TY - JOUR
T1 - Reversal of trauma-induced amnesia in mice by a thrombin receptor antagonist
AU - Itzekson, Zeev
AU - Maggio, Nicola
AU - Milman, Anat
AU - Shavit, Efrat
AU - Pick, Chaim G.
AU - Chapman, Joab
PY - 2014/5
Y1 - 2014/5
N2 - 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.
AB - 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.
KW - Amnesia
KW - Hippocampus
KW - Long term potentiation
KW - PAR1
KW - Thrombin
KW - mTBI
UR - http://www.scopus.com/inward/record.url?scp=84899912346&partnerID=8YFLogxK
U2 - 10.1007/s12031-013-0200-8
DO - 10.1007/s12031-013-0200-8
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AN - SCOPUS:84899912346
SN - 0895-8696
VL - 53
SP - 87
EP - 95
JO - Journal of Molecular Neuroscience
JF - Journal of Molecular Neuroscience
IS - 1
ER -