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Reversal of Trauma-Induced Amnesia in Mice by a Thrombin Receptor Antagonist

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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.

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Acknowledgments

We thank Dr. Vardit Rubovitch for assistance in behavioral test design and analysis and Mrs. Ramona Aharonovitch for her excellent advice and technical guidance in biochemical assays. Dr. Nicola Maggio is a member of Talpiot Medical Leadership Program at the Sheba Medical Center. Zeev Itsekson is a Young Scientist Program for Medical Students scholar at the Sheba Medical Center.

Authorship statement

Dr. Maggio, Mr. Itsekson, and Dr. Milman made a substantial contribution to conception and design, acquisition of data, or analysis and interpretation of data presented in this manuscript. Prof. Chapman, Prof. Pick, and Dr. Shavit-Stein made a substantial contribution to a draft of this article and its critical revision. Prof. Chapman made a final approval of the version to be published.

Conflict of interest

None.

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Authors and Affiliations

  1. Department of Physiology and Pharmacology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel

    Zeev Itzekson, Efrat Shavit & Joab Chapman

  2. Department of Neurology and Joseph Sagol Neuroscience Center, The Chaim Sheba Medical Center, 52621, Tel HaShomer, Israel

    Zeev Itzekson, Nicola Maggio, Efrat Shavit & Joab Chapman

  3. The Talpiot Medical Leadership Program, The Chaim Sheba Medical Center, 52621, Tel HaShomer, Israel

    Nicola Maggio

  4. Department of Anatomy and Anthropology, Sackler Faculty of Medicine, Tel Aviv University, 6997801, Tel Aviv, Israel

    Anat Milman & Chaim G. Pick

  5. Internal Medicine Department B, Tel Aviv Sourasky Medical Center, 64239, Tel Aviv, Israel

    Anat Milman

Authors
  1. Zeev Itzekson
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  2. Nicola Maggio
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  3. Anat Milman
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  4. Efrat Shavit
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  6. Joab Chapman
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Corresponding author

Correspondence to Joab Chapman.

Additional information

Zeev Itzekson and Nicola Maggio contributed equally to this manuscript.

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Itzekson, Z., Maggio, N., Milman, A. et al. Reversal of Trauma-Induced Amnesia in Mice by a Thrombin Receptor Antagonist. J Mol Neurosci 53, 87–95 (2014). https://doi.org/10.1007/s12031-013-0200-8

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  • DOI: https://doi.org/10.1007/s12031-013-0200-8

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