Protection of both grey and white matter is important for improvement in stroke outcome. In the present study the ability of a competitive alpha-amino-3-hydroxy-5-methyl-4-isoxazole propionic acid (AMPA) antagonist to protect axons, oligodendrocytes, and neuronal perikarya, was examined in a rodent model of transient focal cerebral ischemia. SPD 502 (8-methyl-5-(4-( -dimethylsulfamoyl)phenyl)-6,7,8,9-tetrahydro-1H-pyrrolo[3,2h]-isoquinoline-2,3-dione-3-o(4-hydroxybutyricacid-2-yl)oxime) was administered as an intravenous bolus (16 mg/kg) 15 minutes before transient (3-hour) middle cerebral artery (MCA) occlusion, followed by an intravenous infusion (16 mg kg(-1) hr(-1)) of the drug for 4 hours. Twenty-one hours after ischemia, axonal damage was reduced by 45% (P = 0.006) in the SPD 502-treated group compared with the vehicle. The anatomic extent of ischemically damaged oligodendrocytes, determined by Tau1 immunoreactivity, was reduced in the cerebral cortex by 53% (P = 0.024) in SPD 502-treated rats compared with vehicle-treated rats, but there was minimal effect in the subcortex. The volume of neuronal perikaryal damage after MCA occlusion was significantly reduced by SPD 502 in the cerebral cortex (by 68%; P = 0.005), but there was minimal change in the subcortex with drug treatment. The AMPA receptor antagonist significantly reduced the anatomic extent of lipid peroxidation (assessed as the volume of 4-hydroxynonenol immunoreactivity), and this may have contributed to its ability to protect multiple cell types in ischemia. The data demonstrate that AMPA blockade protects both grey and white matter from damage induced by transient focal ischemia.

Angiotensin-converting enzyme (ACE) inhibitors are important agents in blood pressure (BP) management. It was recently shown that the egg-protein hydrolysate NWT-03 inhibited ACE in Zucker diabetic fatty rats. We therefore designed a dose-finding study to assess the effects of 1, 2 and 5 g NWT-03 on daytime, 36-h, and night-time systolic and diastolic BP (SBP and DBP) in ninety-two generally healthy subjects with normal BP (n 29), high-normal BP (n 34) or mild hypertension (n 29). The study had a cross-over design with six treatment arms (1 g NWT-03 or placebo in period 1 and placebo or 1 g NWT-03 in period 2, 2 g NTW-03 or placebo in period 1 and placebo or 2 g NWT-03 in period 2, or 5 g NTW-03 or placebo in period 1 and placebo or 5 g NTW-03 in period 2). A comparable number of subjects from each BP class were included in each study arm. Duration of both treatments in each arm was 7 d, separated by 5-d wash-out periods. BP was measured with an ambulatory BP monitor before and after the treatments. In mild-hypertensive subjects, 2 g NWT-03 significantly decreased daytime SBP (7·9 mmHg; P = 0·006), daytime DBP (4·2 mmHg; P = 0·009), 36-h SBP (6·9 mmHg; P = 0·015) and 36-h DBP (3·5 mmHg; P = 0·035) compared with placebo subjects. In addition, in mild-hypertensive subjects, 5 g NWT-03 significantly decreased night-time SBP (14·8 mmHg; P = 0·008) and night-time DBP (8·4 mmHg; P = 0·020) compared with that in placebo subjects. To conclude, we found that 2 g NWT-03 lowered daytime and 36-h BP in subjects with mild hypertension, and 5 g NWT-03 lowered night-time BP in subjects with mild hypertension. As no doseresponse relationship was evident, these results should be interpreted with care, and additional studies are needed.