Abstract
We modeled the common clinical conditions of human stroke in fully conscious rats through an occlusion of the middle cerebral artery (MCAO) by means of unilateral microinjection of Endothelin-1 (ET1) in the vicinity of the artery (EMCAO model). Since the role of serotonin (5-HT) system in the regulation of the cerebral blood flow has been known for long time and no data are available at present for the effects of 5-HT antagonists in focal ischemia models, we further tested whether a blockade of the serotonin-2A (5-HT2A) receptors by ketanserin (20 min post-ET1) would diminish the late EMCAO-induced functional and morphological changes. The long-term neurological (postural reflex) and electroencephalogram (EEG) changes in the somatosensory cortical region (S1FL) were used to assess the effects of ketanserin on the post-ischemic changes. The study was supplemented by a histopathological examination of S1FL area and striatum of both hemispheres. The EMCAO/ ketanserin-treated rats showed much smaller neurological deficits than the EMCAO rats treated with vehicle. This effect was observed on day 3 and lasted until the end of experiments-14 days after EMCAO. The depression of alpha and beta EEG frequencies found after EMCAO was significantly and earlier restored following ketanserin. Notably, there was not augmentation of the pathological slow EEG waves at day 3 post-ET1 in the EMCAO ketanserin-treated rats compared with that observed in the EMCAO vehicle-treated rats. Although there were mild morphological changes in the penumbral S1FL cortical region after EMCAO, ketanserin reduced the histopathological difference between the ipsilateral and contralateral cortical S1FL regions, but did not change the difference between striatum of both sides. Ketanserin reduced the infarct size in ipsilateral hemisphere (mainly cortex). In conclusion, the results showed that treatment with ketanserin at the early stage of stroke may reduce the consequences of ischemia by improvement of functional and morphological recovery at later stages. Ketanserin appears to be a promising candidate for mitigating the consequences of stroke.
[1] Muir K.W., Lees K.R., Clinical experience with excitatory amino acid antagonist drugs, Stroke, 1995, 26, 503–513 10.1161/01.STR.26.3.503Search in Google Scholar
[2] Kanthan R., Shuaib A., Griebel R., El-Alazounni H., Miyashita H., Kalra J., Evaluation of monoaminergic neurotransmitters in the acute focal ischemic human brain model by intracerebral in vivo microdialysis, Neurochem. Res., 1996, 21, 563–566 http://dx.doi.org/10.1007/BF0252775410.1007/BF02527754Search in Google Scholar
[3] Van Nueten J.M., Janssen P.A., Van Beek J., Xhonneux R., Verbeuren T.J. Vanhoutte P.M., Vascular effects of ketanserin (R 41 468), a novel antagonist of 5-HT2 serotonergic receptors. Pharmacol. Exp. Therap., 1981, 218, 217–230 Search in Google Scholar
[4] Wiernsperger N., Serotonin 5-HT2 receptors and brain circulation, J. Cardiovasc. Pharmacol., 1990, 16, S20–S24 10.1097/00005344-199000163-00005Search in Google Scholar
[5] Baxter G., Kennett G., Blackburn T., Blaney F., 5-HT2 receptor subtypes: A family re-united?, Trends Pharmacol. Sci., 1995, 16, 105–110 http://dx.doi.org/10.1016/S0165-6147(00)88991-910.1016/S0165-6147(00)88991-9Search in Google Scholar
[6] Liechti M.E., Saur M., Gamma A., Hell D., Vollenweider F.X., Psychological and physiological effects of MDMA (“Ecstasy”) after pretreatment with the 5-HT2 antagonist ketanserin in healthy humans, Neuropsychopharmacology, 2000, 23, 396–405 http://dx.doi.org/10.1016/S0893-133X(00)00126-310.1016/S0893-133X(00)00126-3Search in Google Scholar
[7] Globus M.Y.T., Wester P., Buso R., Dietrich W.D., Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats, Stroke, 1992, 23, 1595–1601 10.1161/01.STR.23.11.1595Search in Google Scholar
[8] Karasawa Y., Araki H., Otomo S., Effects of ketanserin and mianserin on delayed neuronal death induced by cerebral ischemia in Mongolian gerbils, Psychopharmacology, 1992, 109, 264–270 http://dx.doi.org/10.1007/BF0224587210.1007/BF02245872Search in Google Scholar
[9] Klisch J., Bode-Greuel K.M., Ketanserin reduces neuronal calcium accumulation and cell death in the hippocampus of the mongolian gerbil after transient forebrain ischemia, Brain Res., 1992, 578, 1–7 http://dx.doi.org/10.1016/0006-8993(92)90221-T10.1016/0006-8993(92)90221-TSearch in Google Scholar
[10] Ohno M., Yamamoto T., Watanabe S., Blockade of 5-HT2 receptors protects against impairment of working memory following transient forebrain ischemia in the rat, Neurosci. Letters, 1991, 129, 185–188 http://dx.doi.org/10.1016/0304-3940(91)90457-510.1016/0304-3940(91)90457-5Search in Google Scholar
[11] Back T., Prado R., Zhao W., Watson B.D., Ginsberg M.D. Ritanserin, a 5-HT2 receptor antagonist, increases subcortical blood flow following photothrombotic middle cerebral artery occlusion in rats, Neurol. Res., 1998, 20, 643–647 10.1080/01616412.1998.11740577Search in Google Scholar PubMed
[12] Takagi K., Ginsberg M.D., Globus M.Y.T., Busto R., Dietrich W.D., The effect of ritanserin, a 5-HT2 receptor antagonist, on ischemic cerebral blood flow and infarct volume in rat middle cerebral artery occlusion, Stroke, 1994, 25, 481–485 10.1161/01.STR.25.2.481Search in Google Scholar
[13] Dietrich W.D., Busto R., Ginsberg M.D., Effect of the serotonin antagonist ketanserin on the hemodynamic and morphological consequences of thrombotic infarction, J. Cereb. Blood Flow Metab., 1989, 9, 812–820 10.1038/jcbfm.1989.115Search in Google Scholar
[14] Sharkey J., Butcher S.P., Characterization of an experimental model of stroke produced by intracerebral microinjection of endothelin-1 adjacent to the rat middle cerebral artery, J. Neurosci. Meth., 1995, 60, 125–131 http://dx.doi.org/10.1016/0165-0270(95)00003-D10.1016/0165-0270(95)00003-DSearch in Google Scholar
[15] Sharkey J., Ritchie I.M., Kelly P.A.T., Perivascular microapplication of endothelin-1: a new model of focal cerebral ischaemia in the rat, J. Cereb. Blood Flow Metab., 1993, 13, 865–871 10.1038/jcbfm.1993.108Search in Google Scholar
[16] Sharkey J., Butcher S.P., Kelly J.S., Endothelin-1 induced middle cerebral artery occlusion: pathological consequences and neuroprotective effects of MK801, J. Auton. Nerv. Syst., 1994, 49, S177–S185 http://dx.doi.org/10.1016/0165-1838(94)90109-010.1016/0165-1838(94)90109-0Search in Google Scholar
[17] Biernaskie J., Corbett D., Peeling J., Wells J., Lei H., A serial MR study of cerebral blood flow changes and lesion development following endothelin-1-induced ischemia in rats, Magn. Reson. Med., 2001, 46, 827–830 http://dx.doi.org/10.1002/mrm.126310.1002/mrm.1263Search in Google Scholar PubMed
[18] Marston H.M., Faber E.S., Crawford J.H., Butcher S.P., Sharkey J., Behavioural assessment of endothelin-1 induced middle cerebral artery occlusion in the rat, Neuroreport, 1995, 6, 1067–1071 http://dx.doi.org/10.1097/00001756-199505090-0002910.1097/00001756-199505090-00029Search in Google Scholar PubMed
[19] Ward N.M., Sharkey J., Brown V.J., Assessment of sensorimotor neglect after occlusion of the middle cerebral artery in the rat, Behav. Neurosci., 1997, 111, 1133–1145 http://dx.doi.org/10.1037/0735-7044.111.5.113310.1037/0735-7044.111.5.1133Search in Google Scholar
[20] Riek-Burchardt M., Henrich-Noack P., G.A. Metz G.A., Reymann K.G., Detection of chronic sensorimotor impairments in the ladder rung walking task in rats with endothelin-1-induced mild focal ischemia, J. Neurosci. Meth., 2004, 137, 227–233 http://dx.doi.org/10.1016/j.jneumeth.2004.02.01210.1016/j.jneumeth.2004.02.012Search in Google Scholar PubMed
[21] Baldauf K., Henrich-Noack P., Reymann K.G., Detrimental effects of halothane narcosis on damage after endothelin-1-induced MCAO, J. Neurosci. Meth., 2007, 162, 14–18 http://dx.doi.org/10.1016/j.jneumeth.2006.11.01910.1016/j.jneumeth.2006.11.019Search in Google Scholar PubMed
[22] Moyanova S., Kirov R., Kortenska L., Multi-unit activity suppression and sensorimotor deficits after endothelin-1-induced middle cerebral artery occlusion in conscious rats, J. Neurol. Sci., 2003, 212, 59–67 http://dx.doi.org/10.1016/S0022-510X(03)00102-310.1016/S0022-510X(03)00102-3Search in Google Scholar
[23] Moyanova S., Kortenska L., Kirov R., Iliev I., Quantitative electroencephalographic changes due to middle cerebral artery occlusion by endothelin-1 in conscious rats, Arch. Physiol. Biochem., 1998, 106, 384–391 http://dx.doi.org/10.1076/apab.106.5.384.436210.1076/apab.106.5.384.4362Search in Google Scholar PubMed
[24] Moyanova S.G., Kortenska L.V., Mitreva R.G., Pashova V.D., Ngomba R.T., Nicoletti F., Multimodal assessment of neuroprotection applied to the use of MK-801 in the endothelin-1 model of transient focal brain ischemia, Brain Res., 2007, 1153, 58–67 http://dx.doi.org/10.1016/j.brainres.2007.03.07010.1016/j.brainres.2007.03.070Search in Google Scholar PubMed
[25] Karhunen H., Jolkkonen J., Sivenius J., Pitkanen A., Epileptogenesis after experimental focal cerebral ischemia, Neurochem. Res., 2005, 30, 1529–1542 http://dx.doi.org/10.1007/s11064-005-8831-y10.1007/s11064-005-8831-ySearch in Google Scholar PubMed
[26] STAIR (Stroke Therapy Academic Industry Roundtable). Recommendations for standards regarding preclinical neuroprotective and restorative drug development, Stroke, 1999, 30, 2752–2258 10.1161/01.STR.30.12.2752Search in Google Scholar
[27] Glennon R.A., Dukat M., Serotonin receptor subtypes, In: F.E. Bloom, D.J. Kupfer (Eds.), Psychopharmacology: The Fourth Generation of Progress, Raven Press, New York, 1995, 415–429 Search in Google Scholar
[28] Paxinos G, Watson C., The rat brain in stereotaxic coordinates. Academic Press, New York, 1997 Search in Google Scholar
[29] Bederson J.O.B., Pitts L.A.H.R., Tsuji M., Nishimura M.C., Davis R.L., Bartkowski H., Rat middle cerebral artery occlusion: evaluation of the model and development of neurologic examination, Stroke, 1986, 17, 472–476 10.1161/01.STR.17.3.472Search in Google Scholar
[30] Scremin O.U., Cerebral vascular system. In: G. Paxinos [Ed.] The Rat Nervous System, Academic Press, San Diego, 1995, 3–35 Search in Google Scholar
[31] Gramsbergen J.B., Skjøth-Rasmussen J., Rasmussen C., Lambertsen K.L., On-line monitoring of striatum glucose and lactate in the endothelin-1 rat model of transient focal cerebral ischemia using microdialysis and flow-injection analysis with biosensors, J. Neurosci. Meth., 2004, 140, 93–101 http://dx.doi.org/10.1016/j.jneumeth.2004.03.02710.1016/j.jneumeth.2004.03.027Search in Google Scholar PubMed
[32] Schmid-Elsaesser R., Hungerhuber E., Zausinger S., Baethmann A., Reulen H.-J., Combination drug therapy and mild hypothermia. A promising treatment strategy for reversible focal cerebral ischemia, Stroke, 1999, 30, 1891–1899 10.1161/01.STR.30.9.1891Search in Google Scholar PubMed
[33] Bolay H., Dalkara T., Mechanisms of motor dysfunction after transient MCA occlusion: persistent transmission failure in cortical synapses is a major determinant, Stroke, 1998, 29, 1988–1994 10.1161/01.STR.29.9.1988Search in Google Scholar PubMed
[34] Williams A.J., Lu X.-C.M., Hartings J.A., Tortella F.C., Neuroprotection assessment by topographic electroencephalographic analysis: effects of a sodium channel blocker to reduce polymorphic delta activity following ischaemic brain injury in rats, Fundam. Clin. Pharmacol., 2003, 17, 581–593 http://dx.doi.org/10.1046/j.1472-8206.2003.00183.x10.1046/j.1472-8206.2003.00183.xSearch in Google Scholar PubMed
[35] Hartings J.A., Williams A.J., Tortella F.C., Occurrence of nonconvulsive seizures, periodic lateralized epileptiform discharges and rhythmic delta activity in rat focal ischemia, Exp. Neurol., 2003, 179, 139–149 http://dx.doi.org/10.1016/S0014-4886(02)00013-410.1016/S0014-4886(02)00013-4Search in Google Scholar
[36] Burghaus L., Hilker R., Dohmen C., Bosche B., Winhuisen L., Galldiks N., Szelies B., Heiss W.-D., Early electroencephalography in acute ischemic stroke: Prediction of a malignant course?, Clin. Neurol. Neurosurg., 2007, 109, 45–49 http://dx.doi.org/10.1016/j.clineuro.2006.06.00310.1016/j.clineuro.2006.06.003Search in Google Scholar
[37] Faught E., Current role of electroencephalography in cerebral ischemia, Stroke, 1993, 24, 609–613 10.1161/01.STR.24.4.609Search in Google Scholar
[38] Windle V., Szymanska A., Granter-Button S., White C., Buist R., Peeling J., Corbett D., An analysis of four different methods of producing focal cerebral ischemia with endothelin-1 in the rat, Exp. Neurology, 2006, 201, 324–334 http://dx.doi.org/10.1016/j.expneurol.2006.04.01210.1016/j.expneurol.2006.04.012Search in Google Scholar
[39] Zilles K., Wree A., Cortex: Areal and laminar structure, In: G. Paxinos (Ed.), The Rat Nervous System, Academic Press, San Diego, 1995, 649–685 Search in Google Scholar
[40] Marek G.J., Aghajanian G.K., 5-HT2A receptor or alpha1-adrenoceptor activation induces excitatory postsynaptic currents in layer V pyramidal cells of the medial prefrontal cortex, Eur. J Pharmacol., 1999; 367, 197–206 http://dx.doi.org/10.1016/S0014-2999(98)00945-510.1016/S0014-2999(98)00945-5Search in Google Scholar
[41] McCormick D.A., Neurotransmitter actions in the thalamus and cerebral cortex and their role in neuromodulation of thalamocortical activity, Prog. Neurobiol., 1992, 39, 337–388 http://dx.doi.org/10.1016/0301-0082(92)90012-410.1016/0301-0082(92)90012-4Search in Google Scholar
[42] Dawson L.A., Galandak J., Djali S., Attenuation of ischemic efflux of endogenous amino acids by the novel 5-HT1A/5-HT2 receptor ligand adatanserin, Neurochem. Int., 2002, 40, 203–209 http://dx.doi.org/10.1016/S0197-0186(01)00082-110.1016/S0197-0186(01)00082-1Search in Google Scholar
[43] Van Hemelrijck A., Vermijlen D., Hachimi-Idrissi S., Sarre S., Ebinger G., Michotte Y., Effect of resuscitative mild hypothermia on glutamate and dopamine release, apoptosis and ischaemic brain damage in the endothelin-1 rat model for focal cerebral ischaemia, J. Neurochem., 2003, 87, 66–75 http://dx.doi.org/10.1046/j.1471-4159.2003.01977.x10.1046/j.1471-4159.2003.01977.xSearch in Google Scholar
[44] Yang B.C., Nichols W.W., Lawson D.L., Mehta J. L., 5-Hydroxytryptamine potentiates vasoconstrictor effect of endothelin-1, Am. J. Physiol., 1992, 262, H931–936 10.1152/ajpheart.1992.262.4.H931Search in Google Scholar
[45] Van Wijngaarden I., Tulp M.Th.M., Soudijn W., The concept of selectivity in 5-HT receptor research, Eur. J. Pharmacol., 1990, 188, 301–312 http://dx.doi.org/10.1016/0922-4106(90)90190-910.1016/0922-4106(90)90190-9Search in Google Scholar
[46] Orallo F., Rosa E., Garcia-Ferreiro T., Campos-Toimil M., Cadavid M.I., Loza M.I., Cardiovascular effects of ketanserin on normotensive rats in vivo and in vitro, Gen. Pharmacol., 2000, 35, 95–105 10.1016/S0306-3623(01)00099-4Search in Google Scholar
[47] Centurion D., Mehotra S., Sánchez-López A., Gupta S., MaassenVanDenBrink A., Villalón C.M., Potential vascular α1-adrenoceptor blocking properties of an array of 5-HT receptor ligands in the rat, Eur. J. Pharmacol., 2006, 535, 234–242 http://dx.doi.org/10.1016/j.ejphar.2006.02.01010.1016/j.ejphar.2006.02.010Search in Google Scholar PubMed
[48] Marwood J.F., Influence of alpha 1-adrenoceptor antagonism of ketanserin on the nature of its 5-HT2 receptor antagonism, Clin. Exp. Pharmacol. Physiol., 1994, 21, 955–961 http://dx.doi.org/10.1111/j.1440-1681.1994.tb02657.x10.1111/j.1440-1681.1994.tb02657.xSearch in Google Scholar PubMed
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