Abstract
We aimed to examine whether thalidomide might inhibit the neuronal damage resulting from focal cerebral ischemia, and if so to explore the neuroprotective mechanism. Focal cerebral ischemia was induced by permanent middle cerebral artery occlusion (MCAO) in mice, and thalidomide was intraperitoneally administered a total of three times (at 10 min before, just before, and 1 h after MCAO). Thalidomide significantly reduced (a) the infarct area and volume at 24 and 72 h after MCAO and (b) the neurological score at 72 h after MCAO. Brains were also histochemically assessed for apoptosis and lipid peroxidation using terminal deoxynucleotidyl transferase-mediated dUTP nick end-labeling (TUNEL) staining and an antibody recognizing 8-hydroxy-2'-deoxyguanosine (8-OHdG), respectively. Thalidomide reduced both the number of TUNEL-positive cells and the oxidative damage. However, post-treatment of thalidomide [20 mg/kg, three times (at just after, 1 h after, 3 h after MCAO)] did not reduce the infarct volume. In an in vitro study, we examined the effects of thalidomide on lipid peroxidation in mouse brain homogenates and on the production of various radical species. Thalidomide inhibited both the lipid peroxidation and the production of H(2)O(2) and O(2).(-) (but not HO(-)) radicals. We also measured the brain concentration of TNF-alpha by ELISA. The TNF-alpha level in the brain was significantly increased at 9-24 h after MCAO. However, thalidomide did not reduce the elevated TNF-alpha level at either 12 or 24 h after MCAO. These findings indicate that thalidomide has neuroprotective effects against ischemic neuronal damage in mice, and that an inhibitory action of thalidomide against oxidative stress may be partly responsible for these neuroprotective effects.