title: Neuroprotective effects of a nanocrystal formulation of sPLA(2) inhibitor PX-18 in cerebral ischemia/reperfusion in gerbils.
abstract: The group IIA secretory phospholipase A2 (sPLA(2)-IIA) has been studied extensively because of its involvement in inflammatory processes. Up-regulation of this enzyme has been shown in a number of neurodegenerative diseases including cerebral ischemia and Alzheimer's disease. PX-18 is a selective sPLA(2) inhibitor effective in reducing tissue damage resulting from myocardial infarction. However, its use as a neuroprotective agent has been hampered due to its low solubility. In this study, we test the possible neuroprotective effects of PX-18 formulated as a suspension of nanocrystals. Transient global cerebral ischemia was induced in gerbils by occlusion of both common carotid arteries for 5 min. Four days after ischemia/reperfusion (I/R), extensive delayed neuronal death, DNA damage, and increases in reactive astrocytes and microglial cells were observed in the hippocampal CA1 region. PX-18 nanocrystals (30 and 60 mg/kg body wt) and vehicle controls were injected i.p. immediately after I/R. PX-18 nanocrystal injection significantly reduced delayed neuronal death, DNA damage, as well as glial cell activation. These findings demonstrated the effective neuroprotection of PX-18 in the form of nanocrystal against I/R-induced neuronal damage. The results also suggest that nanocrystals hold promise as an effective strategy for the delivery of compounds with poor solubility that would otherwise be precluded from preclinical development.
authors.affiliation: Department of Biochemistry, University of Missouri School of Medicine, Columbia, MO 65211, USA.
authors.forename: Qun
authors.initials: Q
authors.lastname: Wang
authors.forename: Albert Y
authors.initials: AY
authors.lastname: Sun
authors.forename: Jana
authors.initials: J
authors.lastname: Pardeike
authors.forename: Rainer H
authors.initials: RH
authors.lastname: Müller
authors.forename: Agnes
authors.initials: A
authors.lastname: Simonyi
authors.forename: Grace Y
authors.initials: GY
authors.lastname: Sun
mesh_terms: D017738:Alkanesulfonic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D000818:Animals; D001921:Brain / Q000187:drug effects* / Q000201:enzymology / Q000503:physiopathology; D002545:Brain Ischemia / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016923:Cell Death / Q000187:drug effects / Q000502:physiology; D004195:Disease Models, Animal; D004791:Enzyme Inhibitors / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D005849:Gerbillinae; D005911:Gliosis / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D006624:Hippocampus / Q000187:drug effects / Q000201:enzymology / Q000473:pathology; D008297:Male; D053758:Nanoparticles; D009410:Nerve Degeneration / Q000188:drug therapy / Q000209:etiology / Q000473:pathology; D009457:Neuroglia / Q000187:drug effects / Q000473:pathology; D018696:Neuroprotective Agents / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D009829:Oleic Acids / Q000737:chemistry / Q000494:pharmacology* / Q000627:therapeutic use; D054497:Phospholipases A2, Secretory / Q000037:antagonists & inhibitors* / Q000378:metabolism; D015427:Reperfusion Injury / Q000188:drug therapy* / Q000201:enzymology / Q000503:physiopathology; D016896:Treatment Outcome
chemical_list: C545517:2-(N,N-bis(oleoyloxyethyl)amino)-1-ethanesulfonic acid; D017738:Alkanesulfonic Acids; D004791:Enzyme Inhibitors; D018696:Neuroprotective Agents; D009829:Oleic Acids; D054497:Phospholipases A2, Secretory