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  • Ameliorating Trauma induced Hyperlocomotion by Adenosine A2A Receptor Selective Antagonist SCH56261 in Mongolian Gerbils

    Final Number:

    Saad H Mullah MBBS, PhD; Motoki Inaji MD; Tadashi Nariai MD, PhD; Satorou Ishibashi MD, PhD; Meada Jun; Higuchi Makoto; Kikuo Ohno MD

    Study Design:
    Laboratory Investigation

    Subject Category:

    Meeting: Congress of Neurological Surgeons 2012 Annual Meeting

    Introduction: Different type of brain insults, such as ischemia, trauma, inflammation etc causes an increase in intracerebral adenosine level which contributes to secondary brain damage. Previous reports suggested Adenosine A2A receptor antagonist has improved behavior outcome in ischemic models. In this study we aimed to find out the effect of adenosine A2A receptor selective antagonist SCH58261 on hyperactivity seen after traumatic brain injury.

    Methods: We used Mongolian Gerbils of 23-37 weeks age weighing 60-100 grams in the study. Lateral Fluid Percussion (LFP) was induced at 26-32 PSI pressure on the intact dura on the right parietal lobe via craniotomy. SCH58261 was injected intra-peritoneally in the treatment group for different durations: single administration, 5 days continuous administration, 9 days continuous administration. Trauma control group received saline for 5 days. Sham operated animals received either medication or saline. On every alternate day before and till day 9 after injury, animals were placed individually in an open field apparatus. A video tracking system recorded the movement. The total distance (cm/10min) moved by each animal was analyzed by a software. Animals were also tested for their grabbing tendency by forelimbs. Gerbils were allowed to grab a net weighing 40 grams and the time they lift it freely was recorded. After the behavior evaluation animals were sacrificed, brains were collected and cooled down rapidly. In vitro autoradiography was done with the frozen sections by using 3H-ZM241385.

    Results: Trauma-saline group moved significantly higher total distance in open field study. In treatment group the drug significantly reduced the trauma induced hyperlocomotion to the level of the sham group. No significant difference was observed between single administration and continuous administration of the drug. The trauma-saline group also grabbed the weight for longer time duration compared to other groups. Medication reduced this grabbing time of the injured animals to the level of sham operated animals. In autoradiography, there was no significant difference in A2A receptor density between the cortex and the striatum among the groups.

    Conclusions: The selective adenosine A2A antagonist SCH58261 successfully ameliorated the hyperactivity seen after traumatic brain injury in animal models.

    Patient Care: Increase in adenosine release due to metabolic failure seen after the different brain insults plays crucial role in the neurotransmitter balance leading to secondary damage. This study is the first of its type to find out the effect of the A2A antagonist in the secondary damage after the primary brain injury. Our findings will provide the baseline to look for the usefulness of adenosine antagonist in clinical setting.

    Learning Objectives: 1. To evaluate the effect of SCH 58261 in TBI. 2. To compare the effects between single administration and continuous treatment. 3. To evaluate the binding potential of the A2A receptors by in vitro autoradiography (postsynaptic function).

    References: Alessia Melani, Leonardo Pantone, Francesca Bordoni, Marco Gianfriddo, Loria Bianchi, Maria Guiliana Vannucchi, Rosalia Bertorelli, Angela Monopoli, Felicita Pedata. 2003 The slective A2A receptor antagonist SCH 58261 reduces striatal transmitter outflow, turning behavior and ischemic brain damage induced by permanent focal ischemia in the rat. Brain Res 959:243-250 Kiyotaka katsuta, Kazuo Umemura, Noriko Ueyama, Nobuya Matsuoka. 2003. Pharmacologiacl evidence for correlation between hippocampal CA1 cell damage and hyperlocomotion following global cerebral ischemia in gerbils. European Journal of Pharmacology, 467: 103-109 Pedata, F., Corsi, C., Melani, A., Bordoni, F., Latini, S., 2001. Adenosine extracellular brain concentrations and role of A2A receptors in ischemia. Ann. NY Acad. Sci. 939, 74-84 Shiholg Li, Toshihiko Kuroiwa, Noriko Katsumata, Satoru Ishihashi, Li Yuan Sun, Shu Endo, Kikuo Ohno. 2006. Transient versus prolonged Hyperlocotion Following Lateral fluid Percussuion Injury in Mongolian Gerbils. J Neurosci Res 83:292-300 W.Li, S.Dai, J.AN, P.Li, X Chen, R.Xiong, P.Liu, H.Wang, Y.Zhao, M.Zhu, X.Liu, P.Zhu, J.-F.Chen, Y.Zhou. Chronic but not Acute Treatment with Caffeine attenuates Traumatic Brain Injury in the Mouse Cortical Impact model. Neuroscience 151: 1198-1207

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