Richard Keep , Ph.D. ~Crosby Kahn Collegiate Professor of Neurosurgery and Neuroanatomy ~Director Crosby Neurosurgical Laboratories ~ Associate Chair for Research, Department of Neurosurgery ~Professor, Department of Molecular and Integrative Physiology Ph.D., University of Aberdeen (Scotland), 1984 rKeep@umich.edu

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:

Xi, G., Fewel, M.E., Hua, Y., Thompson, B.G., Hoff, J.T. and Keep, R.F. Intracerebral hemorrhage: pathophysiology and therapy. Neurocritical Care 1: 5-18, 2004.

Ocheltree, S.M., Shen, H., Hu, Y., Xiang, J., Keep, R.F. and Smith, D.E. Mechanisms of cefadroxil uptake in the choroid plexus: studies with wild type and PEPT2 knockout mice. J. Pharmacol. Exp. Ther 308: 462-467, 2004.

Karabiyikoglu, M., Hua, Y, Keep, R.F., Ennis, S.R. and Xi, G. Intracerebral hirudin injection attenuates ischemic tissue damage and neurological deficits without altering local cerebral blood flow. J. Cereb. Blood Flow Metab 24: 159-166, 2004.

Teuscher, N.S., Shen, H., Shu, C., Xiang, J., Keep, R.F. and Smith, D.E. Carnosine uptake in rat choroid plexus primary cell cultures and choroid plexus whole tissue from PEPT2 null mice. J. Neurochem. 89: 375-382, 2004.

Nakamura, T., Keep, R.F., Hua, Y., Schallert, T., Hoff, J.T. and Xi, G. Deferoxamine attenuates brain edema and neurological deficits after experimental intracerebral hemorrhage. J. Neurosurg. 100: 672-678, 2004.

Nakamura, T., Xi, G., Hua, Y., Schallert, T., Hoff, J.T. and Keep, R.F. Intracerebral hemorrhage in mice: model characterization and application for genetically modified mice. J. Cereb. Blood Flow Metab. 24: 487-494, 2004.

Shen, H., Smith, D.E., Keep, R.F. and Brosius, F.C. Immunolocalization of the proton-coupled oligopeptide transporter PEPT2 in developing rat brain. Molecular Pharmaceutics. 1: 248-256, 2004.

Ocheltree, S.M., Shen, H., Hu, Y., Xiang, J., Keep, R.F. and Smith, D.E. Role of PEPT2 in the choroid plexus uptake of glycylsarcosine and 5-aminolevulinic acid: studies in wild-type and null mice Pharm. Res. 21: 1680-1685; 2004.

Gong, Y., Hua, Y., Keep, R.F., Hoff, J.T. and Xi, G. Intracerebral hemorrhage: effects of aging on brain edema and neurological deficits. Stroke 35: 2571-2575; 2004.

Cannon, J., 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. 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. Thrombosis & Hemostasis 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. Effects of estrogen on brain injury after intracerebral hemorrhage. 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.

Ennis, S.R. and Keep, R.F.  The effects of cerebral ischemia on the rat choroid plexus.  J. Cereb. Blood Flow Metab.(in press)

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. (in press)

Xi, G., Keep, R.F., Hoff, J.T. Mechanisms of brain injury after intracerebral hemorrhage. Lancet Neurology (in press)

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. (in press)

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(in press)

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. (in press)

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. (in press)

Back to list of faculty