الفهرس 
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Abstract
In the present study, the protective effect of two test agents angiotensin receptor blocker (ARB) telmisartan and angiotensin converting enzyme II (ACE2) activator xanthenone each in three dose levels were investigated in cerebral ischemia/reperfusion (I/R) injury induced experimentally in rats in compared to standard treatment nimodipine in a dose of 10 mg/kg/day.
To fulfill this aim, I/R was induced experimentally in rats. Briefly, Rats were anesthetized with thiopental (50 mg/kg, i.p.) and a midline ventral incision was made in the neck. Bilateral carotid arteries were separated from the adjacent tissues and vagus nerve, then the bilateral carotid arteries were occluded using small artery clips to induce global cerebral ischemia for 30-min followed by a 24-h reperfusion period as the clips were removed to restore circulation.
The effect was studied after administration of the test drugs for 2 weeks before I/R. 10 rats in each group were sacrificed by cervical dislocation for biochemical analysis, however, intracardiac perfusion was performed for histopathological and immunohistochemical assessment in 3 rats in the 5 groups. Namely sham, I/R control, nimodipine, telmisartan (10 mg/kg) and XTN (2 mg/kg).
The protective effect of test drugs was evaluated based on estimation of total nitrate/nitrite (NOx) level, as well as oxidative stress markers as reduced glutathione (GSH) and malondialdehyde (MDA) levels in brain homogenates. Additionally, inflammatory cytokines parameters as tumor necrosis factor-alpha (TNF-α) and interlukine-6 (IL-6) levels and anti-inflammatory cytokines as IL-10 levels were estimated. The apoptotic marker caspase-3 was also assessed biochemically. The brain ACE and ACE2 gene expression were assessed using RT-PCR. Finally, To confirm the results of biochemical estimations, histopathological examination and immunohistochemical evaluation of glial fibrillary acidic protein (GFAP) were performed in cerebral cortex and hippocampus sections.
6.1-The Main Findings of the Present Investigation Can Be Summarized as Follows:
1. Cerebral I/R injury was manifested by significant increase of both MDA and NOx while significant decrease of GSH as compared to sham control.
2. Standard treatment nimodipine significantly decreased MDA and NOx levels as compared to I/R control.
3. Telmisartan in doses of 3 and 10 mg/kg and xanthenone in doses of 0.5, 1 and 2 mg/kg significantly increased brain GSH and significantly decreased MDA and NOx levels as compared to I/R control.
4. Induction of cerebral I/R injury significantly decreased IL-10 while significantly increased both TNF-α and IL-6 levels in brain homogenate as compared to sham control.
5. Standard treatment nimodipine significantly decreased both TNF-α and IL-6 levels in brain homogenate as compared to I/R control.
6. Telmisartan and xanthenone each in three dose levels significantly decreased both TNF-α and IL-6 levels, also, significantly increased IL-10 level as compared to I/R control.
7. Induction of cerebral I/R injury significantly increased caspase-3 level in brain homogenate as compared to sham control.
8. Standard treatment nimodipine significantly decreased caspase-3 level in brain homogenate as compared to I/R control.
9. Telmisartan and xanthenone each in three dose levels significantly decreased caspase-3 level in brain homogenate as compared to I/R control.
10. Induction of cerebral I/R injury induced significant increase in ACE mRNA gene expression and significant decrease in ACE2 mRNA gene expression in brain tissue as compared to sham control.
11. Administration of nimodipine induced significant decrease in ACE and significant increase in ACE2 mRNA gene expression in brain tissue as compared to I/R control.
12. Telmisartan and xanthenone each in the highest dose level significantly decreased ACE and significant increased ACE2 mRNA gene expression in brain tissue as compared to I/R control.
13. Induction of cerebral I/R injury induced significant increase in cortex and hippocampus GFAP.
14. Administration of standard treatment nimodipine induced significant decrease in cortex GFAP only, while administration of telmisartan and xanthenone each in the highest dose level significantly decreased both cortex and hippocampus GFAP.
15. Induction of cerebral I/R injury induced severe degenerated and necrotized neurocytes, in the form of shrunken, pyknotic and hyperchromatic nuclei in cortex also severe damaged apoptotic neurons of the pyramidal layer in the form of pyknotic and shrunken neurons with hyperchromatic nuclei in hippocampus.
16. Administration of standard treatment nimodipine induced moderate degenerated and necrotised neurocytes in the cerebral cortex and moderate degeneration in the neurons of the pyramidal layer in hippocampus.
17. Telmisartan and xanthenone each in three dose levels improved cerebral cortex and hippocampus architecture, and it was interesting that the highest dose of both telmisartan and xanthenone nearly normalized brain architectures.
6.2-from the Previous Findings, the Following Could Be Concluded:
1. Telmisartan, the angiotensin II receptor blocker, may have potential protecting effects against experimentally-induced cerebral I/R injury in rats probably due to its antioxidant, anti-inflammatory and anti-apoptotic effects.
2. Xanthenone, the angiotensin-converting enzyme II activator, showed potential action as anti-oxidant, anti-inflammatory agent and anti-apoptotic effects.
3. Finally, that study can reveal that the organ-localized renin-angiotensin system (RAS) is now considered to play a vital role in pathological oxidative and inflammatory damage in cerebral I/R injury, and interference with RAS’s may have beneficial outcomes either through suppression of the classic ACE pathway or stimulation of its antagonist pathway ACE2.
In conclusion, modulation of brain ACE and ACE2 pathways may be a promising protective strategy against cerebral ischemia/reperfusion injury; an experimental trial in rats, and may be promising for further clinical trials for prophylaxis against ischemic stroke in human.