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

Abstract

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.

Antiplatelet Therapy in Acute Cerebral Ischemia

“…20 Although it is now well established that antiplatelet monotherapy using either aspirin 20,21 or adenosine receptor antagonists such as ticlopidine 21 is clearly efficacious in reducing neurological sequelae/recurrent events following a TIA or stroke, the examination of antiplatelet agents as monotherapy for the treatment of acute cerebral ischemia has received little attention either clinically 4 or experimentally. [22][23][24][25][26] In contrast to the clinical treatment of strokes (acute and subacute), which has focused primarily on aspirin therapy, antiplatelet therapies for animal models of acute cerebral ischemia have generally focused on either (1) very specific alterations of the AA cascade, attempting to either increase levels of the vasodilator/platelet inhibitor prostacyclin (PGI 2 ) 22 or reducing the level/activity of the vasoconstrictor/platelet proaggregant thromboxane A 2 (TXA 2 ) 23,24 or (2) serotonin (5-HT 2 ) receptor antagonism. 25,26 These therapies have produced variable results.…”

“…[22][23][24][25][26] In contrast to the clinical treatment of strokes (acute and subacute), which has focused primarily on aspirin therapy, antiplatelet therapies for animal models of acute cerebral ischemia have generally focused on either (1) very specific alterations of the AA cascade, attempting to either increase levels of the vasodilator/platelet inhibitor prostacyclin (PGI 2 ) 22 or reducing the level/activity of the vasoconstrictor/platelet proaggregant thromboxane A 2 (TXA 2 ) 23,24 or (2) serotonin (5-HT 2 ) receptor antagonism. 25,26 These therapies have produced variable results. It is also of interest that several studies employing the prophylactic use of aspirin for stroke prevention in "low-risk" patients have reported either no benefit or an increase in stroke incidence.…”

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

“…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.…”

“…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]. Importantly, animal models of focal transient ischemia are the most relevant to the pathophysiology of human stroke, since reperfusion frequently occurs after stroke as a result of recanalization.…”

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

“…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).…”