title: Neuroprotective effects of argatroban and C5a receptor antagonist (PMX53) following intracerebral haemorrhage.
abstract: Intracerebral haemorrhage (ICH) is a subtype of stroke that associated with neurological dysfunction and inflammation, which may be ameliorated by a neuroprotective strategy targeting the complement cascade. The protective effect of C5a-receptor antagonist (PMX53) solely and in combination with thrombin antagonist (argatroban) was investigated in the ICH mouse model, respectively. Adult male C57BL/6J wild-type (WT) mice and C3(-/-) mice were randomized to receive PMX53/argatroban 1, 3 and 5 days after ICH. A double injection technique was used to infuse 25 μl of autologous whole blood into the right striatum. Mice in the sham group received only needle insertion. Brain water content and mRNA of inflammatory factors were measured on the first, third and fifth days after ICH, respectively. Neurological dysfunction was assessed using a 28-point neurological scoring system in the three cohorts, namely, on days 1, 3 and 5 following ICH. Animals treated with PMX53/argatroban demonstrated significant improvements in neurological function and fewer neurological apoptosis detected by TUNEL [terminal deoxynucleotidyl transferase (TdT)-mediated dUTP nick end-labelling] and βIII-tubulin dual-staining compared with vehicle-treated animals. Compared with sham-treated mice, the brain water content in argatroban/PMX53-treated mice was decreased significantly in both the ipsilateral cortex and ipsilateral striatum. Administration of PMX53/argatroban provided a synergistic neuroprotective effect via reducing inflammatory factors and brain oedema, leading to improvements in neurofunctional outcome. The results of this study indicated that simultaneous blockade of the thrombin and C5a receptors represent a promising neuroprotective strategy in haemorrhagic stroke.
authors.affiliation: Department of Cerebrovascular, the First Affliated Hospital of Zunyi Medical College, Zunyi, Guizhou, China.
authors.forename: G
authors.initials: G
authors.lastname: Li
authors.forename: R-M
authors.initials: RM
authors.lastname: Fan
authors.forename: J-L
authors.initials: JL
authors.lastname: Chen
authors.forename: C-M
authors.initials: CM
authors.lastname: Wang
authors.forename: Y-C
authors.initials: YC
authors.lastname: Zeng
authors.forename: C
authors.initials: C
authors.lastname: Han
authors.forename: S
authors.initials: S
authors.lastname: Jiao
authors.forename: X-P
authors.initials: XP
authors.lastname: Xia
authors.forename: W
authors.initials: W
authors.lastname: Chen
authors.forename: S-T
authors.initials: ST
authors.lastname: Yao
mesh_terms: D000818:Animals; D017209:Apoptosis / Q000187:drug effects; D001120:Arginine / Q000031:analogs & derivatives; D001929:Brain Edema / Q000188:drug therapy; D002543:Cerebral Hemorrhage / Q000188:drug therapy*; D015936:Complement C5a / Q000037:antagonists & inhibitors*; D007249:Inflammation / Q000188:drug therapy / Q000276:immunology; D008297:Male; D051379:Mice; D008810:Mice, Inbred C57BL; D018345:Mice, Knockout; D018696:Neuroprotective Agents / Q000627:therapeutic use; D010456:Peptides, Cyclic / Q000627:therapeutic use; D010875:Pipecolic Acids / Q000627:therapeutic use*; D010975:Platelet Aggregation Inhibitors / Q000627:therapeutic use*; D012333:RNA, Messenger / Q000032:analysis; D044087:Receptor, Anaphylatoxin C5a / Q000037:antagonists & inhibitors*; D020521:Stroke / Q000188:drug therapy; D013449:Sulfonamides; D014404:Tubulin
chemical_list: C438957:AcPhe(ornithine-Pro-cyclohexylamine-Trp-Arg); D018696:Neuroprotective Agents; D010456:Peptides, Cyclic; D010875:Pipecolic Acids; D010975:Platelet Aggregation Inhibitors; D012333:RNA, Messenger; D044087:Receptor, Anaphylatoxin C5a; D013449:Sulfonamides; D014404:Tubulin; C462941:beta3 tubulin, mouse; D015936:Complement C5a; D001120:Arginine; C031942:argatroban
keywords: C5aR; argatroban; complement; intracerebral haemorrhage; microglia