Comparison between single and combined treatment with candesartan and pioglitazone following transient focal ischemia in rat brain.
Angiotensin AT1 receptor blockers (ARBs) and thiazolidinediones (TZDs) have become well established drugs for the treatment of major risk factors of stroke. Since several studies provided evidence that ARBs and TZDs also have additional anti-inflammatory effects, we hypothesized that a combined treatment with the ARB, candesartan, and the TZD, pioglitazone, ameliorates ischemia-induced brain injury and inflammation by synergistic anti-inflammatory actions. Normotensive Wistar rats were pre-treated for 5 days with vehicle (0.9% NaCl), 0.2 mg/kg/day candesartan (s.c.), and/or 2 and/or 20 mg/kg/day pioglitazone (p.o.), respectively and underwent 90 min of middle cerebral artery occlusion (MCAO) with successive reperfusion. Neurological deficits and infarct size were determined 24 h and 48 h after MCAO, respectively, followed by tissue sampling. Animals treated with candesartan, pioglitazone, and the combination of candesartan and pioglitazone had reduced neurological deficits 24 h and 48 h after MCAO, respectively (P<0.05-0.01). Infarct size was reduced by treatment of candesartan, pioglitazone, and their respective combination (each P<0.05) 48 h after stroke compared to vehicle. Treatment with candesartan, pioglitazone, and their combination resulted in significantly reduced mRNA expression of the inflammatory markers CXCL1 and TNFalpha in vivo (P<0.01). The combination of candesartan plus pioglitazone is equally effective compared to their single applications concerning neuroprotection and attenuation of inflammation after MCAO. Therefore, we conclude that a direct synergistic neuroprotective action of parallel ARB and TZD treatment is unlikely.
Schmerbach
Kristin
K
Center for Cardiovascular Research/Institute of Pharmacology, Charité-Universitätsmedizin Berlin, Berlin, Germany.
Schefe
Jan H
JH
Krikov
Maxim
M
Müller
Susanne
S
Villringer
Arno
A
Kintscher
Ulrich
U
Unger
Thomas
T
Thoene-Reineke
Christa
C
D047228:Angiotensin II Type 1 Receptor Blockers / Q000627:therapeutic use*; D000818:Animals; D000831:Animals, Newborn; D001253:Astrocytes / Q000187:drug effects; D001562:Benzimidazoles / Q000627:therapeutic use*; D001713:Biphenyl Compounds; D001921:Brain / Q000187:drug effects*; D002478:Cells, Cultured; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004359:Drug Therapy, Combination; D015870:Gene Expression / Q000187:drug effects; D007004:Hypoglycemic Agents / Q000627:therapeutic use*; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008279:Magnetic Resonance Imaging; D008297:Male; D009460:Neurologic Examination; D047495:PPAR gamma / Q000235:genetics / Q000378:metabolism; D000077205:Pioglitazone; D051381:Rats; D017208:Rats, Wistar; D013777:Tetrazoles / Q000627:therapeutic use*; D045162:Thiazolidinediones / Q000627:therapeutic use*
D047228:Angiotensin II Type 1 Receptor Blockers; D001562:Benzimidazoles; D001713:Biphenyl Compounds; D007004:Hypoglycemic Agents; D047495:PPAR gamma; D013777:Tetrazoles; D045162:Thiazolidinediones; C081643:candesartan; D000077205:Pioglitazone