title: Neuroprotective activity of a nanoparticulate formulation of the glycineB site antagonist MRZ 2/576 in transient focal ischaemia in rats.
abstract: The objective of the present study was to characterise the neuroprotective activity of the novel glycineB site NMDA (N-methyl-D-aspartate) receptor antagonist MRZ 2/576 (8-chloro-4-hydroxy-l-oxo- 1,2-dihydropyridazino[4,5-b]quinolin-5-oxide choline salt, CAS 202807-80-5) in a rodent model of focal cerebral ischaemia. Since the solubility of MRZ 2/576 at a physiological pH, is minimal and adequate concentrations can be achieved only at relatively high basic pH the in vivo use of the substance is substantially limited. Therefore, a special nanoparticle formulation was developed to provide means for lengthy i.v. administration of experimentally relevant doses within the physiological range of pH. Focal ischaemia of 75 min duration was induced in rats by a reversible occlusion of the middle cerebral artery (MCAo). MRZ 2/576 (18 mg/kg over 10 min followed by 18 mg/kg/h over 6 h) or placebo treatment was initiated immediately after onset of MCAo. Neurological deficit was evaluated daily for 3 consecutive days and then brain infarct analysis was performed. MRZ 2/576 significantly improved the neurological score at 24 h and 72 h post stroke (p < 0.05 vs. placebo). It also produced a 53.0% reduction of total infarct size, 60.4% of cortical and 42.3% of striatal infarction (p < 0.05 vs. placebo). Temporary drug-induced hypothermia and ataxia were observed during infusions. This leads to the conclusion that prolonged administration of the glycineB site antagonist MRZ 2/576 in form of the nanoparticle suspension ameliorates ischaemic damage induced by the transient MCAo in rats. The results suggest that nanoparticles hold promise as an effective strategy e.g. for substances with physico-chemical characteristics that otherwise would preclude them from pre-clinical development and/or clinical application.
authors.affiliation: Preclinical Research & Development, Merz+Co., Frankfurt/Main, Germany.
authors.forename: Monika
authors.initials: M
authors.lastname: Sopala
authors.forename: Steffen
authors.initials: S
authors.lastname: Schweizer
authors.forename: Nicole
authors.initials: N
authors.lastname: Schäfer
authors.forename: Eberhard
authors.initials: E
authors.lastname: Nürnberg
authors.forename: Jörg
authors.initials: J
authors.lastname: Kreuter
authors.forename: Erhard
authors.initials: E
authors.lastname: Seiller
authors.forename: Wojciech
authors.initials: W
authors.lastname: Danysz
mesh_terms: D000818:Animals; D001522:Behavior, Animal / Q000187:drug effects; D002544:Cerebral Infarction / Q000473:pathology; D007035:Hypothermia / Q000139:chemically induced; D007262:Infusions, Intravenous; D002546:Ischemic Attack, Transient / Q000188:drug therapy* / Q000473:pathology; D008297:Male; D008863:Microspheres; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010316:Particle Size; D010793:Phthalazines / Q000008:administration & dosage / Q000627:therapeutic use*; D051381:Rats; D017207:Rats, Sprague-Dawley; D018009:Receptors, Glycine / Q000037:antagonists & inhibitors*; D013535:Suspensions
chemical_list: C491948:Glrb protein, rat; C112266:MRZ 2-576; D018696:Neuroprotective Agents; D010793:Phthalazines; D018009:Receptors, Glycine; D013535:Suspensions