title: In Situ Microparticles Loaded with S-Nitrosoglutathione Protect from Stroke.
abstract: Treatment of stroke, especially during the first hours or days, is still lacking. S-nitrosoglutathione (GSNO), a cerebroprotective agent with short life time, may help if administered early with a sustain delivery while avoiding intensive reduction in blood pressure. We developed in situ forming implants (biocompatible biodegradable copolymer) and microparticles (same polymer and solvent emulsified with an external oily phase) of GSNO to lengthen its effects and allow cerebroprotection after a single subcutaneous administration to Wistar rats. Arterial pressure was recorded for 3 days (telemetry, n = 14), whole-blood platelet aggregation up to 13 days (aggregometry, n = 58), and neurological score, cerebral infarct size and edema volume for 2 days after obstruction of the middle cerebral artery by autologous blood clots (n = 30). GSNO-loaded formulations (30 mg/kg) induced a slighter and longer hypotension (-10 vs. -56 ± 6 mmHg mean arterial pressure, 18 h vs. 40 min) than free GSNO at the same dose. The change in pulse pressure (-50%) lasted even up to 42 h for microparticles. GSNO-loaded formulations (30 mg/kg) prevented the transient 24 h hyper-aggregability observed with free GSNO and 7.5 mg/kg-loaded formulations. When injected 2 h after stroke, GSNO-loaded microparticles (30 mg/kg) reduced neurological score at 24 (-62%) and 48 h (-75%) vs. empty microparticles and free GSNO 7.5 mg/kg and, compared to free GSNO, divided infarct size by 10 and edema volume by 8 at 48 h. Corresponding implants reduced infarct size and edema volume by 2.5 to 3 times. The longer (at least 2 days) but slight effects on arterial pressures show sustained delivery of GSNO-loaded formulations (30 mg/kg), which prevent transient platelet hyper-responsiveness and afford cerebroprotection against the consequences of stroke. In conclusion, in situ GSNO-loaded formulations are promising candidates for the treatment of stroke.
authors.affiliation: CITHÉFOR EA 3452, Faculty of Pharmacy, Université de Lorraine, Nancy, France.
authors.forename: Marianne
authors.initials: M
authors.lastname: Parent
authors.affiliation: CITHÉFOR EA 3452, Faculty of Pharmacy, Université de Lorraine, Nancy, France.
authors.forename: Ariane
authors.initials: A
authors.lastname: Boudier
authors.affiliation: INSERM U1116, Faculty of Medicine, Université de Lorraine, Vandœuvre-lès-Nancy, France.
authors.forename: Julien
authors.initials: J
authors.lastname: Perrin
authors.affiliation: CITHÉFOR EA 3452, Faculty of Pharmacy, Université de Lorraine, Nancy, France.
authors.forename: Claude
authors.initials: C
authors.lastname: Vigneron
authors.affiliation: CITHÉFOR EA 3452, Faculty of Pharmacy, Université de Lorraine, Nancy, France.
authors.forename: Philippe
authors.initials: P
authors.lastname: Maincent
authors.affiliation: ETAP-Ethologie Appliquée, Research Centre in Pharmacology, Nutrition and Toxicology, Vandœuvre-lès-Nancy, France.
authors.forename: Nicolas
authors.initials: N
authors.lastname: Violle
authors.affiliation: ETAP-Ethologie Appliquée, Research Centre in Pharmacology, Nutrition and Toxicology, Vandœuvre-lès-Nancy, France.
authors.forename: Jean-François
authors.initials: JF
authors.lastname: Bisson
authors.affiliation: CITHÉFOR EA 3452, Faculty of Pharmacy, Université de Lorraine, Nancy, France.
authors.forename: Isabelle
authors.initials: I
authors.lastname: Lartaud
authors.affiliation: CITHÉFOR EA 3452, Faculty of Pharmacy, Université de Lorraine, Nancy, France.
authors.forename: François
authors.initials: F
authors.lastname: Dupuis
mesh_terms: D000818:Animals; D001794:Blood Pressure / Q000187:drug effects; D004195:Disease Models, Animal; D007279:Injections, Subcutaneous; D008297:Male; D008863:Microspheres; D018696:Neuroprotective Agents / Q000008:administration & dosage / Q000627:therapeutic use*; D010974:Platelet Aggregation / Q000187:drug effects; D051381:Rats; D017208:Rats, Wistar; D026422:S-Nitrosoglutathione / Q000008:administration & dosage / Q000627:therapeutic use*; D020521:Stroke / Q000188:drug therapy*; D013686:Telemetry
chemical_list: D018696:Neuroprotective Agents; D026422:S-Nitrosoglutathione