We have examined the significance of the serotonergic system in the pathophysiology of ischemic brain damage. Permanent occlusion of the middle cerebral artery (MCA) was performed in male NMRI mice. After 48 h, the animals received a transcardiac injection of
carbon black. The area of
ischemia was restricted to the neocortex and its size was determined planimetrically by means of an image analyzing system. In control experiments, the
NMDA antagonist
dizocilpine (MK-801), the
AMPA/
kainate antagonist
NBQX (2,3-dihydroxy-6-nitro-7-sulfamoylbenzo(F)-quinoxaline) and the
L-type calcium channel blocker
nimodipine all produced a significant reduction in ischemic injury of the mouse neocortex. Interestingly, all of the 5-HT1A agonists tested (
ipsapirone,
CM 57493 [4-(3-trifluoromethylphenyl)-1-(2-cyanoethyl)-1,2,3,6-
tetrahydropyridine ] and
urapidil) were equally efficacious in reducing ischemic injury. On the other hand, the
5-HT2 antagonist naftidrofuryl failed to protect the brain tissue significantly against ischemic brain damage.
Roxindole, a
5-HT1A agonist and
5-HT uptake inhibitor, was the most potent serotonergic compound tested. In order to examine the effects of
5-HT1A receptor activation in a different context, 10 min of forebrain
ischemia was induced in male Wistar rats by a bilateral occlusion of the common carotid arteries combined with systemic
hypotension. Administration of the
5-HT1A agonist CM 57493 reduced the neuronal damage within the ventral hippocampus and the entorhinal cortex as assessed histologically 7 days after
ischemia. Finally, we found that 5-HT1A agonists are capable of reducing neuronal damage of cultured neocortical and hippocampal neurons subjected to a chemical
hypoxia or
glutamate in a dose dependent manner. These data suggest that
5-HT, released during
ischemia, may have protective effects in the pathophysiology of ischemic brain damage through a direct action on neurons mediated via the inhibitory
5-HT1A receptor subtype. The results obtained from different in vivo and in vitro models indicate that 5-HT1A agonists are promising agents for the treatment of ischemic
brain disorders.