which will ensure progress proteomic studies of the human body conditions in combination with the detailed analysis of the metabolic processes that enhance the quality potential of the modern clinical laboratory biochemistry.
Definition of a set ofbiomarkers of acute and chronic brain ischemia can personalize organizational approaches when planning volume medical and diagnostic care for patients.
Inclusion in clinical studies of markers of cerebrovascular diseases accelerate the search for new therapeutic strategies and facilitates an objective assessment of the results of ongoing clinical trials [9; 10].
The most promising for routine use in a stroke unit recognized endothelial hemostatic, inflammatory serum biomark-ers and protein molecules are formed due to deterioration of brain neurons and glia [1; 12].
During the last decade it was proposed several biomark-ers for the prediction and diagnosis of brain damage. Of great interest to S100B in serum as a biomarker for neurological and neuro-cognitive outcome measure heart surgery was caused by reports that the S100 B was correlated with brain damage after a stroke, traumatic brain injury and cardiac arrest [3]. S100B is a calcium-regulatory protein found primarily in glial cells and Schwann cells.
Another potential biomarker for cerebrovascular effects resulting from cardiac surgery is C-reactive protein (CRP), acute-phase agent and the indicator of the underlying general inflammation. CRP is a novel plasma marker for atherothrom-botic disease, and an indicator of cardiovascular disease.
Recently it has been proposed N-methyl-D-aspartate (NMDA) -retseptornye proteins and antibody as biomarkers of neurotoxicity underlying cerebral ischemia and stroke [4; 11].
By limiting the blood flow to any portion of the brain tissue survival depends on a set of principal factors: the presence of collateral circulation, duration of ischemia, and reduction in size and flow velocity. These factors in turn determine the exact anatomical location and size of the damage and, consequently, the parameters of clinical deficits [12].
There is a hierarchy of CNS cells, which exhibit selective susceptibility to ischemia. Neurons are the most vulnerable
BIOLOGICAL MARKERS IN THE DIAGNOSIS OF CEREBRAL ISCHEMIA
brain cells, although glial cells (oligodendrocytes and astrocytes) and are very reactive to the damaging effects. Activation of glial cells, usually accompanies the pathogenesis of cerebral ischemia. Of considerable importance is great individual variability of the sensitivity of neuronal populations in different regions of the CNS, which depends on the characteristics of regional cerebral blood flow, cerebral metabolic needs of the cells and their neurochemical specialization [1].
Currently it found that by limiting blood flow to the brain tissue run a complex cascade of biochemical, genetic, immu-nological processes, which lead to damage and, ultimately, to the death of nerve cells. In the modern theory of the "excito-toxicity" a special role in launching the mechanisms of cell damage during ischemia give excitatory neurotransmitters -glutamate in the first place. Its excessive release and neuronal accumulation causes edema and cell death. It is shown that apoksiya increases glutamate release and its accumulation in increased amounts in the cerebrospinal fluid during ischemia [8; 9]. Glutamate removal from the synaptic cleft or blockade of glutamate receptors prevents neuronal damage [1].
In brain ischemia involves glutamate powerful emission in the extracellular space leading to hyperactivity of the pre- and postsynaptic glutamate receptors. Massive entrance of Ca2 + into nerve cells gives intracellular levels of second messenger, triggers a cascade of reactions that terminate rapid or delayed cell death by necrosis or apoptosis mechanism [2; 6].
According to modern views glutamate it is regarded as a mediator, provides multiple neuron response to a variety of physiological and biochemical stimuli. The variability based on stimuli of the same order of reaction is different neuron specificity glutamate receptors. It should speak of a whole system of glutamate receptors, their isotopes which as the main reaction mediate synapse membrane depolarization, i.e. formation of action potential (inotropic receptors, iGluR) or regulation of the magnitude and potential duration (mGluR). For glutamate receptors characteristic multidimensional interaction, and functionally coupled with other neurotransmitter systems of the brain.
Glutamate receptors are divided into two main groups: ionotropic and metabotropic. Neuroreceptors are divided into ionotropic NMDA (80% of the number of excitatory synapses), AMPA, kainite and L-AP4. Currently we identified three classes of NMDA-receptors. Origin (NR-1), appear to be represented by a single gene, and the other (NR-2A-NR2D and NR3A) - multiple genes encoding the synthesis of proteins, consisting of approximately 900 and 1450 amino acids. NMDA-receptor complex can be modified during ischemia. The result is disturbance of ion permeability and / or selectivity. Immediate consequences of these processes are to increase cell membrane permeability to sodium ions and its swelling.
However, the most damaging factor is considered to further increase the concentration of Ca2 [11].
It is well known that receptors (NMDA) are the major excitatory neuroreceptor that regulate neuronal electrical signals. Substantial progress in the understanding of mechanisms of stroke was made on the basis of the effects on NMDA-receptor regulation of cerebral vessels. NMDA-receptors are localized at the surface epithelium of microvessels which form the blood-brain barrier and to control the function of the mi-crovasculature. NR2 peptide fragments are rapidly cleaved by the NMDA receptor-activated serine proteases thrombin due to a cerebral ischemic event. After leaving the bloodstream through the blood-brain barrier is disturbed within a few minutes after the start, NR2 peptides remain detectable in the blood for at least three days after being [4; 8].
The researchers hypothesized that the NMDA receptors by different processes neurotoxicity reflect the early stages of a stroke, expression of NMDA receptors increases during ischemia and hemorrhage decreases as [4]. When ischemia excessive amounts of glutamate leads to disruption of the functioning of NMDA receptors, and their subsequent destruction, and to peptide fragments initiation of apoptosis. Impaired BBB misses destructive molecules from the brain into the bloodstream, causing the activation of the immune system that produces autoantibodies to their own brain antigens. When cerebral hemorrhage neurotoxicity caused by glutamate leads to necrosis of the nervous tissue and reduce NMDA receptor expression, so the formation of autoantibodies suppressed. This phenomenon may be useful for the development of rapid haemo-test.
All these successive processes lead to the destruction of the membrane of nerve cells. It has been found that damage to glutamatergic neurons in ischemia leads to accumulation NR2 [11]. NR2 biomarker level in this case can serve as a criterion for ischemia of brain tissue. According Dambinovoy et al, diagnostic value NR2-antitel in ischemic stroke with a volume of 5-70 cm ischemia approaching 95.9%, and with transient ischemic attacks - 98% to [4]. Studies have shown that elevated levels of NR2 peptide [> 1.0 ng/mL] were related to the immediate risk of acute stroke, whereas levels below 1.0 ng/ml characterize non-ischemic events [e.g., healthy controls and stroke mimics]. This constant evidence of neurotoxicity underlying cerebral ischemia.
Thus, a simple and rapid analysis of blood biomarkers can reveal acute cerebral ischemia, cerebral ischemia differentiate from "mimic" a stroke or predict the short-term risk of recurrent TIA or stroke. For patients with a syndrome similar to a stroke, the use of biomarkers in conjunction with clinical evaluation and brain imaging may provide greater diagnostic sensitivity and specificity.
It is also important to determine specific biomarkers in This can help the doctor to identify patients who are at high
the blood of patients in the early stages of cerebral circulation. risk of stroke in the short term.
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