Baicalein, an antioxidant 12/15-lipoxygenase inhibitor improves clinical rating scores following multiple infarct embolic strokes

• Published in: Neuroscience Vol. 150; no. 3; pp. 585 - 591
• Main Authors: Lapchak, P.A, Maher, P, Schubert, D, Zivin, J.A
• Format: Journal Article
• Language: English
• Published: Oxford Elsevier Ltd 12-12-2007; Elsevier
• Subjects: 12/15-LOX inhibitor; Animals; anti-inflammatory; antioxidant; Antioxidants - pharmacology; Arachidonate 12-Lipoxygenase; Arachidonate 15-Lipoxygenase; Biological and medical sciences; Cell Survival - drug effects; Cells, Cultured; Disease Models, Animal; Dose-Response Relationship, Drug; Flavanones - pharmacology; free radical; Fundamental and applied biological sciences. Psychology; Intracranial Embolism - drug therapy; Intracranial Embolism - metabolism; Intracranial Embolism - pathology; Lipoxygenase Inhibitors; Male; matrix metalloproteinase inhibitor; Motor Activity; Neurology; neuroprotection; Neuroprotective Agents - pharmacology; Oxidative Stress - drug effects; Rabbits; Severity of Illness Index; Stroke - drug therapy; Stroke - metabolism; Stroke - pathology; Vertebrates: nervous system and sense organs; [tert-butylimino)methyl] benzene-1,3-disulfonate N-oxide; iodoacetic acid; tissue plasminogen activator; generic NXY-059; G3PDH; estimated dose for 50% cell survival; MTT; 12/15-LOX; DMEM; 1,3,4,5-tetrahydroxycyclo-hexanecarboxylic acid 3-(3,4-dihydroxycinnamate); Dulbecco’s Modified Eagle’s Medium; chlorogenic acid; reactive oxygen species; anti-inflammatory; free radical; MCAO; RSCEM; antioxidant; tPA; 12/15-LOX inhibitor; IAA; matrix metalloproteinase inhibitor; AIS; 3-(4,5-dimethylthiazol-2-yl)-2,5-diphenyltetrazolium-bromide; 12/15-lipoxygenase inhibitor; neuroprotection; acute ischemic stroke; EC 50; ROS; rabbit small clot embolic stroke model; middle cerebral artery occlusion; glyceraldehyde 3-phosphate dehydrogenase; Neuroprotection; Enzyme; Antiinflammatory agent; Metalloendopeptidases; Antioxidant; Free radical; Peptidases; Hydrolases; Metalloproteinase; Oxidoreductases; Lipoxygenase
• ISSN: 0306-4522; 1873-7544
• DOI: 10.1016/j.neuroscience.2007.09.033

Abstract The present study assessed whether baicalein (5,6,7-trihydroxyflavone), a polyphenolic antioxidant 12/15-lipoxygenase inhibitor would attenuate oxidative cell death in vitro using a mouse hippocampal HT22 cell assay. Moreover, we determined if baicalein would be useful to attenuate behavioral deficits associated with multiple infarct ischemic events in vivo using a rabbit small clot embolic stroke model (RSCEM). Using HT22 cell in vitro , baicalein was shown to significantly promote cell survival with an estimated dose for 50% cell survival of 2 μM following incubation in the presence of iodoacetic acid (20 μM), an irreversible inhibitor of the glycolytic pathway that results in the free radical production, lipid peroxidation and cell death. Since baicalein was neuroprotective and attenuated iodoacetic acid (IAA) toxicity in vitro , we studied its effects in vivo in an embolic stroke model using behavioral measures as the endpoint. Quantal analysis for each treatment in the embolism model identifies the quantity of microclots (mg) that produce neurologic dysfunction in 50% of a group of animals (P50 ), with intervention considered neuroprotective if it increases the P50 compared with controls. Baicalein (100 mg/kg, s.c.) injected 5 and 60 min post-embolization significantly ( P <0.05) improved behavioral function. The calculated P50 values were 2.85±0.64 mg ( n =21) and 2.15±0.12 mg ( n =14), respectively compared with 1.37±0.20 mg ( n =23) for the control group. In conclusion, we have shown that baicalein effectively attenuated cell death in vitro using HT22 cells and also significantly reduced behavioral deficits in rabbits when given up to 1 h following an embolic stroke. The results suggest that baicalein, or derivatives of baicalein with multiple pharmacological activities may be useful to develop as novel treatments for acute ischemic stroke.