1 The ecacy of the free radical trapping agent NXY-059 in reducing the infarct volume following both transient and permanent focal ischaemia has been examined in rats. 2 In the transient ischaemia model, rats were subjected to a 2 h occlusion of the middle cerebral artery (MCA). Intravenous infusion of NXY-059 (1, 10 and 30 mg kg 71 h) for 21.75 h starting 2.25 h after the occlusion, produced a dose-dependent decrease in both neurological impairment and the histologically measured infarct volume (a mean 59% decrease at 10 mg kg 71 h). 3 In the permanent ischaemia model, animals were injected (s.c.) with a loading dose of NXY-059 of 32.5, 53.8 or 75.4 mg kg 71 and osmotic minipumps were implanted which had been primed to deliver respectively 30, 50 or 70 mg kg 71 h. When treatment was initiated 5 min after MCA occlusion there was a dose dependent protection of both cortical and sub-cortical tissue (cortex: 63% at the mid-range dose). Protection was related linearly to plasma concentration (plasma unbound NXY-059 concentration at 1 h: 37+16 mmol l 71 at the mid-range dose). 4 When the mid range dose was administered between 5 min ± 4 h after MCA occlusion, a marked and statistically signi®cant protection was seen at all time points (44% protection in cortex at 4 h). 5 These data demonstrate the substantial neuroprotective ecacy of NXY-059 at plasma concentrations that can be achieved clinically and indicate that NXY-059 also has a therapeutic window of opportunity that is clinically relevant.

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1 The effect of chlormethiazole has been studied in a transient middle cerebral artery (MCA) occlusion model of cerebral ischaemia in the rat. The MCA was occluded for 1 h by use of an intraluminal suture technique, with reperfusion for 24 h following removal of the occluding filament. Neuronal damage was determined by measurement of the area of necrosis following Cresyl Violet staining of sections taken through the ischaemic region. 2 In the initial experiment, occlusion of the MCA produced a large volume of ischaemic damage in both cortex and striatum, characterized by necrosis and pyknosis (total volume of damage, 287 + 13 mm3; n = 9). Rats injected with chlormethiazole (1000 Jmol kg-', i.p.) 60 min before occlusion had a reduced volume of damage in both regions (104 ± 11 mm3; n = 9; P <0.001). 3 In a subsequent study systemic physiological parameters (heart rate, blood pressure, blood pH, blood gases and rectal temperature) were measured throughout the ischaemic period. 4 Chlormethiazole (1 000 mol kg-') pretreatment produced little change in systemic physiology and the neuroprotective effect of the drug when given 60 min prior to the MCA occlusion was confirmed. Chlormethiazole was also neuroprotective when given 10 min following the start of reperfusion (control group: 244 ± 52mm3, n = 10; chlormethiazole pretreatment group: 102 ± 23 mm3, n = 10; P<0.001; chlormethiazole post-ischaemia group: 122 ± 16 mm3; P < 0.001, n = 10). 5 It is concluded that chlormethiazole is an effective neuroprotective agent in this model of transient focal ischaemia. The observation that chlormethiazole is protective when given after reperfusion indicates that the effect of the drug is unlikely to be due to an alteration of intra-ischaemic cerebral blood flow, but is more probably a direct effect on the development of ischaemic damage.

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