Document Detail


Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia.
MedLine Citation:
PMID:  22511009     Owner:  NLM     Status:  MEDLINE    
Abstract/OtherAbstract:
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.
Authors:
Ki Yong Lee; Ok-Nam Bae; Kelsey Serfozo; Siamk Hejabian; Ahmad Moussa; Mathew Reeves; Wilson Rumbeiha; Scott D Fitzgerald; Gary Stein; Seung-Hoon Baek; John Goudreau; Mounzer Kassab; Arshad Majid
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Publication Detail:
Type:  Journal Article; Research Support, N.I.H., Extramural; Research Support, Non-U.S. Gov't     Date:  2012-04-17
Journal Detail:
Title:  Stroke; a journal of cerebral circulation     Volume:  43     ISSN:  1524-4628     ISO Abbreviation:  Stroke     Publication Date:  2012 Jun 
Date Detail:
Created Date:  2012-05-28     Completed Date:  2012-08-16     Revised Date:  2013-06-26    
Medline Journal Info:
Nlm Unique ID:  0235266     Medline TA:  Stroke     Country:  United States    
Other Details:
Languages:  eng     Pagination:  1632-8     Citation Subset:  IM    
Affiliation:
Division of Cerebrovascular Diseases, Michigan State University, East Lansing, MI, USA.
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MeSH Terms
Descriptor/Qualifier:
Animals
Brain Infarction* / drug therapy,  metabolism,  pathology
Disease Models, Animal
Enzyme Activation / drug effects
Enzyme Induction / drug effects
Female
Male
Matrix Metalloproteinase 9 / biosynthesis*
Mice
Mitochondria / metabolism*,  pathology
Neuroprotective Agents* / pharmacokinetics,  pharmacology
Pentacyclic Triterpenes* / pharmacokinetics,  pharmacology
Rats
Rats, Sprague-Dawley
Stroke / drug therapy,  metabolism,  pathology
Grant Support
ID/Acronym/Agency:
R21 NS064343-02/NS/NINDS NIH HHS
Chemical
Reg. No./Substance:
0/Neuroprotective Agents; 0/Pentacyclic Triterpenes; 9PA5A687X5/asiatic acid; EC 3.4.24.-/Mmp9 protein, mouse; EC 3.4.24.-/Mmp9 protein, rat; EC 3.4.24.35/Matrix Metalloproteinase 9
Comments/Corrections

From MEDLINE®/PubMed®, a database of the U.S. National Library of Medicine


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