Asiatic Acid Attenuates Infarct Volume, Mitochondrial Dysfunction, and Matrix Metalloproteinase-9 Induction After Focal Cerebral Ischemia

Stroke - Tập 43 Số 6 - Trang 1632-1638 - 2012
Ki Yong Lee1,2,3,4,5, Ok‐Nam Bae1,2,3,4,5, Kelsey Serfozo1,2,3,4,5, Siamk Hejabian1,2,3,4,5, Ahmad Moussa1,2,3,4,5, Mathew J. Reeves1,2,3,4,5, Wilson K. Rumbeiha1,2,3,4,5, Scott D. Fitzgerald1,2,3,4,5, Gary R Stein1,2,3,4,5, Seung‐Hoon Baek1,2,3,4,5, John L. Goudreau1,2,3,4,5, Mounzer Kassab1,2,3,4,5, Arshad Majid1,2,3,4,5
1From the Division of Cerebrovascular Diseases (K.Y.L., O.B., K.S., S.H., A.M., S.B., J.G., M.K., A.M.), Department of Neurology and Ophthalmology, Department of Pathobiology and Diagnostic Investigation, and Diagnostic Center for Population & Animal Health (S.D.F.), Department of Epidemiology (M.R.), and Department of Medicine (G.S.), Michigan State University, East Lansing, MI; the College of Pharmacy (O.B.), Hanyang University, Ansan, Gyeonggido, Korea; the College of Pharmacy (S.B.), Ajou...
2Veterinary Diagnostic and Production Animal Medicine (W.R.), College of Veterinary Medicine, Iowa State University, Ames, IA
3the College of Pharmacy (O.B.), Hanyang University, Ansan, Gyeonggido, Korea
4the College of Pharmacy (S.B.), Ajou University, Suwon, Gyeonggido, Korea
5the Department of Neurology (A.M.), Salford Royal Hospital, Salford, UK.

Tóm tắt

Background and Purpose— Asiatic acid (AA) has been shown to attenuate cerebral infarction in a mouse model of focal ischemia and shows promise as a neuroprotective stroke therapy. To facilitate translation of these findings to clinical studies, we determined pharmacokinetics, a dose–response relationship, the therapeutic time window, and efficacy using multiple stroke models. We also explored potential mechanisms of action. Methods— Escalating doses of intravenous AA were administered and serum concentrations were measured at multiple time points for the pharmacokinetic studies. Subsequently, a dose–response relationship was determined followed by administration at different intervals after the onset of ischemia to establish a therapeutic time window for neuroprotection. Outcome measurements included both histological and behavioral. Mitochondrial function and matrix metalloproteinase activity in controls and treated rats were also determined. Results— The pharmacokinetic studies showed that AA (75 mg/kg) has a half-life of 2.0 hours. AA significantly decreased infarct volume and improved neurological outcome even when administration was at time points up to 12 hours after the onset of ischemia. Infarct volume was also significantly decreased in female rats and spontaneously hypertensive rats. AA attenuated mitochondrial dysfunction and reduced matrix metalloproteinase-9 induction. Conclusions— Our study shows AA is effective against multiple models of focal ischemia, has a long therapeutic time window, and is also effective in females and hypertensive animals. AA may mediate neuroprotection by protecting mitochondria and inhibiting matrix metalloproteinase-9 induction and activation. Taken together these data suggest that AA is an excellent candidate for development as a stroke therapy.

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Stroke

Tập 43 Số 6

1632-1638

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