The pharmacotherapy of focal cortical ischaemia in the mouse

The measurement of cortical omega 3 (peripheral-type benzodiazepine binding) site densities provides an accurate index for the detection and quantification of ischaemic brain lesions following middle cerebral artery occlusion (MCAO) in mice. Here, we have used this marker to assess the neuroprotective activity of potential anti-ischaemic drugs belonging to several chemical classes. In untreated mice, the mean infarcted volume measured 96 h after unilateral coagulation of the middle cerebral artery was 27.9 +/- 4.3 mm3 (17.5% of the hemisphere volume) and omega 3 site densities (measured by incubation with 3H-PK 11195) were increased by 107.3 +/- 4.8% (cortical homogenates) or by 81% (coronal brain sections). The administration of the anti-ischaemic agent SL 82.0715 (10 mg/kg i.p.), 5 min, 6 h and 18 h after the occlusion and then twice daily until sacrifice evoked a decrease of similar magnitude (ca. 60-70%) in the volume of the infarction and in the proliferation of omega 3 sites. The constant tissue sparing effect of SL 82.0715 allowed the examination of the window of therapeutic opportunity. A significant diminution of cortical omega 3 sites was still noted when the first administration was delayed until 3 h post-occlusion. Moreover, the protective effect of SL 82.0715 was enhanced by repeated treatment for the first 36 h but not thereafter. Based on the histological, autoradiographic and homogenate binding results obtained with SL 82.0715, we studied the protective effects of several competitive and non-competitive NMDA receptor antagonists. When administered according to the above-described standard protocol, these drugs reduced omega 3 site levels in cortical homogenates from MCAO mice in a dose-dependent manner. The dose preventing by 50% the increase in omega 3 site levels (in mg/kg i.p.) and the maximal inhibition were respectively: MK-801 (0.2, 93%); TCP (1.6, 66%); kynurenate (260, 58%); ifenprodil (7.0, 58%); SL 82.0715 (1.1, 72%); CGS 19755 (46% at 10 mg/kg); dextromethorphan (46% at 30 mg/kg). In contrast, agents acting preferentially upon sigma (sigma) opiate receptors ((+)-3PPP, 1-10 mg/kg i.p. and haloperidol, 0.3-3 mg/kg i.p.) did not provide a significant protection. In general, calcium channel blockers (nimodipine, flunarizine, verapamil, perhexiline, diltiazem) were devoid of a clear neuroprotective potential when administered at non-toxic doses after the coagulation of the middle cerebral artery. Diltiazem (3 and 10 mg/kg i.p.) provided a significant protection when the first administration was performed 10 min prior to the occlusion. Limited protection was observed with adenosine A1 receptor agonists (N6-cyclohexyladenosine and 2-chloro-adenosine).(ABSTRACT TRUNCATED AT 400 WORDS)