title: Reversal of trauma-induced amnesia in mice by a thrombin receptor antagonist.
abstract: Minimal traumatic brain injury (mTBI) is associated with the existence of retrograde amnesia and microscopic bleeds containing activated coagulation factors. In an mTBI model, we report that thrombin induces amnesia through its receptor protease-activated receptor 1 (PAR-1). Thrombin activity was significantly elevated (32 %, p < 0.05) 5 min following mTBI compared to controls. Amnesia was assessed by the novel object recognition test in mTBI animals and in animals injected intracerebroventricularly (ICV) with either thrombin or a PAR-1 agonist 1 h after the acquisition phase. Saline-injected controls had a preference index of over 0.3 while mTBI animals and those injected with thrombin or the PAR-1 agonist spent equal time with both objects indicating no recall of the object presented to them 24 h previously (p < 0.05). Co-injecting a PAR-1 antagonist (SCH79797) completely blocked the amnestic effects of mTBI, thrombin, and the PAR-1 agonist. Long-term potentiation, measured in hippocampal slices 24 h after mTBI, ICV thrombin or the PAR-1 agonist, was significantly impaired and this effect was completely reversed by the PAR-1 antagonist. The results support a crucial role for PAR-1 in the generation of amnesia following mTBI, revealing a novel therapeutic target for the cognitive effects of brain trauma.
authors.affiliation: Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel.
authors.forename: Zeev
authors.initials: Z
authors.lastname: Itzekson
authors.forename: Nicola
authors.initials: N
authors.lastname: Maggio
authors.forename: Anat
authors.initials: A
authors.lastname: Milman
authors.forename: Efrat
authors.initials: E
authors.lastname: Shavit
authors.forename: Chaim G
authors.initials: CG
authors.lastname: Pick
authors.forename: Joab
authors.initials: J
authors.lastname: Chapman
mesh_terms: D000647:Amnesia / Q000188:drug therapy* / Q000209:etiology; D000818:Animals; D001930:Brain Injuries / Q000150:complications / Q000188:drug therapy*; D006624:Hippocampus / Q000187:drug effects / Q000378:metabolism / Q000502:physiology; D017774:Long-Term Potentiation; D051379:Mice; D008813:Mice, Inbred ICR; D011758:Pyrroles / Q000494:pharmacology*; D011799:Quinazolines / Q000494:pharmacology*; D044463:Receptor, PAR-1 / Q000819:agonists / Q000378:metabolism; D013917:Thrombin / Q000494:pharmacology; D010975:Platelet Aggregation Inhibitors
chemical_list: C415424:N3-cyclopropyl-7-((4-(1-methylethyl)phenyl)methyl)-7H-pyrrolo(3, 2-f)quinazoline-1,3-diamine; D011758:Pyrroles; D011799:Quinazolines; D044463:Receptor, PAR-1; D013917:Thrombin; D010975:Platelet Aggregation Inhibitors