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Recent findings suggest a key role for platelet activating factor in neuroinjury. For this reason we evaluated the effects of the platelet activating factor antagonist apafant (4-(2-chlorophenyl)-9-methyl-2[3(4-morpholinyl)-3-propanol-1- yl[6H-thieno[3.2-f[[1.2.4]triazolo]4,3-1]]1.4]diazepine on farct volume and local cerebral blood flow following irreversible occlusion of the left middle cerebral artery in rats to assess the direct and vascular components of apafant's action. We measured infarct volume 48 hours after middle cerebral artery occlusion. The effect of multiple doses of apafant (30 mg/kg p.o.) was tested in both pretreatment (n = 8) and posttreatment (n = 8) groups. In the pretreatment group apafant was given 30 minutes before and 2, 6, and 18 hours after occlusion. Rats of the posttreatment group received apafant 1, 6, and 18 hours after middle cerebral artery occlusion. We also examined the effect of a single dose of apafant given 30 minutes prior to occlusion (n = 9) on local cerebral blood flow determined 2 hours after middle cerebral artery occlusion. Both regimens of apafant effectively decreased infarct volume. The reduction in cortical infarct volume was 59% (p less than 0.01; H test, U test) when the rats were treated before and after vessel occlusion whereas the decrease was 47% (p less than 0.05; H test, U test) when treatment began 1 hour after occlusion. Apafant did not change local cerebral blood flow after occlusion compared with controls. We suggest that the cytoprotection afforded by apafant occurs mainly via a direct effect on brain tissue and has no major vascular component.

The objective of this study was to determine the effect of nimodipine on infarct development and local brain pH after middle cerebral artery occlusion in the rat. Female Fischer-344 rats were subjected to permanent occlusion of the left middle cerebral artery by electrocoagulation. After 6, 12, or 24 hours, brains were frozen, and infarct size, degree of edema formation, and local brain pH were quantified by standard histology or the umbelliferone technique, respectively. In control rats, cortical infarct size was increased from 29.5 microliters at 6 hours to 72.5 microliters at 24 hours after vessel occlusion. In striatum only, an insignificant increase from 15.2 to 24.7 microliters in infarct volume was observed during this period. Edema increased from 7% to 22% in cortical and from 4% to 39% in the striatal infarct areas during this time. Nimodipine (0.1 mg/kg s.c.), given 45 minutes before and again 8 and 16 hours after middle cerebral artery occlusion, did not alter infarct size at 6 hours but considerably improved outcome at later times. Edema formation was lower at 12 hours in the group treated with the calcium antagonist (p less than 0.05). By contrast, effects on local brain pH were seen as early as 6 hours after the vessel occlusion. Nimodipine greatly reduced the areas exhibiting the lowest pH values beyond pH 6.0 (p less than 0.05). Similar effects by nimodipine on brain pH were observed in the 12-hour series, whereas at 24 hours after middle cerebral artery occlusion, a shift to more alkalotic values was noted with no overt differences between control and drug-treated groups.(ABSTRACT TRUNCATED AT 250 WORDS)

We conducted the present study to investigate the effects of 5-hydroxytryptamine agonists on brain morphology after the induction of focal cerebral ischemia by permanent occlusion of the left middle cerebral artery in rats and mice. Forty-eight hours after vessel occlusion, the damage was quantified in rats by planimetry and subsequent integration on cresyl violet-stained serial sections and in mice by planimetric analysis of the damaged cortical surface after counterstaining with carbon black. All 5-HT1A agonists investigated substantially decreased cortical infarct size in the rat focal ischemia model (p less than 0.05). Drugs were applied 30 minutes before the induction of ischemia, and efficacy was demonstrated for 8-OH-DPAT (1 mg/kg s.c.), buspirone (10 mg/kg i.p.), gepirone (10 mg/kg i.p.), ipsapirone (10 or 30 mg/kg i.p.), and Bay R 1531 (1 mg/kg i.p.). The most pronounced effects were seen with the higher dose of ipsapirone and Bay R 1531, both compounds reducing cortical infarct size by more than 60%. Except for 8-OH-DPAT, the 5-HT1A agonists also caused a reduction in total infarct volumes. In a separate series, ipsapirone (30 mg/kg i.p.), applied 1 hour after vessel occlusion, led to a reduction in cortical and total infarct volumes by about 50% compared with corresponding controls (p less than 0.05). In neither series was striatal damage influenced. We tested the compounds in the mouse ischemia model over a broad dose range.(ABSTRACT TRUNCATED AT 250 WORDS)

The present study investigates the effects of the 5-hydroxytryptamine1A agonist ipsapirone on electroencephalography and somatosensory evoked potentials after middle cerebral artery occlusion in the rat. We implanted 17 silver ball electrodes symmetrically distributed over the skull in 14 rats and registered electroencephalography activity and somatosensory evoked potentials before, 1 hour, and 1 week after permanent occlusion of the left middle cerebral artery. Before vessel occlusion, a symmetric distribution of electroencephalography power was seen over both hemispheres. Middle cerebral artery occlusion caused a complete abolishment of electroencephalography power in the frontolateral aspects of the affected hemisphere. When electroencephalographic recordings 7 days after the insult were superimposed with three-dimensional-reconstructed pictures of the infarct, a close correspondence of the extention and spatial orientation was noted. Two negative and two positive peaks were consistently recorded before middle cerebral artery occlusion. In both control and ipsapirone-treated (30 mg/kg i.p. 30 minutes after induction of ischemia) animals, the vessel occlusion caused a severe reduction in amplitudes of somatosensory evoked potentials in all areas under record (p less than 0.05). One week after middle cerebral artery occlusion, amplitudes of somatosensory potentials over the lesioned hemisphere were still significantly (p less than 0.05) lower than preischemic values in the control group. When compared with the corresponding values 1 hour after middle cerebral artery occlusion, an albeit insignificant tendency toward increased amplitudes was observed in most areas under record. By contrast, in ipsapirone-treated animals, significant differences compared with preischemic values were no longer present 1 week after the vessel occlusion.(ABSTRACT TRUNCATED AT 250 WORDS)