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TADALAFIL AS AN AGENT OF PHARMACOLOGICAL PRECONDITIONING IN ISCHEMIC - REPERFUSION BRAIN INJURY

Introduction: Ischemic stroke or cerebral infarction is the main pathology among severe forms of vascular lesions of the brain. One of the more effective non-medicamental methods of treatment is pharmacological preconditioning. Pharmacological neuroprotection is one of the treatment areas to reduce the damage in ischemic stroke and other modifications of brain ischemia. Therefore, the development and introduction of new pharmacological agents that can reduce the degree of ischemic-reperfusion injury of the brain, remains one of the major challenges of modern medicine. The most promising to explore, from our point of view, is a PDE-5 inhibitor.

Goal: Improving the efficiency of pharmacological cerebroprotective with pharmacological preconditioning of the PDE-5 inhibitor (tadalafil) in comparison with recombinant erythropoietin («Epocrin») and a neuroprotectant "Gliatilin".

Materials and methods: In the pilot study used an integrated approach to the study of neuroprotective effects of pharmacological preconditioning in animals with ischemia-reperfusion brain damage in four-vascular total ischemia of the brain. In the complex of methods included evaluation of neurological deficit, behavioral status, level of markers of brain damage S100b and NSE, morphometry. To compare the efficacy of tadalafil (1 mg/kg) in the experiment used recombinant erythropoietin «Epocrin» (50 IU/kg) and the neuroprotectant "Gliatilin" (85.7 mg/kg).

Results and discussion: Prophylactic intraperitoneal administration of PDE-5 inhibitor, tadalafil (1 mg/kg) exerted cerebroprotective effect in modeling of ischemia-reperfusion, expressed in reducing the severity of neurological deficit (0.8±0.21 points), compared with the control group (of 2.05±0.49 points); increase in the number of stands at 1.7 times and 2.2 hanging times; not a big increase in overall activity, patterns of movement, maximum speed, total distance increased 1.5 times, decrease rest time by 1.2 times; the reduction in the concentration of damage markers S100b 3.5 times and the NSE in 2 times. A number of distinctive characteristics the morphometric study, as well as a set of symptoms, manifestations of behavioral reactions confirm the fact of cerebroprotective properties of tadalafil in comparison with the control group animals.

Conclusions: the conducted research showed cerebroprotective property of an inhibitor of phosphodiesterase type 5, tadalafil. The results of the study clearly indicate the prospects of its use in vascular pathology of the brain.

Иллюстрации

Fig. 1. Effect of tadalafil on indicators of activity of the animals in the modeling of cerebral ischemia (iFDE-5)

 

Fig. 2. Effect of tadalafil on the concentration of markers of brain damage in the plasma of animals in 3 days (S100b-g/l; NSE - ng/ml) (M ± m; n = 10).

Note – * p<0.05, # – p < 0.05 in relation to intact rats

 

Fig. 3. Brain Slices rat СI and prior to the introduction of tadalafil

A- the frontal lobe, X 400, hematoxylin+eosin;

B – hippocampus X 400 Deposit. hematoxylin+eosin

 Fig. 4. The Effect of recombinant erythropoietin («Epocrin») on indicators of activity of animals in modeling cerebral ischemia

Fig. 5. Effect of recombinant erythropoietin («Epocrin») on markers of brain damage in the plasma of animals in 3 days (S100b-g/l; NSE - ng/ml) (M ± m; n = 10).

Note – * p<0.05, # – p < 0.05 in relation to intact rats

Fig. 6. Brain Slices rat IGM and prior to the introduction of "Epocrin":

A – frontal lobe, X 400, hematoxylin+eosin;

B – hippocampus X 400 Deposit. hematoxylin+eosin

 Fig. 7. Influence of neuroprotectant "Gliatilin" on indicators of activity of animals in modeling cerebral ischemia

Fig. 8. Influence of neuroprotectant "Gliatilin" markers of brain damage in the plasma of animals in 3 days (S100b-µg/l; NSE - ng/ml) (M ± m; n = 10).

Note – * – p<0.05, # – p < 0.05 in relation to intact rats

Fig. 9. Brain Slices of a rat a prophylactic introduction of "Gliatelin":

A – frontal lobe, X 400, hematoxylin+eosin;

 B – hippocampus X 400,. hematoxylin+eosin

 

Fig. 10. Brain Slices of the rat with a medical introduction of the "Gliatilin":

A – frontal lobe, X 400, hematoxylin+eosin;

B – hippocampus, X 400, hematoxylin+eosin

Fig. 11. The Effect of combination of tadalafil (iPDE -5)and neuroprotectant "Gliatilin" on indicators of activity of animals in modeling cerebral ischemia

Fig. 12. Effect of combination of tadalafil (iPDE-5) and neuroprotectant "Gliatilin" markers of brain damage in the plasma of animals in 3 days (S100b-g/l; NSE - ng/ml) (M ± m; n =10).

Note – * p<0.05, # – p < 0.05 in relation to intact rats

Fig. 13. The brain Slices of the rat group "iPDE-5+IGM+Gliatilin":

A – frontal lobe, X 400, hematoxylin+eosin;

 B – hippocampus, X 400, hematoxylin+eosin

 Fig. 14. Effect of tadalafil (iPDE-5), "Epocrin" with the prior introduction of glibenclamid on the activity of animals in modeling cerebral ischemia

Fig. 15. Effect of tadalafil (iPDE-5), "Epocrin" with the prior introduction of glibenclamid on the concentration of markers of brain damage in the plasma of animals in 3 days (S100b-g/l; NSE - ng/ml) (M ± m; n =10).

Note – * p<0.05, # – p < 0.05 in relation to intact rats

Fig. 16. Brain Slices of the rat group "Glib +iFDE-5+ CI":

A – frontal lobe, X 400, env. hematoxylin+eosin; B – hippocampus, X 400,

env. hematoxylin+eosin

 

Fig. 17. Brain Slices of the rat group "Glib +EPO+ CI":

A – frontal lobe, X 400, hematoxylin+eosin;

B – hippocampus, X 400,  hematoxylin+eosin

Fig. 18. Impact of duration and severity of the ischemic episode on the indicators of activity of animals in the experiment

 Fig. 19. Influence of used drugs on the activity rate of animals with cerebral ischemia

 Fig. 20. Influence of used drugs on the activity rate of animals with cerebral ischemia

Fig. 21. Influence of used drugs on the duration of stay of animals in the test of actimetry 

 Fig. 22. Influence of used drugs on the level of specific markers of damage of the rat brain S100b and NSE

 Fig. 23. Area values radar chart of the experimental groups

DOI: 10.18413/2313-8971-2017-3-3-20-36
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