Suppression of Cerebral Ischemia/Reperfusion Injury by Efficient Release of Encapsulated Ifenprodil From Liposomes Under Weakly Acidic pH Conditions

Although N-methyl-d-aspartate receptor antagonists are hopeful therapeutic agents against cerebral ischemia/reperfusion (I/R) injury, effective approaches are needed to allow such agents to pass through the blood-brain barrier, thus increasing bioavailability of the antagonists to realize secure treatment. We previously demonstrated the usefulness of liposomal delivery of neuroprotectants via spaces between the disrupted blood-brain barrier induced after cerebral I/R. In the present study, a liposomal formulation of an N-methyl-d-aspartate receptor antagonist, ifenprodil, was newly designed; and the potential of liposomal ifenprodil was evaluated in transient middle cerebral artery occlusion rats. Ifenprodil was encapsulated into liposomes by a remote loading method using pH gradient between internal and external water phases of liposomes, focusing on differences of its solubility in water depending on pH. The encapsulated ifenprodil could be quickly released from the liposomes in vitro under a weakly acidic pH condition, which is a distinctive condition after cerebral I/R. Liposomal ifenprodil treatment significantly alleviated I/R-induced increase in permeability of the BBB by inhibiting superoxide anion production, resulting in ameliorating ischemic brain damage. Taken together, these results suggest that Ifen-Lip could become a hopeful neuroprotectant for cerebral I/R injury via efficient release of the encapsulated ifenprodil under weakly acidic pH conditions.