Faculty Profiles

 

Current Research: 
My primary interests focus on the blood-brain and blood-CSF barriers (the tissue interfaces between the brain and blood) and on stroke. In particular, I am interested in how pathological conditions affect the blood-brain barriers, how the barriers can be protected by techniques such as preconditioning, the normal physiological functions of the barrier tissues and drug transport between blood and brain. These processes are examined in vivo (using rodent models of disease) and using in vitro models of the blood-brain and blood-CSF barriers.

 

In relation to stroke, we investigate the mechanisms of brain injury that follows hemorrhagic and ischemic stroke. Using rodent models of intracerebral hemorrhage, we are focusing on the roles of thrombin, iron, complement and inflammation in inducing brain injury. In ischemic stroke, we are focusing on the roles of thrombin, endothelial injury and inflammation in brain injury. We are also examining the effects of novel preconditioning stimuli on both hemorrhagic and ischemic brain injury.

 

Recent Publications:
Cannon, J.R., *Keep, R.F.*, Hua, Y., Richardson, R.J., Schallert, T. and Xi, G. Thrombin preconditioning provides protection in a 6-hydroxydopamine Parkinson’s disease model. Neurosci. Lett. 373: 189-194; 2005

 

Nakamura, T., Xi, G., Park, J.-W., Hua, Y., Hoff, J.T. and *Keep, R.F.* Holo-transferrin and thrombin can interact to cause brain injury. Stroke 36: 348-352; 2005.

 

Nakamura, T., *Keep, R.F.*, Hua, Y., Hoff, J.T. and Xi, G. Oxidative DNA injury after experimental intracerebral hemorrhage.  Brain Res. 1039: 30-36; 2005.

 

Hua, Y., Wu, J., Pecina, S., Yang, S., Schallert, T., *Keep, R.F.* and Xi, G. Ischemic preconditioning procedure induces behavioral deficits in the absence of brain injury? J. Neurological Res. 27: 261-267; 2005

 

Hua, Y. Tang, L., *Keep, R.F.*, Schallert, T. Fewel, M.E., Muraszko, K.M., Hoff, J.T. and Xi, G. The role of thrombin in gliomas. J. Thromb Haemost 3: 1917-1923; 2005

 

Stamatovic, S.M., Shakui, P., *Keep, R.F.*, Moore, B., Kunkel, S.L., Van Roojen, N. and Andjelkovic, A.V. Monocyte chemoattractant protein-1 regulation of blood-brain barrier permeability.  J. Cereb. Blood Flow Metab. 25: 593-606; 2005.

*Keep, R.F.*, Xi, G., Hua, Y. and Hoff, J.T. The deleterious or beneficial effects of different agents in intracerebral hemorrhage: think big, think small or is hematoma size important? Stroke 36: 1594-1596; 2005

 

Nakamura, T., Hua, Y., *Keep, R.F.*, Park, J.W., Xi, G. and Hoff, J.T. Estrogen therapy for experimental intracerebral hemorrhage in rats. J. Neurosurg. 103: 97-103; 2005.

 

Hu, Y., Ocheltree, S.M., Xiang, J., *Keep, R.F.* and Smith, D.E. Glycyl-L-glutamine disposition in rat choroid plexus epithelial cells in primary culture: role of PEPT2. Pharm Res. 22: 1281-1286; 2005.

 

Karabiyikoglu, M., *Keep, R.F.*, Hua, Y, and Xi, G.  Acute subdural hematoma: new model delineation and effects of coagulation inhibitors. Neurosurgery 57:565-572; 2005.

 

Ocheltree, S.M., Shen, H., Hu, Y., *Keep, R.F.*, Smith, D.E. Role and relevance of PEPT2 in the kidney and choroid plexus: In vivo studies with glycylsarcosine in wild-type and PEPT2 knockout mice. J. Pharmacol. Exp. Ther. 315:240-247; 2005.

 

Shen, H., Hu, Y., *Keep, R.F.*, Smith, D.E. PEPT2 (Slc15a2)-mediated unidirectional transport of cefadroxil from CSF into choroid plexus. J. Pharmacol. Exp. Ther. 315: 1101-1108; 2005.

 

Patel, K., Tang, H., Grever, W., Ng, S., Xiang, J., *Keep, R.F.*, Cao, T., McAllister, J.P In vitro evaluation of polymer and self-assembled monolayer coated silicone surfaces to reduce neural cell growth. Biomaterials 27: 1519-1526; 2006.

 

Xi, G., *Keep, R.F.*, Hoff, J.T. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurology 5: 53-63; 2006

 

Hua, Y., Nakamura, T., *Keep, R.F.*, Wu, J., Kitaoka, T., Schallert, T., Hoff, J.T. and Xi, G. Long-term effects of experimental intracerebral hemorrhage: role of iron. J. Neurosurg. 104: 305-312, 2006

 

Xiang, J., Chiang, P.P., Hu, Y., Smith, D.E., *Keep, R.F.* Role of PEPT2 in glycylsarcosine transport in astrocyte and glioma cultures. Neurosci. Lett. 396: 225-229, 2006

 

Hua, Y., Wu, J., Nakamura, T., *Keep, R.F.*, Hoff, J.T. and Xi, G Tumor necrosis factor-a increases in the brain following intracerebral hemorrhage and thrombin stimulation Neurosurgery. 58: 542-550, 2006

 

Ennis, S.R. and *Keep, R.F.*  The effects of cerebral ischemia on the rat choroid plexus.  J. Cereb. Blood Flow Metab. 26: 675-683, 2006

 

Stamatovic, S.M., Dimitrijevic, O., *Keep, R.F.*, Andjelkovic, A.V. Protein kinase C-alpha:RhoA cross talk in CCL2-induced alterations in brain endothelial permeability. J. Biol. Chem. 281: 8379-8388; 2006.

 

Dimitrijevic, O., Stamatovic, S.M., *Keep, R.F.*, Andjelkovic, A.V. Effects of the chemokine CCL2 on blood-brain barrier permeability during ischemia-reperfusion injury. J. Cereb. Blood Flow. Metab. 26: 797-810; 2006.

 

Stamatovic, S.M., *Keep, R.F.*, Mostarica-Stojkovic, M, Andjelkovic, A.V. CCL2 regulates angiogenesis via activation of ets-1 transcription factors. J. Immunol 177: 2651-2661; 2006.

 

Cannon, J.R., *Keep, R.F.*, Schallert, T.M., Hua, Y., Richardson, R.J., Xi, G. Protease-activated receptor-1 mediates protection elicited by thrombin preconditioning in a 6-hydroxydopamine model of Parkinson’s disease. Brain Res. 1116: 177-186; 2006.

 

Xiang, J., Hu, Y., Smith, D.E., *Keep, R.F.* PEPT2-mediated transport of 5-aminolevulinic acid and carnosine in astrocytes. Brain Res. 1122: 18-23; 2006.

 

Yang, S., Nakamura, T., Hua, Y., *Keep, R.F.*, Younger, J., He, Y., Hoff, J.T., Xi, G. The role of complement C3 in intracerebral hemorrhage-induced brain injury. J. Cereb. Blood Flow. Metab. 26: 1490-1495; 2006.

 

Hua, Y, *Keep, R.F.*, Hoff, J.T. and Xi, G. Brain injury after intracerebral hemorrhage: the role of thrombin and iron. Stroke  38: 759-762; 2007.

 

Dimitrijevic, O., Stamatovic, S.M., *Keep, R.F.*, Andjelkovic, A.V. Absence of the chemokine receptor CCR2 protects against cerebral ischemia/reperfusion injury in mice. Stroke 38: 1345-1353; 2007.

 

Qin, Z., Karabiyikoglu, M., Silbergleit, R., *Keep, R.F.*, Xi, G. Hyperbaric oxygen induced attenuation of hemorrhagic transformation after experimental focal transient focal cerebral ischemia. Stroke 38: 1362-1367; 2007.

 

Qin, Z., Song, S., Xi, G., Silbergleit, R., *Keep, R.F.*, Hoff, J.T., Hua, Y. Hyperbaric oxygen preconditioning attenuates brain edema after experimental intracerebral hemorrhage. Neurosurgical Focus 22(5): E13 (pages 1-6); 2007.

 

Shen, H., Ocheltree, S.M., Hu, Y., *Keep, R.F.*, Smith, D.E. Impact of genetic knockout of PEPT2 on cefadroxil pharmacokinetics, renal tubular reabsorption and brain penetration in mice. Drug Metabolism and Disposition 35: 1209-1216; 2007.

 

Ennis, S.R. and *Keep, R.F.* Effects of sustained-mild and transient-severe hyperglycemia on ischemia-induced blood-brain barrier opening. J. Cereb. Blood Flow Metab. 27: 1573-1582, 2007.

 

Cannon, J.R., Hua, Y., Richardson, R.J., Xi, G., *Keep, R.F.* Schallert, T.M. The effects of thrombin on a 6-hydroxydopmanie model of Parkinson’s disease depends on timing. Behavioural Brain Research 183: 161-168, 2007.

 

Song, S., Hua, Y., *Keep, R.F.*, Hoff, J.T., Xi, G. A new hippocampal model for examining intracerebral hemorrhage-related neuronal death: Effects of deferoxamine on hemoglobin-induced neuronal death. Stroke. 38: 2861-2863; 2007.

 

Cannon, J.R., Xi, G. and *Keep, R.F.*  Recent research on changes in genomic regulation and protein expression in intracerebral hemorrhage.  Int. J. Stroke 2: 265-269, 2007.

 

Hu, Y.,Shen, H., *Keep, R.F.* Smith, D.E. Peptide transporter 2 (PEPT2) expression in brain protects against 5-aminolevulinic acid neurotoxicity. J. Neurochem. 103: 2058-2065; 2007.

 

Nakamura, T., Kuroda, Y., Zhang, X., Miyamoto, O., Tamiya, T., Nagao, S., Xi, G., *Keep, R.F.*, Itano, T. Edaravone attenuates brain edema and neurological deficits in a rat model of intracerebral hemorrhage. Stroke 39: 463-469; 2008.

 

Lee, J.Y., Huang, D.L., *Keep, R.F.*, Sagher, O. Characterization of an improved double hemorrhage rat model. J. Neurosci. Methods 168: 358-366; 2008.

 

He, Y., Wan, S., Hua, Y., *Keep, R.F.*, Xi, G. Autophagy after intracerebral hemorrhage. J. Cereb Blood Flow Metab. (in press)

Yang, S, Song, S, Hua, Y., Nakamura, T., *Keep, R.F.*, Xi G. Role of thrombin in neurogenesis after intracerebral hemorrhage. Stroke (in press)

 

Foster, D.J., Heacock, A.M., *Keep, R.F.*, Fisher, S.K. Activation of muscarinic cholinergic receptors on human SH-SY5Y neuroblastoma cells enhances both the influx and efflux of K+ under conditions of hypoosmolality. J. Pharmacol. Exp. Ther. (in press)

 

Lee, J.Y., Huang, D.L., *Keep, R.F.*, Sagher, O. Effect of electrical stimulation of the cervical spinal cord on blood flow after subarachnoid hemorrhage. J. Neurosurgery (in press)

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