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6MEDICAL SCIENCES
NEUROPROTECTIVE THERAPY IN A COMPREHENSIVE TREATMENT OF MILD
CRANIOCEREBRAL INJURY
Zhukovskyi O.O.
Higher State Educational Establishment of Ukraine "Bukovinian State Medical University ", Chernivtsi
ABSTRACT
The efficacy of Trimetazidine administration in a comprehensive treatment of brain concussion has been studied. A normalization effect of the drug on hypoxia processes, condition of the pro- and antioxidant systems, neuron-specific enolase level has been determined. Keywords: brain concussion, Trimetazidine.
Introduction. Considering an important role of hypoxia, disorders of pro- and antioxidant balance, development of autoimmune reactions in pathogenesis of mild neurotrauma and brain concussion (BC) in particular, the necessity to control all these parameters is of no doubt, as well as administration of drugs possessing neuroprotective properties in a comprehensive treatment [1,7]. From this point of view the study of Trimetazidine ("Preductal") efficacy, a drug possessing pronounced anti-hypoxic and antioxidant properties, is rather topical and perspective [4].
Materials and methods. To solve the tasks 60 individuals were examined comprehensively. They were distributed into three groups:
1 group - practically healthy individuals (20 people);
2 group - BC patients receiving basic therapy (20 people);
3 group - BC patients receiving Trimetazidine in addition to the basic therapy (20 people).
The basic therapy included analgesics, diuretics, sedatives, vasoactive and nootropic agents. Trimeta-zidine was administered in a daily dose of 60 mg 3 times a day for the whole course of treatment (7-10 days). Biochemical examinations of plasma and eryth-rocytes of the patients and donors were made on the
first, fifth day after injury, and after completion of treatment. The levels of lactate, protein oxidative modification (POM), Malone aldehyde (MA), reduced glutathione [8], HS-groups [5], activity of ceruloplasmin [2] and catalase [3] were examined. The content of neuron-specific enolase (NSE) in the blood serum was determined by means of indirect immune-enzyme analysis. The data were processed statistically using Student criterion.
Results and discussion. On the first day after trauma all the patients with BC developed statistically reliable increase of lactate in the blood plasma which was indicative of activation of hypoxic processes in the nervous tissue. A gradual dynamic increase of lactate content was observed in patients with BC who received a comprehensive treatment. The situation was a little different in the third group of patients, who received Trimetazidine in addition to basic therapy. Lactic acid level in those patients did not increase, but it statistically reliably decreased. After initiated treatment in the patients from the third group the indices of lactate content were close to that of normal. On the basis of the data obtained a conclusion can be drawn that Trimeta-zidine inhibits accumulation of lactate and prevents the development of hypoxia in the cerebral tissue.
Table 1
Lactate content in the blood of patients with brain concussion
Index 1 control group (n=20) On admission 5 day After treatment
2 group (n=20) 3 group (n=20) 2 group (n=20) 3 group (n=20) 2 group (n=20) 3 group (n=20)
Lactate content, mmol/L 2,10+0,02 2,47+0,02 P1<0,01 2,48+0,02 P1<0,01 P2>0,05 2,72+0,03 P1<0,01 2,36+0,02 P1<0,01 P2<0,01 2,78+0,02 P1<0,01 2,18+0,01 P1>0,05 P2<0,01
Notes: pi - difference between patients with BC and control group; P2 - difference between both groups of patients
Hypoxia development results in different metabolic disorders including changes of pro- and antioxidant balance. Considering an important role of the processes of lipid and protein peroxide oxidation in the development of irreversible changes in case of neurological injuries, we have examined these indices, and the condition of the blood antioxidant system in patients with BC. Having analyzed the indices of lipid and protein peroxide oxidation at the first day after injury
statistically reliable increase of MA level, one of the final products of lipid peroxidation was found, as well as the degree of protein oxidative modification (POM) in comparison with the control indices (Table 2). Violent reaction of these processes after injury as naturally associated with the body protective reaction - increased activity of the antioxidant system. Thus, increased activity of catalase and ceruloplasmin, increased level of
reduced glutathione, as the main component of the pro- groups in comparison with the indices of the control tective glutathione system, and the content of HS- group were determined in all the victims.
Table 2
Indices of lipid and protein peroxide oxidation
and blood antioxidant system in
patients with brain concussion
Index 1control group (n=20) On admission 5 day After treatment
2 group (n=20) 3 group (n=20) 2 group (n=20) 3 group (n=20) 2 group (n=20) 3 group (n=20)
Ceruloplasmin conten, AE/g of protein 186,26+2,3 217,59+5,2 P1<0,01 218,40+4,4 P1<0,01 201,30+5,4 234,16+4,9 P2<0,01 189,24+4,8 240,2+4,8 P2<0,01
POM degree o.o.r./g of protein 6,63+0,23 7,94+0,23 P1<0,01 7,93+0,25 P1<0,01 8,93+0,34 7,06+0,19 P2<0,01 10,54+0,35 6,97+0,38 P2<0,01
Malone aldehyde content, mcmol/L 7,74+0,28 10,71+0,56 P1<0,01 10,68+0,69 P1<0,01 14,61+0,70 8,93+0,57 P2<0,01 15,77+0,68 7,39+0,53 P2<0,01
Reduced glutathione content, mcmol/ml 0,30+0,06 0,54+0,02 P1<0,01 0,53+0,03 P1<0,01 0,41+0,02 0,62+0,02 P2<0,01 0,32+0,01 0,64+0,02 P2<0,01
Content of HS- groups, mcmol/ml 1,58+0,03 1,77+0,02 P1<0,01 1,76+0,02 P1<0,01 1,62+0,03 1,84+0,03 P2<0,01 1,54+0,03 1,9+0,03 P2<0,01
Catalase activity, mcmol/min-ml 11,6+0,54 13,4+0,54 P1<0,05 13,3+0,49 P1<0,05 12,4+0,41 14,2+0,42 P2<0,01 11,1+0,38 15,1+0,30 P2<0,01
Notes: pi - difference between patients with BC and control group; P2 - difference between both groups of patients
Having analyzed the above mentioned indices in dynamic observation we have determined that intensity of the processes of lipid peroxidation and protein peroxide oxidation continued to increase in the blood of patients from the second group who received basic therapy. Thus, on the fifth day after injury the content of MA and POM degree increased in comparison with the similar indices at the first day. These processes occurred against the ground of reduced activity of antioxidant enzymes - catalase, ceruloplasmin, level of reduced glutathione and HS-groups. Further observation determined stable high content of pro-oxidants in the blood of patients with BC associated with a low level of antioxidant protection factors. Decreased activity of catalase, ceruloplasmin, reduced glutathione and sulfhydryl groups occurred at the expense of exhaustion of the antioxidant system. The situation with patients from the third group who received cytoprotective drug Trimetazidine in addition to a comprehensive therapy was different. Thus, on the fifth day after injury the intensity of the processes of lipid peroxidation and blood protein peroxide oxidation decreased in comparison with the indices of the first day. At the same time, a clear tendency to increasing the activity of antioxidant protection factors was found. After treatment the indices of the processes of lipid peroxidation and protein peroxide oxidation in the third group of patients were close to those of the first group. The level of activity of antioxidant enzymes, reduced glutathione and HS-groups after treatment remained high.
The presented results are indicative of the fact that administration of Trimetazidine in a comprehensive treatment of patients with BC indirectly decreases a negative effect of lipid and protein peroxide oxidation activation at the expense of stabilization of the content and activity of antioxidant protection factors.
The level of neurospecific proteins is an integral index of metabolic disorders intensity and destructive changes in the nervous tissue [6]. Concerning the aspect of modern views about the role of anti-cerebral antigens and NSE in particular in pathogenesis of traumatic disease of the brain, investigation of its content in the blood serum of patients with BC in dynamics is important of course. On the first day after injury mean indices of NSE content as a marker of neuron injury were not higher than those of normal in patients with BC (Table 3). Although on the fifth day after injury considerable changes were found to occur in NSE concentration. Thus, in 85% of patients from the second group statistically reliable increase of NSE content was found. And in spite of the initiated treatment the individuals of this group developed a noticeable tendency to reduction of NSE level in comparison with the data of the fifth day, although its content in the blood serum was higher than that of the normal one. The situation in the third group of patients who received Trimetazidine was different. In this group of patients NSE level in the blood serum did not practically differ from the initial one during the whole course of treatment.
Table 3
Neuron-specific enolase content in the blood serum of patients with brain concussion
Index 1 control group (n=20) On admission 5 day After treatment
2 group (n=20) 3 group (n=20) 2 group (n=20) 3 group (n=20) 2 group (n=20) 3 group (n=20)
NSE content mcg/L 8,44+0,45 8,52+0,61 pi>0,05 8,50+0,58 pi>0,05 P2>0,05 15,9+0,61 pi<0,01 8,85+0,73 P2<0,01 13,1+0,42 P1<0,01 8,67+0,53 P2<0,01
Notes: pi - difference between patients with BC and control group; P2 - difference between the indices of both groups of patients with BC
Therefore, administration of cytoprotective drug Trimetazidine in a comprehensive treatment of patients with BC prevents the development of destructive processes in the nervous tissue.
Conclusions.
1. Brain concussion results in the development of hypoxic disorders, changes of the pro- and antioxidant balance, and as a result, appearance of neuron injury marker in the peripheral blood.
2. Administration of Trimetazidine in a comprehensive treatment of patients with brain concussion evidenced a pronounced anti-hypoxic, antioxidant and neuroprotective effects of the drug.
Further studies are stipulated by the necessity to investigate the effect of neuroprotective drugs in case of craniocerebral injuries - perspective and pathogeni-cally substantiated direction in treatment.
References
1. Бульон В.В., Зарубина И.В., Коваленко А.Л., Алексеева Л.Е., Сапронов Н.С. Церебропро-тективный эффект цитофлавина при закрытой черепно-мозговой травме //Экспер. и клин. фармак. -2003. - Т.66, №6. - С.56-58.
2. Колб В.Г., Камышников В.С. Справочник по клинической химии. - Минск: Беларусь, 1982.290 с.
3. Королюк М.А., Иванова Л.И., Майорова И.Г. Метод определения активности каталазы //Лаб. дело. - 1998. - №1. - С. 16-19.
4. Ланкин В.З., Тихадзе А.К., Жарова Е.А., Беленков Ю.Н. Исследование антиоксидантных свойств цитопротекторного препарата триметази-дина //Кардиология. - 2001. - №3. - С. 21-28.
5. Мещишен 1.Ф., Григорьева Н.П. Метод шлькюного визначення HS-груп у кровi //Буковин-ський мед. вюник. - 2002. - Т.6, №2. - С. 190-192.
6. Мироненко Т.В., Панченко Е.Н. Применение продигиозана в комплексной терапии последствий лёгкой закрытой черепно-мозговой травмы //Шк. справа/Врач. дело. - 1999. - №5. - С.101-105.
7. Современные представления о патогенезе закрытой черепно-мозговой травмы / Под ред. Е.Г. Педаченко. - К.: ТОВ «Задруга», 1996. - 282 с.
8. Травина О.В. Руководство по биохимическим исследованиям. М.: Медгиз, 1955. -256 с.
