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Lack of efficacy of 5‐HT 2A receptor antagonists to reduce brain damage after 3 minutes of transient global cerebral ischaemia in gerbils
Author(s) -
Piera MJ,
Beaughard M.,
Michelin MT,
Winslow E.,
Massingham R.
Publication year - 1995
Publication title -
fundamental and clinical pharmacology
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.655
H-Index - 73
eISSN - 1472-8206
pISSN - 0767-3981
DOI - 10.1111/j.1472-8206.1995.tb00534.x
Subject(s) - cerebral ischaemia , ischemia , 5 ht receptor , transient (computer programming) , medicine , anesthesia , serotonin , receptor , cardiology , computer science , operating system
Summary— Stimulation of the 5‐HT 2A receptors by serotonin has been reported to exert an excitatory effect on neocortical neurons in rats and mice, to facilitate ischaemia‐induced release of excitatory amino acids and to mediate the vasomotor constrictor component of the response of blood vessels to 5‐HT. 5‐HT 2A receptor antagonists have, therefore, been proposed as potential protectants against the effects of cerebral ischaemia. The aim of this study was to evaluate the effects of two relatively selective 5‐HT 2A receptor antagonists, ketanserin and ritanserin, on delayed hyperactivity and the ensuing neuronal degeneration induced by 3 minutes of bilateral carotid artery ligation in Mongolian gerbils. Effects were compared to that of flunarizine, which blocks calcium overload and served as a positive control in this paradigm. Temporal and/or rectal temperatures were measured and strictly controlled during the ischaemia and the early reperfusion phase. Locomotor activity was measured one day after the ischaemia and neuronal degeneration quantified 7 days later using an image analysis system (Quantimet 570, Leica). Global ischaemia in gerbils elicits hyperactivity associated with a delayed neuronal degeneration predominantly in the CA1 zone of the hippocampus. Ketanserin and ritanserin (3 and 10 mg/kg ip, twice daily for 3 days, pre‐ and postischaemia) did not protect the CA1 neurons against ischaemic damage. The postischaemic hyperactivity was inhibited only with the higher dose of ketanserin. As previously reported, flunarizine (30 mg/kg po ) markedly reduced neuronal degeneration (‐44.2%, p < 0.01) and totally abolished the ischaemia‐induced hyperactivity. These data demonstrate that ketanserin and ritanserin are not effective protectants of the gerbil hippocampus against ischaemic damage when the body temperature of the animals is controlled, thus suggesting that 5‐HT 2A receptors are not directly implicated in the pathogenesis of global cerebral ischaemia in this model.