Restricted accessResearch articleFirst published online 2009-12
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 (AT1R) 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 A2 (cPLA2), 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, cPLA2 reactivity was localized in ischemic neurons but not in intact neurons. On immunoblots, protein expression levels of total and active cPLA2 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 cPLA2 protein expression in peri-infarct cortex, suggesting an association between neuroprotection and inhibition of cPLA2 signaling in cerebral ischemia.
Get full access to this article
View all access options for this article.
References
1.
AdibhatlaR.M., HatcherJ.F.2006. Phopholipase A2, reactive oxygen species, and lipid peroxidation in cerebral ischemia. Free Radic. Biol. Med., 40:376–387.
2.
BedersonJ., PittsL.H., GermanoS.M., NishimuraM.C., DavisR.L., BartkowskiH.M.1986b. Evaluation of 2,3,5-triphenyltetrazolium chloride as a stain for detection and quantification of experimental cerebral infarction in rats. Stroke, 17:1304–1308.
3.
BedersonJ.B., PittsL.H., TsujiM., NishimuraM.C., DavisR.L., BartkowskiH.M.1986a. Rat middle cerebral artery occlusion: evaluation of the model and development of a neurologic examination. Stroke, 17:472–476.
4.
BensonS.C., PershadsinghH.A., HoC.I., ChittiboyinaA., DesaiP., PravenecM., QiN., WangJ., AveryM.A., KurtzT.W.2004. Identification of Telmisartan as a unique angiotensin II receptor antagonist with selective PPARγ-modulating activity. Hypertension, 43:993–1002.
5.
BernardoA., MinghettiL.2006. PPAR-γ agonists as regulators of microglial activation and brain inflammation. Curr. Pharm. Design, 12:93–109.
6.
BonventreJ.V., HuangZ., TaheriM.R., O'LearyE., LiE., MoskowitzM.A., SapirsteinA.1997. Reduced fertility and postischemic brain injury in mice deficient in cytosolic phospholipase A2. Nature, 390:622–625.
7.
ChungO., StollM., UngerT.1996. Physiologic and pharmacologic implications of AT1 versus AT2 receptors. Blood Press Suppl., 2:47–52.
8.
CoulonL., CaizadaC., MoulinP., VéricelE., LagardeM.2003. Activation of p38 mitogen-activated protein kinase/cytosolic phospholipase A2 cascade in hydroxyl peroxide-stressed platelets. Free Radic. Biol. Med., 35:616–625.
9.
De RyckM., Van ReemptsJ., DuytschaeverH., Van DeurenB., ClinckeG.1992. Neocortical localization of tactile/proprioceptive limb placing reactions in the rat. Brain Res., 573:44–60.
10.
DronadulaN., LiuZ., WangC., CaoH., RaoG.N.2005. STAT3-dependent cytosolic phospholipase A2 expression is required for thrombin-induced vascular smooth muscle cell moiety. J. Biol. Chem., 280:3112–3120.
11.
HamaiM., IwaiM., IdeA., TomochikaH., TomonoY., MogiM., HoriuchiM.2006. Comparison of inhibitory action of candesartan and enalapril on brain ischemia through inhibition of oxidative stress. Neuropharmacology, 51:822–828.
12.
HunyadyL., CattK.J.2006. Pleiotropic AT1 receptor signaling pathways mediating physiological and pathogenic actions of angiotensin II. Mol. Endocrinol., 20:953–970.
13.
KawamataT., AlexisN.E., DietrichW.D., FinklesteinS.P.1996. Intracisternal basic fibroblast growth factor (bFGF) enhances behavioral recovery following focal cerebral infarction in the rat. J. Cereb. Blood Flow Metab., 16:542–547.
14.
KawamataT., DietrichW.D., SchallertT., GottsJ.E., CockeR.R., BenowitzL.I., FinklesteinS.P.1997. Intracisternal basic fibroblast growth factor enhances function recovery and up-regulates the expansion of a molecular marker of neuronal sprouting following focal cerebral infarction. Proc. Natl. Acad. Sci. USA, 94:8179–8184.
15.
KawamataT., RenJ., ChaJ.H., FinklesteinS.P.1999. Intracisternal antisense oligonucleotide to growth associated protein-43 blocks the recovery-promoting effects of basic fibroblast growth factor after focal stroke. Exp. Neurol., 158:89–96.
16.
KobayashiT., KawamataT., MitsuyamaT., HoriT.2007. Modified permanent middle cerebral artery occlusion rat model aiming to reduce variability in infarct size. Neurol. Res., 29:884–887.
17.
KozakA., ErgulA., El-RemessyA.B., JohnsonM.H., MachadoL.S., ElewaH.F., AbdelsaidM., WileyD.C., FaganS.C.2009. Candesartan augments ischemia-induced proangiogenic state and results in sustained improvement after stroke. Stroke, 40:1870–1876.
18.
KozakW., KozakA., JohnsonM.H., ElewaH.F., FaganS.C.2008. Vascular protection with candesartan after experimental acute stroke in hypertensive rats: a dose-response study. J. Pharmacol. Exp. Ther., 326:773–782.
Lang-RollinI.C.J., RideoutH.J., NoticewalaM., StefanisL.2003. Mechanisms of caspase-independent neuronal death: energy depletion and free radical generation. J. Neurosci., 23:11015–11025.
21.
LazarewiczJ.W., WroblewskiJ.T., CostaE.1990. N-Methyl-D-aspartate-sensitive glutamate receptors induce calcium-mediated arachidonic acid release in primary cultures of cerebellar granule cells. J. Neurochem., 55:1875–1881.
22.
LuoS.F., LinW.N., YangC.M., LeeC.W., LiaoC.H., LeuY.L., HsiaoL.D.2006. Induction of cytosolic phospholipase A2 by lipopolysaccharide in canine tracheal smooth muscle cells: involvement of MAPKs and NF-κB pathways. Cell Signal, 18:1201–1211.
23.
MassicotteG., VanderklishP., LynchG., BandryM.1991. Modulation of DL-alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid/quisqualate receptors by phospholipase A2: a necessary step in long-term potentiation? Proc. Natl. Acad. Sci. USA, 88:1893–1897.
24.
MillerB., SarantisM., TraynelisS.F., AttwellD.1992. Potentiation of NMDA receptor currents by arachidonic acid. Nature, 355:722–725.
25.
MitsuyamaT., KawamataT., YamaneF., AwayaA., HoriT.2002. Role of a synthetic pyrimidine compound, MS-818, in reduction of infarct size and amelioration of sensorimotor dysfunction following permanent focal cerebral ischemia in rats. J. Neurosurg., 96:1072–1076.
26.
NandaB.L., NatarajuA., RajeshR., RangappaK.S., ShekarM.A., VishwanathB.S.2007. PLA2 mediated arachidonate free radicals: PLA2 inhibition and neutralization of free radicals by anti-oxidants—a new role of anti-inflammatory molecules. Curr. Top. Med. Chem., 7:765–777.
27.
SaavedraJ.M.2005. Brain angiotensin II: new developments, unanswered questions and therapeutic opportunities. Cell Mol. Neurobiol., 25:485–512.
SchraderJ., LüdersS., KulschewskiA., HammersenF., PlateK., BergerJ., ZidekW., DominiakP., DienerH.C.MOSES Study Group. 2005. Morbidity and mortality after stroke, eprosartan compared with nitrendipine for secondary prevention: principal results of a prospective randomized controlled study (MOSES)Stroke, 36:1218–1226.
30.
StellaN., TenceM., GlowinskiJ., PremontJ.1994. Glutamate-evoked release of arachidonic acid from mouse brain astrocytes. J. Neurosci., 14:568–575.
31.
SunG.Y., HorrocksL.A., FarooquiA.A.2007. The roles of NADPH oxidase and phospholipases A2 in oxidative and inflammatory responses in neurodegenerative diseases. J. Neurochem., 103:1–16.
32.
SunG.Y., XuJ., JensenM.D., SimonylA.2004. Phospholipase A2 in the central nervous system: implications for neurodegenerative diseases. J. Lipid Res., 45:205–213.
33.
SwansonR.A., MortonM.T., Tsao-WuG., SavalosR.A., DavidsonC., SharpF.R.1990. A semiautomated method for measuring brain infarct volume. J. Cereb. Blood Flow Metab., 10:290–293.
34.
TontonozP., SpiegelmanB.M.2008. Fat and beyond: the diverse biology of PPARγAnnu. Rev. Biochem., 77:289–312.
35.
van PuttenV., RefaatZ., DessevC., BlaineS., WickM., ButterfieldL., HanS.Y., HeasleyL.E., NemenoffR.A.2001. Induction of cytosolic phospholipase A2 by oncogene Ras is mediated through the JNK and ERK pathways in rat epithelial cells. J. Biol. Chem., 276:1226–1232.
36.
WagnerJ., DrabM., BohlenderJ., AmannK., WienenW., GantenD.1998. Effects of AT1 receptor blockade on blood pressure and the renin-angiotensin system in spontaneously hypertensive rats of the stroke prone strain. Clin. Exp. Hypertens., 20:205–221.
37.
YusufS., DienerH.C., SaccoR.L., CottonD., OunpuuS., LawtonW.A., PaleschY., MartinR.H., AlbersG.W., BathP., BornsteinN., ChanB.P.L., ChenS.T., CunhaL., DahlöfB., De KeyserJ., DonnanG.A., EstolC., GorelickP., GuV., HermanssonK., HilbrichL., KasteM., LuC., MachnigT., PaisP., RobertsR., SkvortsovaV., TealP., ToniD., VanderMaelenC., VoigtT., WeberM., YoonB.W.PRoFESS Study Group. 2008. Telmisartan to prevent recurrent stroke and cardiovascular events. N. Engl. J. Med., 359:1225–1237.
38.
ZhaoY., PatzerA., GohlkeP., HerdegenT., CulmanJ.2005. The intracerebral application of the PPARgamma-ligand pioglitazone confers neuroprotection against focal ischemia in the rat brain. Eur. J. Neurosci., 22:278–282.
