Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats.

Globus, Mordecai Y.‐T.; Wester, Per; Busto, Raul; Dietrich, W. Dalton

doi:10.1161/01.str.23.11.1595

Cited by 69 publications

(31 citation statements)

References 56 publications

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“…Given that serotonin plays a pathological role in a number of low blood flow conditions [2][3][4], the properties of some serotoninergic receptor agonists and antagonists as putative neuroprotectants have been explored. The antagonists of 5-HT 2 receptors such as ritanserin, ketanserin and mianserin were shown to reduce the volume of the brain infarct, to improve behavioral performance, or to have beneficial effects on the local cerebral blood flow in models of global and forebrain ischemia and in models of permanent focal ischemia in rats and gerbils [7][8][9][10][11][12][13]. However, data about the effects of the 5-HT 2 receptor antagonists in models of transient focal ischemia are lacking.…”

Section: Discussionmentioning

confidence: 99%

“…However, data for their use as neuroprotective drugs in human acute cerebrovascular disorders are lacking. 5-HT 2 receptor antagonists have been shown to have neuroprotective properties in models of global and forebrain transient ischemia [7][8][9][10]. However, in models of focal ischemia, the data about their effects are not sufficient (obtained only in models of permanent focal ischemia) and contradictory [11][12][13].…”

Section: Introductionmentioning

confidence: 99%

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Ketanserin reduces the postischemic EEG and behavioural changes following Endothelin-1-induced occlusion of the middle cerebral artery in conscious rats

et al. 2008

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AbstractWe 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.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Ketanserin reduces the postischemic EEG and behavioural changes following Endothelin-1-induced occlusion of the middle cerebral artery in conscious rats

et al. 2008

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“…3134 Furthermore, serotonergic denervation partially protects the striatum from kainic acid-mediated damage. 26 In a previous report from our laboratory, Globus et al 23 reported the involvement of serotonin in ischemic neuronal dam-age in the setting of transient global forebrain ischemia. Therefore, it is possible that a selective 5-HT 2 receptor antagonist might have a protective effect against ischemic damage in focal ischemia.…”

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confidence: 91%

“…Previous studies from our laboratory have examined the effects of preischemic administration of 5-HT 2 antagonist on ischemic outcome. 23 In this study, ritanserin was administered after middle cerebral artery occlusion, and systemic blood pressure and cerebral blood flow (CBF) were measured during the ischemic period.…”

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The effect of ritanserin, a 5-HT2 receptor antagonist, on ischemic cerebral blood flow and infarct volume in rat middle cerebral artery occlusion.

Takagi

Ginsberg

Globus

et al. 1994

Stroke

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Background and PurposeIn a previous study from our laboratory, ritanserin, a specific 5-HT 2 serotonin receptor antagonist, reduced ischemic damage in the setting of transient global ischemia. In this study, we examined the effect of ritanserin on ischemic cerebral blood flow, systemic blood pressure, and infarct volume in the model of permanent focal ischemia with brain temperature controlled at 35.0°C to 36.0°C.Methods Thirty-seven male Sprague-Dawley rats were used. The right middle cerebral artery was permanently occluded. Ritanserin (8 mg/kg) or vehicle was continuously administered intravenously for 90 minutes starting 10 minutes after middle cerebral artery occlusion. Cerebral blood flow was monitored by laser Doppler flowmetry in the ischemic cortex before and for 2 hours after arterial occlusion. Brains were perfusion-fixed 3 days later, and infarct volumes were measured.

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“…Excessive release of glutamate is believed to play an important role in the development of the neuronal damage. However, it has also been shown that extracellular serotonin level is increased in hippocampus during cerebral ischaemia (Globus et al 1992). Several studies have shown the possibility of protecting neurones from ischaemic damage by stimulation or inhibition of different serotonergic receptors.…”

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Is the 5‐HT_2C Receptor a Therapeutic Target in Cerebral Ischaemia?

Torup¹,

Diemer²

2000

Pharmacology & Toxicology

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This study examines the effect of a 5-HT 2C agonist (RO 60-0175, (s)-2-(chloro-5-fluoro-indol-1-yl)-1-methylethylamine) and a 5-HT 2C antagonist (RO 43-0440, benzofuran-2-carboxamidine) for neuroprotective activity in a rat model of global cerebral ischaemia. A mini-osmotic pump implanted subcutaneously delivered 0.25 mg/kg/hr. Seven days after ischaemia the rats were sacrificed and the damage in the CA1 pyramidal cell layer in hippocampus was estimated and the treated groups were compared with vehicle groups. Pretreatment with the 5-HT 2C agonist RO 60-0175 significantly increased the damage, whereas the 5-HT 2C antagonist RO 43-0440 had no effect on the cell damage. Measurement of the core temperature in a RO 60-0175-treated group of rats revealed no effect compared to a vehicle-treated group. Thus the aggravation of damage in the RO 60-0175-treated group cannot be explained by temperature effect. Our data do not indicate the 5-HT 2C receptor as a therapeutic target in cerebral ischaemia.Transient global cerebral ischaemia causes delayed neuronal damage in specific brain areas. Most prominent is the damage in the CA1 pyramidal cells in hippocampus occurring after 2-4 days. Excessive release of glutamate is believed to play an important role in the development of the neuronal damage. However, it has also been shown that extracellular serotonin level is increased in hippocampus during cerebral ischaemia (Globus et al. 1992). Several studies have shown the possibility of protecting neurones from ischaemic damage by stimulation or inhibition of different serotonergic receptors. The serotonin (5-HT) receptors can be divided into seven subfamilies, 5-HT 1 through 5-HT 7 . Both 5-HT 1A agonists and 5-HT 2A antagonists have been shown to have neuroprotective properties (Nakayama et al. 1988; Bielenberg & Burkhardt 1990;Block et al. 1990;Bode-Greuel et al. 1990;Prehn et al. 1991;Klisch & Bode-Greuel 1992;Prehn et al. 1993;Takagi et al. 1994;Piera et al. 1995). Inhibition of the serotonin transporter has been shown to protect against neuronal damage in rodent models of cerebral ischaemia (Nakata et al. 1992). On the other hand, a lesion of the serotonergic system with 5,7-dihydroxytryptamine aggravates the ischaemic damage (Nakata et al. 1997). Serotonin receptor stimulation has been found to be able to inhibit glutamate receptor activation (Maura et al. 1988). Marcoli et al. (1997) suggested that the 5-HT 2C receptor could mediate inhibition of cGMP response elicited by Nmethyl-D-aspartate (NMDA). As a member of the 5-HT 2 family, the 5-HT 2C receptor is coupled to the phosphoinositide hydrolysis pathway. 5-HT 2C receptors (formerly desig- Materials and MethodsIschaemia. Male wistar rats (Møllegaard Breeding Center, Denmark) weighing 300-320 g were subjected to transient forebrain ischaemia using a modified 4-vessel occlusion model (Pulsinelli & Brierley 1979; Jørgensen & Diemer 1982). The surgical procedure was carried out over two days. On the first day the vertebral arteries were electrocauterized under ...

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Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats.

Cited by 69 publications

References 56 publications

Ketanserin reduces the postischemic EEG and behavioural changes following Endothelin-1-induced occlusion of the middle cerebral artery in conscious rats

Ketanserin reduces the postischemic EEG and behavioural changes following Endothelin-1-induced occlusion of the middle cerebral artery in conscious rats

The effect of ritanserin, a 5-HT2 receptor antagonist, on ischemic cerebral blood flow and infarct volume in rat middle cerebral artery occlusion.

Is the 5‐HT_2C Receptor a Therapeutic Target in Cerebral Ischaemia?

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Ischemia-induced extracellular release of serotonin plays a role in CA1 neuronal cell death in rats.

Cited by 69 publications

References 56 publications

Ketanserin reduces the postischemic EEG and behavioural changes following Endothelin-1-induced occlusion of the middle cerebral artery in conscious rats

Ketanserin reduces the postischemic EEG and behavioural changes following Endothelin-1-induced occlusion of the middle cerebral artery in conscious rats

The effect of ritanserin, a 5-HT2 receptor antagonist, on ischemic cerebral blood flow and infarct volume in rat middle cerebral artery occlusion.

Is the 5‐HT2C Receptor a Therapeutic Target in Cerebral Ischaemia?

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Is the 5‐HT_2C Receptor a Therapeutic Target in Cerebral Ischaemia?