Sustained blockade of brain AT1 receptors before and after focal cerebral ischemia alleviates neurologic deficits and reduces neuronal injury, apoptosis, and inflammatory responses in the rat

J Cereb Blood Flow Metab. 2004 May;24(5):536-47. doi: 10.1097/00004647-200405000-00008.


In the present study, we investigate whether a long-term blockade of brain AT1 receptors in male Wistar rats before and after ischemic injury exerts neuroprotective effects and modulates apoptosis and inflammatory responses, which are associated with the post-ischemic progression of brain damage. The AT1 receptor antagonist irbesartan was continuously infused intracerebroventricularly using osmotic minipumps over a 5-day period before and for 3 or 7 days after middle cerebral artery occlusion (MCAO) for 90 minutes. Neurologic status was evaluated daily, starting 24 hours after MCAO. After MCAO (3 and 7 days), brains were removed for the measurement of infarct size and immunohistochemical evaluation of apoptosis and accumulation of reactive microglia and macrophages. Treatment with irbesartan before ischemia improved motor functions, whereas post-ischemic treatment improved sensory functions. Blockade of brain AT1 receptors reduced the infarct size on days 3 and 7 after MCAO. In the peri-infarct cortex, irbesartan treatment decreased the number of apoptotic cells on day 3 and attenuated the invasion of activated microg-lia and macrophages on days 3 and 7 after ischemia. Long-term blockade of brain AT1 receptors improves the recovery from cerebral ischemia. Antiapoptotic mechanisms and inhibition of post-ischemic inflammation are involved in the AT1 receptor blockade-induced neuroprotective effects in ischemic brain tissue.

MeSH terms

  • Angiotensin II Type 1 Receptor Blockers
  • Animals
  • Apoptosis / physiology*
  • Biphenyl Compounds / pharmacology
  • Brain / cytology
  • Brain / drug effects
  • Brain / pathology
  • Brain / physiology
  • Brain Ischemia / metabolism*
  • Brain Ischemia / pathology
  • Hemodynamics
  • Immunohistochemistry
  • In Situ Nick-End Labeling
  • Infarction, Middle Cerebral Artery
  • Inflammation*
  • Irbesartan
  • Male
  • Neuroprotective Agents / pharmacology
  • Peptide Fragments / metabolism
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Proteins / metabolism
  • Rats
  • Rats, Wistar
  • Receptor, Angiotensin, Type 1 / metabolism*
  • Tetrazoles / pharmacology


  • Angiotensin II Type 1 Receptor Blockers
  • Biphenyl Compounds
  • Neuroprotective Agents
  • Peptide Fragments
  • Proteins
  • Receptor, Angiotensin, Type 1
  • Tetrazoles
  • Parp1 protein, rat
  • Poly (ADP-Ribose) Polymerase-1
  • Poly(ADP-ribose) Polymerases
  • Irbesartan