.JPG) |
Academic Rank: Prof.
Phone: 972-2-6757513
Fax 972-2-675-8741
Email: esty@cc.huji.ac.il
Room no.: 612
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Traumatic brain injury, inflammation, oxidative stress, endocannabinoids, neuroprotection, brain-bone relationship
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Prof. Rafi Mechoulam, Medicinal Chemistry
Prof. Michal Horowitz, Physiology
Dr. Rami Yaka, Pharmacology
Prof. Itai Bab, Bone laboratory, School of Dentistry
Prof. Anat Biegon, Brookhaven National Labs, USA
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Major research interests include the pathophysiology of traumatic brain injury (TBI). In an experimental model of closed head injury in rat and mouse we investigate the secondary mechanisms which are activated in the brain after traumatic injury. Using neurochemical, pharmacological and genetic tools we have identified harmful and protective mechanisms, and attempt to provide novel therapeutic modalities to the clinical head injury. We have focused on the role of cytokines and oxidative stress, and later, on the endocannabinoid system in the post traumatic pathologies. We also study the effect of heat acclimation on outcome after TBI, as a model for endogenous neuroprotective mechanisms. In addition, we now focus on the dynamic changes in the glutamate NMDA receptor after TBI, and its consequences in brain damage and as a therapeutic target. We have recently begun to explore the cross-talk between brain and bone, looking for mediators and processes that link between these organs, in health and disease.
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- Our model of closed head injury closely mimics the same condition in humans, and therefore it is attractive to pharmaceutical companies who wish to test compounds for neuroprotective properties. Our laboratory has contracts with some companies and we investigate the effects of their products in our model. In recent years we have collaborated with several companies in Israel, USA, Germany and Switzerland. In these projects the beneficial effects of various compounds were tested, and the outcome measures such as clinical and cognitive function, edema, blood-brain barrier and cell survival were assessed.
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Shein NA, Doron H, Horowitz M, Trembovler V, Alexandrovich AG, and Shohami E. Altered Cytokine Expression and Sustained Hypothermia Following Traumatic Brain Injury in Heat Acclimated Mice. Brain Res, in press, 2007
Mechoulam R. and Shohami E. Endocannabinoids and traumatic brain injury. Molecular Neurobiology, in press 2007
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Yaka R, Biegon A, Grigoriadis N, Simeonidou C, Grigoriadis S, Alexandrovich AG, Matzner H, Schumann J, Trembovler V, Tsenter J and Shohami E. D-cycloserine improves functional recovery and reinstates long-term potentiation (LTP) in a mouse model of closed head injury. FASEB J 21:2033-2041, 2007
Shein NA, Horowitz M, Shohami E. Heat acclimation: a unique model of physiologically mediated global preconditioning against traumatic brain injury. Prog Brain Res. 161:353-363, 2007
Marciano D, Shohami E, Kloog Y, Alexandrovitch A, Brandeis R, Goelman G. Neuroprotective effects of the ras inhibitor s-trans-trans-farnesylthiosalicylic Acid, measured by diffusion-weighted imaging after traumatic brain injury in rats.
J Neurotrauma. 24:1378-1386, 2007
Tam J, Trembovler V, Di Marzo V, Petrosino S, Leo G, Alexandrovich AG, Regev E, Casap N, Shteyer A Ledent C, Karsak M, Zimmer A, Mechoulam R, Yirmiya R, Shohami E, Bab I. The Cannabinoid CB1 Receptor Regulates Bone Formation by Modulating Adrenergic Signaling. FASEB J. EPub, Aug 2007
Shein NA, Tsenter J, Alexandrovich AG, Horowitz M, Shohami E. Akt phosphorylation is required for heat acclimation-induced neuroprotection. J Neurochem. Aug 22; [Epub ahead of print] 2007
Panikashvili, D, Shein NA, Mechoulam R, Trembovler V, Kohen R, Alexandrovich A, and Shohami E. The Endocannabinoid 2-AG Protects the Blood Brain Barrier after Closed Head Injury and Inhibits Expression of Proinflammatory Cytokines. Neurobiology of Disease, 22:257-264, 2006
Yirmiya R, Goshen I, Bajayo A, Kreisel T, Feldman S, Tam J, Trembovler V, Csernus V, Shohami E, Bab I. Depression induces bone loss through stimulation of the sympathetic nervous system. Proc Natl Acad Sci U S A. 103:16876-81, 2006
Shein, NA Horowitz, M., Alexandrovich, A., Tsenter, J., Shohami, E. Heat Acclimation Increases Hypoxia Inducible Factor 1α and Erythropoietin Receptor Expression : Implication for Neuroprotection after Closed Head Injury in Mice. J. Cereb Blood Flow & Metabol. 25:1456-1465, 2005
Yatsiv I, Grigoriadis N, Simeonidou C, Stahel PF, Schmidt OI, Alexandrovitch AG, Tsenter J, Shohami E. Erythropoietin is neuroprotective, improves functional recovery, and reduces neuronal apoptosis and inflammation in a rodent model of experimental closed head injury. FASEB J. 12:1701-1703. 2005
Biegon A., Fry P.A., Paden C.M., Alexandrovich A., Tsenter J., Shohami E., Delayed Activation, rather than inhibition, of glutamate NMDA receptors improves neurological outcome after closed head injury in mice. Proc Natl Acad Sci USA 101:5117-5122, 2004
Beni SM, Kohen R., Reiter RJ, Tan D-X, Shohami E. Melatonin-Induced Neuroprotection after Closed Head Injury is Associated with Increased Brain antioxidants and attenuated late-phase activation of NF-B and AP-1. FASEB J. 18:149-151, 2004
Shohami E., Yatsiv I, Alexandrovich A., Haklai R., Elad- Sfadia G, Grossman R., Biegon A. and Kloog Y. The Ras Inhibitor S-trans, trans-Farnesylthiosalicylic Acid Exerts Long-Lasting Neuroprotection in a Mouse Closed Head Injury Model. J Cereb Blood Flow & Metabol. 23: 728-738, 2003
Panikashvili, D, Simeonidou, C., Ben-Shabat, S., Hanuš, L., Breuer, A., Mechoulam, R., and Shohami, E. 2-Arachidonoyl Glycerol, an Endogenous Cannabinoid, is Neuroprotective After Brain Injury. Nature, 413: 527-531, 2001.
Chen, Y., Lomnitski, L., Michaelson, D.M. and Shohami, E.
Motor and cognitive deficits in apolipoprotein E-deficient mice after closed head injury.
Neurosci. 80:1255-1262 (1997).
Stahel, PF., Shohami, E., Younis, F.M., Kariya, K., Otto, V.I., Lenzlinger, P.M., Grosjean, MB., Eugster, H-P., Trentz, O. Kossmann, T. and Morganti-Kossmann, M.C.
Experimental closed head injury: Analysis of neurological outcome, blood brain barrier dysfunction, intracranial neutrophil infiltration and neuronal cell death in mice deficient in genes for pro-inflammatory cytokines.
J. Cereb Blood Flood and Metabolism, 20:369-380, 2000
Shohami, E., Gati, I., Beit-Yannai, E., Trembovler, V. and Kohen, R.
Closed head injury in the rat induces whole body oxidative stress: overall reducing antioxidant profile.
J. Neurotrauma 16:365-376 (1999).
Lomnitski, L., Chapman, S., Hochman, A., Kohen, R., Shohami, E., Chen, Y., Trembovler, V. and Michaelson, D.M.
Antioxidant mechanisms in ApoE-deficient mice prior to and following closed head injury.
Biochem. Biophys. Acta 1453:359-368 (1999).
Kozlovsky, N., Shohami, E. and Bashan, N
Increased PLA2 is not related to increased GLUT1 expression in L6 myotubes under hypoxic conditions.
Prost. Leuk. Essn. Fatty Acids 56:17-22 (1997).
Klein, B.Y., Shohami, E., Reikhinsthein, Y., Ben-Bassat, H. and Liebergal, M.
Serum-mediated osteogenic effects of head injury on cultured rat marrow stroma cells.
Calcif. Tissue Int. 65:217-222 (1999).
Beit-Yannai, E., Trembovler, V., Horowitz, M., Lazarovici, P., Kohen, R. and Shohami, E.
. Neuroprotection against oxidative stress by serum from heat acclimated rats.
Neurosci. Lett. 254:89-92 (1998).
Chen, Y., Shohami, E., Bass, R., Weinstock, M.
Cerebroprotective effects of ENA-713, a novel acetylcholinesterase inhibitor, in closed head injury in the rat.
Brain Res. 784:18-24 (1998).
Beit-Yannai, E., Kohen, R., Horowitz, M., Trembovler, V. and Shohami, E.
Changes of biological reducing activity in rat brain following closed head injury: a cyclic voltammetry study in normal and heat-acclimated rats.
J. Cereb. Blood Flow & Metabol. 17:273-279 (1997).
Assaf, Y., Beit-Yannai, E., Shohami, E. and Cohen, Y.
Diffusion- and T2-weighted MRI of closed head injury in rats: a time course study and correlation with histology.
Mag. Imaging Reson. 15:77-85 (1997).
Shohami, E., Ginis, I. and Hallenbeck, J.M.
. Dual role of tumor necrosis factor alpha in brain injury.
Cytokines and Growth Factors Reviews. 10:119-130 (1999).
Huang, W., Chen, Y., Shohami, E. and Weinstock, M.
. Neuroprotective effect of rasagiline, a selective MAO-B inhibitor, against closed head injury in the mouse.
Eur. J. Pharmacol. 336:127-135 (1999).
Lomnitski, L., Kohen, R., Chen, Y., Shohami, E., Vogel, T. and Michaelson, D.M.
Reduced levels of antioxidants in brains of apolipoprotein E-deficient mice following closed head injury.
Pharmacol. Biochem. Behav. 56:669-673 (1997).
Leker, R.R., Shohami, E., Abramsky, O. and Ovadia, H.
Dexanabinol: a novel neuroprotective drug in experimental focal cerebral ischemia.
J. Neurosci. Res. 162:114-119 (1999).
Assaf, Y., Holokovsky, A., Berman, E., Shapira, Y., Shohami, E. and Cohen, Y.
. Diffusion and perfusion MRI following closed head injury in rats.
J Neurotrauma. 16:1165-1176. 1999
Gallily, R., Yamin, A., Waksman, Y., Ovadia, H., Weidenfeld, J., Bar Joseph, A., Biegon, A., Mechoulam, R. and Shohami, E.
Protection against septic shock and suppression of TNF production and NO generation by dexanabinol (HU-211), a nonpsychotropic cannabinoid.
J. Pharmacol. Exp. Ther. 283:918-924 (1997).
Elangovan, V., Shohami, E., Gati, I. and Kohen, R.
Increased hepatic lipid soluble antioxidant capacity as compared to other organs of streptozotocine- induced diabetic rat: A cyclic voltammetry study.
Free Rad. Res. 32: 125-134. 2000
Abu-Raya, S., Bloch-Shilderman, E., Lelkes, P.I., Trembovler, V., Shohami, E., Gutman, Y. and Lazarovici, P.
Characterization of pardaxin-induced dopamine release from PC12 cells: the role of calcium and eicosanoids.
J. Pharmacol. Exp. Therap. 288:399-406, 1999
Abu Raya, S., Blaugrund E. Trembovler V. Shilderman-Bloch E., Shohami, E. and Lazarovici P.
Rasagiline, a monoamineoxidase-B inhibitor protects NGF-differentiated PC12 cells against oxygen-glucose deprivation.
J. Neurosci. Res. 58: 456-463, 1999
Chapman S., Grauer E., Chen Y., Shohami E., Weinstock M., and Michaelson DM.
The cognitive and neurochemical effects of the acetylcholinewterase inhibitor ENA713 in apolipoprotein E-deficient mice.
Intl J. Ger. Psychpharmacol. 1:171-175, (1998).
Trembovler, V., Beit-Yannai, E., Younis, F., Gallily, R., Horowitz, M. and Shohami, E.
Antioxidants attenuate acute toxicity of tumor necrosis factor a induced by brain injury in rat.
J. Interferon Cytokine Res. 19:791-795 (1999).
Shohami, E., Beit-Yannai, E., Horowitz, M. and Kohen, R.
Oxidative stress in closed head injury: brain antioxidant capacity as an indicator of functional outcome.
J. Cereb. Blood Flow & Metabol. 17:1007-1019 (1997).
Abu-Raya, S., Bloch-Shilderman, E., Shohami, E., Trembovler, V., Shai, Y., Weidenfeld, J., Yedgar, S., Gutman, Y. and Lazarovici, P. Pardaxin
a new pharmacological tool to stimulate the arachidonic acid cascade in PC12 cells.
J. Pharmacol. Exp. Therap. 287:889-896 (1998).
Morecki S., Yacovlev E., Gelfand Y., Trembobvler V., Shohami E., Slavin S.
. Induction of antitumor immunity by indomethacin.
Cancer Immunol Immunother, 48:613-620, 2000
Shohami, E., Gallily, R., Mechoulam, R., Bass, R. and Ben-Hur, T.
Cytokine production in the brain following closed head injury: dexanabinol (HU-211) is a novel TNFa inhibitor and an effective neuroprotectant.
J. Neuroimmunol. 72:169-177 (1997).
Shohami E, Novikov M, and Bass R.
. Long-term effect of HU-211, a novel non-competitive NMDA antagonist, on motor and memory functions after closed head injury in the rat.
Brain Res. 674 : 55-62 (1995).
Zhang, R., Shohami, E., Beit-Yannai, E., Bass, R., Trembovler, V and Samuni, A.
Mechanism of brain protection by nitroxide radicals in experimental model of closed head injury.
Free Rad. Biol. Med. 24:332-340 (1998).
Chen, Y., Shohami, E., Constanini, S. and Weinstock, M. Rivastigmine
, a brain-selective acetylcholinesterase inhibitor, ameliorates cognitive and motor deficits induced by closed-head injury in the mouse.
J. Neurotrauma 15:231-237 (1998).
Abu-Raya, S., Bloch-Shilderman, E., Trembovler, V., Shohami, E., Gutman, Y. and Lazarovici, P. Pardaxinv
a new pharmacological tool to stimulate the arachidonic acid cascade in PC12 cells. Proc. Int. Symp. Signal Tranduc. in Health and Disease (STUDY), p. 42, Tel Aviv (1997)
Neurosci. Lett. Suppl. 48, S30 (1997).
Chapman, S., Fisher, A., Weinstock, M., Brandeis, R., Shohami, E. and Michaelson, D.M.
The effects of the acetylcholinesterase inhibitor ENA 713 and the M1 agonist AF150(S) on apolipoprotein E deficient mice.
J. Physiol. 92 :299-303 (1998).
Ellren-Kashi, O., Trembovler, V., Abu-Raya, S., Lazarovici, P. and Shohami, E.
Neuroprotective effects of gangliosides on pardaxin-induced toxicity in PC12 cells.
J. Nat. Toxins 6:285-292 (1997).
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Deutsch, J., Shohami, E., Heller, H., Kalderon, B., Rapoport, S.I. and Purdon, D.
ESI/MS evaluation of long chain acyl carnitines in rat brain during cerebral ischemia and cerebral trauma.
Proceedings of the 14th International Mass Spectrometry Conference, Tampere, Finland (1997).
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