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Published on: July 25, 2011
Thalidomide protects against ischemic neuronal damage induced by focal cerebral ischemia in mice
K Hyakkoku1, Y Nakajima, H Izuta
1Department of Biofunctional Evaluation, Molecular Pharmacology, Gifu Pharmaceutical University, 5-6-1 Mitahora-higashi, Gifu 502-8585, Japan.
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.
Insights
Thalidomide demonstrates neuroprotective effects against stroke-induced neuronal damage in mice by reducing infarct size and improving neurological scores. Its mechanism involves inhibiting oxidative stress, though it does not affect TNF-alpha levels.
Area of Science:
- Neuroscience
- Pharmacology
- Ischemic Stroke Research
Background:
- Focal cerebral ischemia, commonly induced by middle cerebral artery occlusion (MCAO), leads to significant neuronal damage.
- Understanding neuroprotective agents and their mechanisms is crucial for developing stroke treatments.
Purpose of the Study:
- To investigate the neuroprotective potential of thalidomide against focal cerebral ischemia in a mouse model.
- To elucidate the underlying neuroprotective mechanisms of thalidomide, focusing on oxidative stress and inflammation.
Main Methods:
- Focal cerebral ischemia was induced in mice via permanent middle cerebral artery occlusion (MCAO).
- Thalidomide was administered intraperitoneally at various time points relative to MCAO.
- Neuroprotection was assessed by measuring infarct area/volume, neurological scores, apoptosis (TUNEL staining), and lipid peroxidation (8-OHdG).
- In vitro studies evaluated thalidomide's effects on lipid peroxidation and radical species production in brain homogenates.
- Tumor necrosis factor-alpha (TNF-alpha) levels were measured using ELISA.
Main Results:
- Thalidomide significantly reduced infarct area and volume, and improved neurological scores at 72 hours post-MCAO.
- Thalidomide decreased apoptosis and lipid peroxidation in the ischemic brain tissue.
- Post-treatment with thalidomide did not reduce infarct volume, suggesting a critical window for its efficacy.
- In vitro, thalidomide inhibited lipid peroxidation and the production of hydrogen peroxide and superoxide radicals.
- Thalidomide did not significantly alter the elevated TNF-alpha levels in the brain after MCAO.
Conclusions:
- Thalidomide exhibits significant neuroprotective effects in a mouse model of focal cerebral ischemia.
- The neuroprotective action of thalidomide appears to be partly mediated by its ability to inhibit oxidative stress.
- These findings suggest thalidomide's potential as a therapeutic agent for ischemic stroke, warranting further investigation into its precise mechanisms and optimal administration timing.
