Neuroprotective efficacy of ebselen, an anti-oxidant with anti-inflammatory actions, in a rodent model of permanent middle cerebral artery occlusion.
1. The aim of this study was to investigate whether delayed treatment with the anti-oxidant and anti-inflammatory agent ebselen reduces the volume of infarction in a rodent model of permanent focal cerebral ischaemia. 2. Ebselen (10 or 30 mg kg-1) or vehicle was administered by gavage 30 min and 12 h after the induction of cerebral ischaemia by permanent occlusion of the left middle cerebral artery (MCA). Animals were killed 24 h following MCA occlusion, and the volumes of ischaemic damage in the ebselen and control groups were evaluated by quantitative histopathology. 3. Ebselen was quickly absorbed following oral (gavage) administration and reached peak levels in the plasma by 1 h post-administration (plasma selenium level of 0.68 +/- 0.04 and 0.84 +/- 0.1 microgram ml-1 for 10 and 30 mg kg-1, respectively, compared to control level of 0.51 +/- 0.02 microgram kg-1). 4. Treatment with the lower dose of ebselen (10 mg kg-1) significantly (P < 0.01) reduced the volume of infarction in the cerebral hemisphere and cerebral cortex (by 31.8% and 36.7%, respectively compared with the placebo group). 5. The neuroprotective efficacy of the higher dose ebselen (30 mg kg-1) was less than that of the lower dose ebselen (10 mg kg-1). The volume of ischaemic damage in the cerebral hemisphere was reduced by 23.7% (P < 0.02), and cerebral cortex by 27.5% (P < 0.01). 6. Both doses of ebselen (10, 30 mg kg-1) had no therapeutic efficacy on the caudate nucleus, where ischaemia was most severe, in this model. 7. Free radical-mediated injury is normally associated with reperfusion of ischaemic tissue. The present results suggest that oxidative injury is also a significant contributor to brain damage in models of maintained (permanent) ischaemia and that ebselen is effective in attenuating this free radical-induced damage.
Takasago
T
T
Wellcome Surgical Institute & Hugh Fraser Neuroscience Labs., University of Glasgow.
Peters
E E
EE
Graham
D I
DI
Masayasu
H
H
Macrae
I M
IM
D000818:Animals; D000894:Anti-Inflammatory Agents, Non-Steroidal / Q000627:therapeutic use*; D000975:Antioxidants / Q000627:therapeutic use*; D001393:Azoles / Q000627:therapeutic use*; D002545:Brain Ischemia / Q000188:drug therapy*; D004195:Disease Models, Animal; D054833:Isoindoles; D008297:Male; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D016566:Organoselenium Compounds / Q000627:therapeutic use*; D051381:Rats; D011916:Rats, Inbred F344
D000894:Anti-Inflammatory Agents, Non-Steroidal; D000975:Antioxidants; D001393:Azoles; D054833:Isoindoles; D018696:Neuroprotective Agents; D016566:Organoselenium Compounds; C042986:ebselen