Angiotensin II type 1 receptor blocker telmisartan reduces cerebral infarct volume and peri-infarct cytosolic phospholipase A(2) level in experimental stroke.
The angiotensin II type 1 receptor (AT(1)R) blocker (ARB) telmisartan is a unique drug that has a neuroprotective action and acts as an agonistic ligand for peroxisome proliferator-activated receptor-gamma. We produced rat models of middle cerebral artery occlusion and examined infarct volume as well as immunohistochemical localization and protein expression levels of cytosolic phospholipase A(2) (cPLA(2)), which is involved in neurotoxicity, in brains obtained 24 h after occlusion. Rats pretreated for 7 days with various doses of telmisartan or vehicle (n = 8) were compared. The infarct volume was significantly reduced in the 1.0 mg/kg dosage group compared with that of other dosage groups and vehicle group. Furthermore, pretreatment with telmisartan 1.0 mg/kg induced significant amelioration of sensorimotor function in forelimb and hindlimb placing tests. Histopathologically, neurons in the peri-infarct cortical regions of vehicle-pretreated rats showed acute ischemic changes, but neurons in telmisartan-pretreated rats appeared normal. Immunohistochemically, cPLA(2) reactivity was localized in ischemic neurons but not in intact neurons. On immunoblots, protein expression levels of total and active cPLA(2) in peri-infarct cortex were significantly reduced in telmisartan-treated rats compared with vehicle-treated rats. The present results provide in vivo evidence that telmisartan reduces cerebral infarct volume and cPLA(2) protein expression in peri-infarct cortex, suggesting an association between neuroprotection and inhibition of cPLA(2) signaling in cerebral ischemia.
Kobayashi
Tomonori
T
Department of Neurosurgery, Tokyo Women's Medical University, Tokyo, Japan.
Kawamata
Takakazu
T
Shibata
Noriyuki
N
Okada
Yoshikazu
Y
Kobayashi
Makio
M
Hori
Tomokatsu
T
D047228:Angiotensin II Type 1 Receptor Blockers / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001562:Benzimidazoles / Q000494:pharmacology* / Q000627:therapeutic use; D001565:Benzoates / Q000494:pharmacology* / Q000627:therapeutic use; D015415:Biomarkers / Q000032:analysis / Q000378:metabolism; D001921:Brain / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D020520:Brain Infarction / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D002545:Brain Ischemia / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D019610:Cytoprotection / Q000187:drug effects / Q000502:physiology; D003600:Cytosol / Q000187:drug effects / Q000201:enzymology; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D015536:Down-Regulation / Q000187:drug effects / Q000502:physiology; D007150:Immunohistochemistry; D020244:Infarction, Middle Cerebral Artery / Q000188:drug therapy / Q000201:enzymology / Q000473:pathology; D008297:Male; D009044:Motor Cortex / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D009474:Neurons / Q000187:drug effects / Q000378:metabolism / Q000473:pathology; D054467:Phospholipases A2 / Q000187:drug effects / Q000378:metabolism; D051381:Rats; D017207:Rats, Sprague-Dawley; D044140:Receptor, Angiotensin, Type 1 / Q000187:drug effects / Q000378:metabolism; D020127:Recovery of Function / Q000187:drug effects / Q000502:physiology; D015398:Signal Transduction / Q000187:drug effects / Q000502:physiology; D020521:Stroke / Q000188:drug therapy* / Q000201:enzymology / Q000473:pathology*; D000077333:Telmisartan
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001565:Benzoates; D015415:Biomarkers; D044140:Receptor, Angiotensin, Type 1; D054467:Phospholipases A2; D000077333:Telmisartan