Single injection of ONO-1301-loaded PLGA microspheres directly after ischaemia reduces ischaemic damage in rats subjected to middle cerebral artery occlusion.
OBJECTIVE
ONO-1301 was developed as a novel long-acting prostacyclin agonist with thromboxane synthase inhibitory activity. In this study, we investigated the therapeutic time window of oral ONO-1301 and the effect of a single subcutaneous injection of ONO-1301-loaded poly(lactide-co-glycolide) (PLGA) microspheres (ONO-1301 PLGA MS) on infarction volume, functional deficits and plasma ONO-1301 levels following a 1 h middle cerebral artery occlusion (MCAO) in rats.


METHODS
Rats were treated with ONO-1301 (3 mg/kg) orally twice-daily starting 1 (directly), 6 or 24 h after MCAO. Rats received a single subcutaneous injection of ONO-1301 PLGA MS (10 mg/kg) directly after MCAO. Neurological scores were evaluated directly after, 1 and 6 h, 1, 2, and 3 days after MCAO. Infarct volume, oedema and plasma ONO-1301 levels were measured three days after MCAO.


RESULTS
Neurological scores, oedema and infarct volume were all significantly improved in rats repeatedly treated with oral ONO-1301 and subcutaneous ONO-1301 PLGA MS directly after MCAO. Plasma ONO-1301 levels were significantly lower in rats treated directly after MCAO (either with ONO-1301 or ONO-1301 PLGA MS) than in rats treated 6 h or 24 h after MCAO.


CONCLUSIONS
ONO-1301 PLGA MS subcutaneous treatment directly after MCAO showed a neuroprotective effect as well as oral ONO-1301. This treatment should be clinically more convenient than ONO-1301 oral administration since it is delivered as a single treatment after MCAO.
Department of Clinical Pharmaceutics, Faculty of Pharmaceutical Sciences, Mukogawa Women's University, Hyogo, Japan.
Mai
M
Hazekawa
Yoshiki
Y
Sakai
Miyako
M
Yoshida
Tamami
T
Haraguchi
Takahiro
T
Uchida
D000818:Animals; D001672:Biocompatible Materials / Q000627:therapeutic use; D011464:Epoprostenol / Q000819:agonists*; D020244:Infarction, Middle Cerebral Artery / Q000150:complications; D007279:Injections, Subcutaneous; D019344:Lactic Acid / Q000627:therapeutic use; D008297:Male; D008863:Microspheres; D018696:Neuroprotective Agents / Q000627:therapeutic use*; D011100:Polyglycolic Acid / Q000627:therapeutic use; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011725:Pyridines / Q000627:therapeutic use*; D051381:Rats; D017208:Rats, Wistar; D015427:Reperfusion Injury / Q000209:etiology / Q000517:prevention & control*; D013223:Statistics as Topic; D013930:Thromboxane-A Synthase / Q000037:antagonists & inhibitors*; D013997:Time Factors
D001672:Biocompatible Materials; D018696:Neuroprotective Agents; D011725:Pyridines; C105488:ONO 1301; D000077182:Polylactic Acid-Polyglycolic Acid Copolymer; D011100:Polyglycolic Acid; D019344:Lactic Acid; D011464:Epoprostenol; D013930:Thromboxane-A Synthase