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Perioperative aspirin improves neurological outcome after focal brain ischemia possibly via inhibition of Notch 1 in rat.

Wang Z, Huang W, Zuo Z - J Neuroinflammation (2014)

Bottom Line: Aspirin given by regimen 2 and 3 but not by regimen 1 improved neurological outcome.DAPT and aspirin given only by regimen 2 and 3 reduced NICD, IL-6 and IL-1β in the ischemic penumbral cortex.NICD was found in microglial nuclei.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, University of Virginia, 1 Hospital Drive, PO Box 800710, Charlottesville, Virginia 22908-0710, USA. zz3c@virginia.edu.

ABSTRACT

Background: Perioperative discontinuation of aspirin is often considered due to bleeding concern. We determined whether this discontinuation affected neurological outcome after brain ischemia.

Methods: Adult male Sprague-Dawley rats were subjected to a 90-minute right middle cerebral arterial occlusion (MCAO). They received 30 mg/kg/day aspirin via gastric gavage: 1) for 2 days at 5 days before MCAO; 2) for 2 days at 5 days before MCAO and for 3 days after MCAO; 3) for 7 days before MCAO; or 4) for 7 days before MCAO and for 3 days after MCAO. Neurological outcome was evaluated 3 days after the MCAO. Ischemic penumbral cortex was harvested 1 or 3 days after MCAO for determining Notch intracellular domain (NICD), IL-6 and IL-1β levels.

Results: Aspirin given by regimen 2 and 3 but not by regimen 1 improved neurological outcome. Neuroprotection was achieved by N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a Notch activation inhibitor. DAPT and aspirin given only by regimen 2 and 3 reduced NICD, IL-6 and IL-1β in the ischemic penumbral cortex. NICD was found in microglial nuclei. Microglial activation in the ischemic tissues was inhibited by aspirin.

Conclusion: Aspirin use during the perioperative period provides neuroprotection. Inhibition of Notch activation and neuroinflammation may contribute to the neuroprotection of aspirin.

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Aspirin-induced inhibition of Notch activation and proinflammatory cytokine production. Rats received various aspirin treatments around a 90-minute middle cerebral arterial occlusion (MCAO). Intracerebroventricular injection of N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was performed immediately after the MCAO. The right frontal cortex area 1 was harvested at 3 days after the MCAO. The cytosol was prepared for Western blotting for Notch intracellular domain (NICD) and ELISA for IL-6 and IL-1β. (A) NICD expression. Top panel shows representative Western blots and bottom panel shows the quantification results. (B) IL-6 results. (C) IL-1β results. Results are the means ± SEM (n = 8). *P < 0.05, compared with sham; ^P < 0.05, compared with the animals subjected to MCAO only. ASA, acetylsalicylic acid.
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Figure 7: Aspirin-induced inhibition of Notch activation and proinflammatory cytokine production. Rats received various aspirin treatments around a 90-minute middle cerebral arterial occlusion (MCAO). Intracerebroventricular injection of N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was performed immediately after the MCAO. The right frontal cortex area 1 was harvested at 3 days after the MCAO. The cytosol was prepared for Western blotting for Notch intracellular domain (NICD) and ELISA for IL-6 and IL-1β. (A) NICD expression. Top panel shows representative Western blots and bottom panel shows the quantification results. (B) IL-6 results. (C) IL-1β results. Results are the means ± SEM (n = 8). *P < 0.05, compared with sham; ^P < 0.05, compared with the animals subjected to MCAO only. ASA, acetylsalicylic acid.

Mentions: As expected, DAPT significantly reduced the expression of NICD, IL-6 and IL-1β in the ischemic penumbral brain tissues. Similarly, aspirin use for 2 days at 5 days before the brain ischemia and then for 3 days starting from surgery day to induce the brain ischemia, continuation of aspirin use throughout the perioperative period, and the combination of DAPT and aspirin use throughout the perioperative period also reduced the expression of NICD, IL-6 and IL-1β in the ischemic penumbral brain tissues (Figure 7).


Perioperative aspirin improves neurological outcome after focal brain ischemia possibly via inhibition of Notch 1 in rat.

Wang Z, Huang W, Zuo Z - J Neuroinflammation (2014)

Aspirin-induced inhibition of Notch activation and proinflammatory cytokine production. Rats received various aspirin treatments around a 90-minute middle cerebral arterial occlusion (MCAO). Intracerebroventricular injection of N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was performed immediately after the MCAO. The right frontal cortex area 1 was harvested at 3 days after the MCAO. The cytosol was prepared for Western blotting for Notch intracellular domain (NICD) and ELISA for IL-6 and IL-1β. (A) NICD expression. Top panel shows representative Western blots and bottom panel shows the quantification results. (B) IL-6 results. (C) IL-1β results. Results are the means ± SEM (n = 8). *P < 0.05, compared with sham; ^P < 0.05, compared with the animals subjected to MCAO only. ASA, acetylsalicylic acid.
© Copyright Policy - open-access
Related In: Results  -  Collection

License 1 - License 2
Show All Figures
getmorefigures.php?uid=PMC3974223&req=5

Figure 7: Aspirin-induced inhibition of Notch activation and proinflammatory cytokine production. Rats received various aspirin treatments around a 90-minute middle cerebral arterial occlusion (MCAO). Intracerebroventricular injection of N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT) was performed immediately after the MCAO. The right frontal cortex area 1 was harvested at 3 days after the MCAO. The cytosol was prepared for Western blotting for Notch intracellular domain (NICD) and ELISA for IL-6 and IL-1β. (A) NICD expression. Top panel shows representative Western blots and bottom panel shows the quantification results. (B) IL-6 results. (C) IL-1β results. Results are the means ± SEM (n = 8). *P < 0.05, compared with sham; ^P < 0.05, compared with the animals subjected to MCAO only. ASA, acetylsalicylic acid.
Mentions: As expected, DAPT significantly reduced the expression of NICD, IL-6 and IL-1β in the ischemic penumbral brain tissues. Similarly, aspirin use for 2 days at 5 days before the brain ischemia and then for 3 days starting from surgery day to induce the brain ischemia, continuation of aspirin use throughout the perioperative period, and the combination of DAPT and aspirin use throughout the perioperative period also reduced the expression of NICD, IL-6 and IL-1β in the ischemic penumbral brain tissues (Figure 7).

Bottom Line: Aspirin given by regimen 2 and 3 but not by regimen 1 improved neurological outcome.DAPT and aspirin given only by regimen 2 and 3 reduced NICD, IL-6 and IL-1β in the ischemic penumbral cortex.NICD was found in microglial nuclei.

View Article: PubMed Central - HTML - PubMed

Affiliation: Department of Anesthesiology, University of Virginia, 1 Hospital Drive, PO Box 800710, Charlottesville, Virginia 22908-0710, USA. zz3c@virginia.edu.

ABSTRACT

Background: Perioperative discontinuation of aspirin is often considered due to bleeding concern. We determined whether this discontinuation affected neurological outcome after brain ischemia.

Methods: Adult male Sprague-Dawley rats were subjected to a 90-minute right middle cerebral arterial occlusion (MCAO). They received 30 mg/kg/day aspirin via gastric gavage: 1) for 2 days at 5 days before MCAO; 2) for 2 days at 5 days before MCAO and for 3 days after MCAO; 3) for 7 days before MCAO; or 4) for 7 days before MCAO and for 3 days after MCAO. Neurological outcome was evaluated 3 days after the MCAO. Ischemic penumbral cortex was harvested 1 or 3 days after MCAO for determining Notch intracellular domain (NICD), IL-6 and IL-1β levels.

Results: Aspirin given by regimen 2 and 3 but not by regimen 1 improved neurological outcome. Neuroprotection was achieved by N-[N-(3,5-Difluorophenacetyl)-L-alanyl]-S-phenylglycine t-butyl ester (DAPT), a Notch activation inhibitor. DAPT and aspirin given only by regimen 2 and 3 reduced NICD, IL-6 and IL-1β in the ischemic penumbral cortex. NICD was found in microglial nuclei. Microglial activation in the ischemic tissues was inhibited by aspirin.

Conclusion: Aspirin use during the perioperative period provides neuroprotection. Inhibition of Notch activation and neuroinflammation may contribute to the neuroprotection of aspirin.

Show MeSH
Related in: MedlinePlus