title: Asiatic acid attenuates infarct volume, mitochondrial dysfunction, and matrix metalloproteinase-9 induction after focal cerebral ischemia.
abstract: OBJECTIVE
  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.affiliation: Division of Cerebrovascular Diseases, Michigan State University, East Lansing, MI, USA.
authors.forename: Ki Yong
authors.initials: KY
authors.lastname: Lee
authors.forename: Ok-Nam
authors.initials: ON
authors.lastname: Bae
authors.forename: Kelsey
authors.initials: K
authors.lastname: Serfozo
authors.forename: Siamk
authors.initials: S
authors.lastname: Hejabian
authors.forename: Ahmad
authors.initials: A
authors.lastname: Moussa
authors.forename: Mathew
authors.initials: M
authors.lastname: Reeves
authors.forename: Wilson
authors.initials: W
authors.lastname: Rumbeiha
authors.forename: Scott D
authors.initials: SD
authors.lastname: Fitzgerald
authors.forename: Gary
authors.initials: G
authors.lastname: Stein
authors.forename: Seung-Hoon
authors.initials: SH
authors.lastname: Baek
authors.forename: John
authors.initials: J
authors.lastname: Goudreau
authors.forename: Mounzer
authors.initials: M
authors.lastname: Kassab
authors.forename: Arshad
authors.initials: A
authors.lastname: Majid
mesh_terms: D000818:Animals; D020520:Brain Infarction / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology; D004195:Disease Models, Animal; D004789:Enzyme Activation / Q000187:drug effects; D004790:Enzyme Induction / Q000187:drug effects; D005260:Female; D008297:Male; D020780:Matrix Metalloproteinase 9 / Q000096:biosynthesis*; D051379:Mice; D008928:Mitochondria / Q000378:metabolism* / Q000473:pathology; D018696:Neuroprotective Agents / Q000493:pharmacokinetics / Q000494:pharmacology; D053978:Pentacyclic Triterpenes / Q000493:pharmacokinetics / Q000494:pharmacology; D051381:Rats; D017207:Rats, Sprague-Dawley; D020521:Stroke / Q000188:drug therapy / Q000378:metabolism / Q000473:pathology
chemical_list: D018696:Neuroprotective Agents; D053978:Pentacyclic Triterpenes; C017032:asiatic acid; D020780:Matrix Metalloproteinase 9; C501830:Mmp9 protein, mouse; C572337:Mmp9 protein, rat