Efficacy of antioxidant therapies in transient focal ischemia in mice.
OBJECTIVE
Ginkgo biloba extract (EGb) and alpha-lipoic acid (LA) are commercially available "antioxidant supplements" with a variety of actions that may be beneficial during acute stroke. These actions include inhibiting platelet and leukocyte activation and adhesion, reducing free radical generation, and increasing cerebral blood flow. Both EGb and LA have been shown to be neuroprotective in cell culture and global central nervous system ischemia models. In this study we investigated the neuroprotective efficacy of EGb and LA in a clinically relevant, transient focal central nervous system ischemic model.


METHODS
In the EGb study, 60 adult C57blk mice were randomized to treatment with EGb given orally (via gavage) for 7 days: low dose, 50 EGb mg/kg daily; high dose, 100 mg/kg daily; matched placebo. On day 7, reversible middle cerebral artery occlusion was produced by advancing a silicone-coated 8-0 filament into the internal carotid artery for 45 minutes followed by reperfusion. At 24 hours, the animals were evaluated on a 28-point clinical scale, and infarct volume was determined with the use of triphenyltetrazolium chloride. In the LA study, 24 C57blk mice were treated with 100 mg/kg SC of LA or placebo 1.5 hours before transient MCAO, as in the EGb study.


RESULTS
In the EGb study, values for infarct volume at 24 hours were as follows (mean+/-SD): low dose (n=18), 13+/-5 mm(3); high dose (n=22), 22+/-12 mm(3); placebo (n=20), 20+/-10 mm(3) (P:=0.03 overall; P=0.02, low dose versus placebo). Infarct percentage of hemisphere values were as follows: low dose, 14+/-5%; high dose, 21+/-11%; placebo, 20+/-9% (P=0.03 overall; P=0.02, low dose versus placebo). Ten percent of the high-dose group showed significant intracerebral hemorrhage (ICH) within the infarct, while no ICH was seen in the other groups. Neurological function scores were as follows: low dose, 11.8+/-1.5; high dose, 11.4+/-1.7; placebo, 11.3+/-1.8 (P=NS). In the LA study, infarct volume was as follows: 100 mg/kg LA (n=12), 16.8+/-8.3 mm(3); placebo (n=12), 27.2+/-14.6 mm(3) (P<0.05). LA also produced a significant improvement in neurological function at 24 hours: LA, 9.5+/-1.2; placebo, 11.2+/-1.8 (P=0.02). There was no evidence of ICH in any of the animals.


CONCLUSIONS
Both oral EGb and LA therapies produced significant reductions in stroke infarct volume. However, for EGb this beneficial effect appears to be dose related, with higher doses potentially increasing the risk of ICH.
Oregon Stroke Center, Department of Neurology, Oregon Health Sciences University, Portland, Oregon, USA. clarkw@ohsu.edu
W M
WM
Clark
L G
LG
Rinker
N S
NS
Lessov
S L
SL
Lowery
M J
MJ
Cipolla
D000284:Administration, Oral; D000818:Animals; D000975:Antioxidants / Q000008:administration & dosage*; D001835:Body Weight / Q000187:drug effects; D001921:Brain / Q000098:blood supply / Q000187:drug effects / Q000473:pathology; D002543:Cerebral Hemorrhage / Q000139:chemically induced / Q000473:pathology; D002560:Cerebrovascular Circulation / Q000187:drug effects; D004195:Disease Models, Animal; D004305:Dose-Response Relationship, Drug; D020441:Ginkgo biloba / Q000009:adverse effects / Q000627:therapeutic use*; D007279:Injections, Subcutaneous; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D008517:Phytotherapy; D010936:Plant Extracts / Q000008:administration & dosage / Q000009:adverse effects; D010946:Plants, Medicinal; D008063:Thioctic Acid / Q000008:administration & dosage*; D016896:Treatment Outcome
D000975:Antioxidants; D010936:Plant Extracts; D008063:Thioctic Acid