Abstract
Background and Purpose This study was performed to assess the efficacy and the therapeutic window for the calmodulin antagonist trifluoperazine in experiments involving transient middle cerebral artery (MCA) occlusion. Methods Male Wistar rats were subjected to transient (2 hours) MCA occlusion by an intraluminal filament technique. Trifluoperazine (5.0 mg · kg −1 ) was injected intraperitoneally 5 minutes, 1 hour, or 2 hours after the induction of ischemia. Drug administration was repeated 24 hours after the first injection. Neurological scores and infarct volumes were evaluated at 48 hours of reperfusion. The effect of trifluoperazine on cortical blood flow was studied with continuous laser-Doppler flowmetry. Results The median value of neurological scores in the control rats (n=7) was 3, while those in the treated groups were 1 (5-minute group; n=7, P <.05) and 2 (1-hour and 2-hour groups; each n=7). The percentage of infarct volume in the control rats was 34.8±4.9% (mean±SD), while those in the treated groups were 11.3±12.3% (5-minute group; P <.01), 24.8±15.1% (1-hour group), and 28.8±8.3% (2-hour group). Trifluoperazine, given at 5 minutes after ischemia, had no influence on blood flow in the neocortical penumbra during and after ischemia. Conclusions The results demonstrate that trifluoperazine markedly reduces infarct volume after 2 hours of MCA occlusion when given 5 minutes after the induction of ischemia. However, the therapeutic window for trifluoperazine seems narrow since the drug had no significant effect when given after 1 or 2 hours.
References
57
Referenced
41
10.1016/0166-2236(88)90200-7
10.1016/0166-2236(95)80018-W
10.1097/00003246-198810000-00006
- Siesjö BK. The role of calcium in cell death. In: Price D Thoenen H Aguayo A eds. Neurodegenerative Disorders: Mechanisms and Prospects for Therapy. New York NY: John Wiley & Sons Ltd; 1991.
- Tymianski M, Tator CH. Normal and abnormal calcium homeostasis in neurons: a basis for the pathophysiology of traumatic and ischemic central nervous system injury. Neurosurgery. 1996;38:1176–1195. / Neurosurgery (1996)
10.1007/BF01906948
- Otani H, Engelman RM, Rousou JA, Breyer RH, Clement R, Prasad R, Klar J, Das DK. Improvement of myocardial function by trifluoperazine, a calmodulin antagonist, after acute coronary artery occlusion and coronary revascularization. J Thorac Cardiovasc Surg. 1992;97:267–74. / J Thorac Cardiovasc Surg (1992)
10.1097/00005344-199208000-00010
- Gabauer I, Slezak J, Styk J, Ziegelhoffer A. Protective effect of calmodulin inhibitors on reperfusion injury. Bratisl Lek Listy. 1991;92:184–194. / Bratisl Lek Listy (1991)
10.1007/BF01744603
10.1038/jcbfm.1993.74
10.1038/jcbfm.1992.54
10.1038/jcbfm.1994.3
10.1016/0024-3205(96)00314-1
- Kristián T Gidö G Kuroda S Schutz A Siesjö BK. Calcium metabolism of focal and penumbral tissues in rats subjected to transient middle cerebral artery occlusion. Exp Brain Res. In press.
- Greenberg JH Uematsu D Araki N Hickey WF Reivich M. Cytosolic free calcium during focal cerebral ischemia and the effects of nimodipine on calcium and histologic damage. Stroke. 1990;21(suppl IV):IV-72-IV-77.
10.1016/0006-8993(94)01251-C
10.1097/00004647-199601000-00013
10.1111/j.1748-1716.1994.tb09816.x
10.1073/pnas.92.11.5057
10.1089/neu.1995.12.943
10.1097/00003643-199605000-00004
10.1002/(SICI)1520-6769(199609)19:2<83::AID-NRC167>3.0.CO;2-V
10.1006/nbdi.1996.0015
- Nakai A Kuroda S Kristían T Siesjö BK. The immunosuppressant FK506 ameliorates secondary mitochondrial failure following transient focal cerebral ischemia in the rat. Neurobiol Dis. In press.
10.3995/jstroke.8.1
10.1007/BF00229002
10.1016/0006-8993(94)91071-5
10.1161/str.17.3.3715945
10.1007/BF02193092
10.1038/jcbfm.1990.47
10.1016/0730-725X(94)00081-D
10.1097/00004647-199603000-00005
10.1038/jcbfm.1989.20
10.1007/BF00690200
-
Zaidan E, Sims N. The calcium content of mitochondria from brain subregions following short-term forebrain ischemia and recirculation in the rat. J Neurochem. 1994;63:1812–1819.
(
10.1046/j.1471-4159.1994.63051812.x
) / J Neurochem (1994) -
Grotta JC Picone CM Dedman JR Rhoades HM Strong RA Earls RM Yao LP. Neuronal protection correlates with prevention of calcium-calmodulin binding in rats. Stroke. 1990;21(suppl III):III-28-III-31.
(
10.1161/01.STR.21.6.948
) 10.1111/j.1471-4159.1984.tb12825.x
10.1038/jcbfm.1987.13
10.1016/0304-3940(87)90376-4
10.1161/str.18.4.3603603
10.1038/jcbfm.1994.104
- Chien KR, Abrams J, Pfau RG, Farber JL. Prevention by chlorpromazine of ischemic liver cell death. Am J Pathol. 1977;88:539–558. / Am J Pathol (1977)
10.1016/0006-8993(89)90560-X
10.1161/str.23.9.1519284
- Beresewicz A, Wasilewska A, Herbaczynskacedro K. Calmodulin antagonist reduced release of malondialdehyde from isolated ischemic/reperfused rat heart. Acta Physiol Pol. 1988;39:442–449. / Acta Physiol Pol (1988)
- Chien KR, Pfau RG, Farber JL. Ischemic myocardial cell injury. Am J Pathol. 1979;97:505–530. / Am J Pathol (1979)
10.1152/ajpcell.1989.257.2.C252
10.1097/00000542-198009000-00002
- Janero DR, Burghardt B. Prevention of oxidative injury to cardiac phospholipid by membrane-active ’stabilizing agents.’ Res Commun Chem Pathol Pharmacol. 1989;63:163–173. / Res Commun Chem Pathol Pharmacol (1989)
10.1523/JNEUROSCI.11-06-01829.1991
10.1016/0006-8993(86)91067-X
10.1016/0022-510X(92)90261-I
10.1038/jcbfm.1995.119
10.1038/jcbfm.1995.118
10.1096/fasebj.4.9.2189775
10.1073/pnas.90.21.9808
Dates
Type | When |
---|---|
Created | 14 years, 2 months ago (June 17, 2011, 4:08 p.m.) |
Deposited | 1 year, 3 months ago (May 12, 2024, 6:16 p.m.) |
Indexed | 11 months, 2 weeks ago (Sept. 15, 2024, 5:21 p.m.) |
Issued | 27 years, 9 months ago (Dec. 1, 1997) |
Published | 27 years, 9 months ago (Dec. 1, 1997) |
Published Print | 27 years, 9 months ago (Dec. 1, 1997) |
@article{Kuroda_1997, title={The Calmodulin Antagonist Trifluoperazine in Transient Focal Brain Ischemia in Rats: Anti-ischemic Effect and Therapeutic Window}, volume={28}, ISSN={1524-4628}, url={http://dx.doi.org/10.1161/01.str.28.12.2539}, DOI={10.1161/01.str.28.12.2539}, number={12}, journal={Stroke}, publisher={Ovid Technologies (Wolters Kluwer Health)}, author={Kuroda, Satoshi and Nakai, Akihito and Kristían, Tibor and Siesjö, Bo K.}, year={1997}, month=dec, pages={2539–2544} }