Professor of Pharmacology, University of Missouri, 1978The focus of my research is the blood brain barrier (BBB)/Neurovasular Unit in health and disease and specifically the effects of inflammation and stroke on the BBB. The BBB plays a vital role in maintaining brain homeostasis. Composition of the brain interstitial fluid is controlled within a precise range, independent of fluctuations within the blood, allowing optimal neuronal function to occur. The BBB is situated at the endothelial tight junctions of the cerebral microvessels.
Fig.1. Schematic showing the BBB/Neurovascular unit. Note the loose association of astrocytes to endothelial cells.
The cerebral endothelial cells form a continuous membrane with no fenestrations, unlike peripheral vessels. The endothelial cells of the BBB are connected via a network of tight junctions that create a rate-limiting barrier to paracellular diffusion of solutes. Structurally, tight junctions form a continuous network of parallel, interconnected, intramembrane protein strands, which are composed of an intricate combination of transmembrane and cytoplasmic proteins linked with the actin-based cytoskeleton, allowing the tight junction to form a seal while remaining capable of rapid modulation and regulation.
Fig.2. Schematic of the tight junctions of the BBB. Tight junctions consist of three main groups of proteins. They are transmembrane proteins (Claudins, occuludin and junctional adhesion molecule), accessory proteins (ZO-1 /2 /3 etc) and cytoskeletal proteins (actin etc). All three groups interact to maintain the tight junctions (for a more detailed review see Hawkins and Davis, 2005). These proteins can be modulated via a number of mechanisms. In neuroinflammatory disorders (Alzheimers, Parkinsons and multiple sclerosis), alterations in these proteins contribute to disease progression.
Wang Y., M. Thiyagarajan, N. Chow, I. Singh, H. Guo, T.P. Davis and B. Zlokovic. Differential Neuroprotection and Risk for Bleeding from Activated Proein C with varying degree of Anticoagulant Activity. Stroke. Dec. 4 [Epub] 2008.
McCaffrey, G.W., M.J. Seelback, W.D. Staatz, N. Nametz, C. Quigley, C.R. Campos, T.A. Brooks and T.P. Davis. Occludin oligomeric assembly at tight junctions of the blood-brain barrier is disrupted by peripheral inflammatory hyperalgesia. J. Neurochemistry; 106(6) 2395-409, 2008
Willis, C.L. and T.P. Davis. Chronic inflammatory pain and the neurovascular unit: a central role for maintaining BBB integrity? Current Pharmaceutical Design 14(16): 1625-1643, 2008.
Brooks, T.A., N. Nametz, R. Charles and T.P. Davis. Diclofenac attenuates the regional effect of Lambda carrageenan on BBB function and cytoarchitecture. J.Pharmacol Exp.Ther. 325(2): 665-673, 2008.
Neuwelt, E., N. Joan Abbott, L.Abrey, W. A. Banks, B. Blakley, T.P. Davis, B. Engelhardt, P.
Grammas, M. Nedergard, J. Nutt, W. Pardridge, G. Rosenberg, Q. Smith and L. Drewes.
Strategies to advance translational research into brain barriers. Lancet Neurology Volume 7, January 2008.
Campos, C.R., S, Hom, R.D. Egleton and T.P. Davis. Nociceptive inhibition prevents inflammatory pain induced changes in the blood brain barrier. Brain Research 1221: 6-13, 2008.
Witt, K.A., K.S. Mark , K. Sandoval and T.P. Davis. Reoxygenation stress on Blood Brain Barrier Paracellular Permeability and Edema in the Rat. Microvascular Research. 75(1):91-96, 2008.
McCaffrey, G., W. Staatz, R. Egleton, M. Seelbach, C. Campos and T.P. Davis. Tight Junctions contain Oligomeric protein assembly critical for maintaining Blood Brain Barrier integrity in vivo. J. Neurochemistry 103:2540-2555, 2007.
Hom, S., M.A. Fleegal, R.D. Egleton, C.R. Campos, B. Hawkins and T.P. Davis. Comparative changes is the blood brain barrier and cerebral infarction of SHR and WKY rats. American Journal of Physiology (Regulatory, Integrative and Comparative Physiology) 292 (5).1881-1892. 2007.
Seelbach, M.J., J.D. Huber, T. Brooks, R.D. Egleton, K.A. Witt and T.P. Davis. Effect of lambda carrageenan-induced inflammatory pain on brain uptake of morphine and the potential role of P-glycoprotein. J. Neurochemistry 102,5.1677-1689. 2007.
Huber, J.D., C.R. Campos, K.S. Mark and T.P. Davis. Alterations in blood-brain barrier ICAM-1 expression and microglial activation following lambda carrageenan induced inflammatory pain. American Journal of Physiology (Heart and Circulatory) 290(2):H732-740. 2006.
Witt, K.A. and T.P. Davis. CNS Drug Delivery: Opioid Peptides and the Blood Brain Barrier. The AAPS Journal 7(4) 9, 2006.
Brooks, T.A., C.R. Campos, R.D. Egleton, M. Seelbach, N. Nametz and T.P. Davis. Biphasic cytoarchitecture and functional changes in the BBB induced by chronic inflammatory pain. Brain Research 1120(1).172-182. 2006.
Fleegal, M.A., S. Hom, L.K. Borg and T.P. Davis. Hypoxia and post-hypoxic reoxygenation modulate PKC activity and protein expression in endothelial cells of the blood-brain barrier. American J. Physiology (Heart and Circulatory).
289(5):H2012-2019, 2005.
Hawkins, B.T. and T.P. Davis. The blood-brain barrier/neurovascular unit in health and disease. Pharmacological Reviews. 57(2):173-185, 2005.
Brooks, T.A., B.T. Hawkins, J.D.Huber, R.D. Egleton and T.P. Davis. Chronic inflammatory pain leads to increased blood-brain barrier permeability and tight junction protein alterations. American J. Physiology (Heart and Circulatory).
289(2):H738-H743, 2005.
Witt, K.A., K.S. Mark, J.D. Huber and T. P. Davis. Hypoxia Inducible Factor and Nuclear Factor Kappa-B Activation in Blood Brain Barrier Endothelium under hypoxic/Reoxygenation Stress. J. Neurochemistry. 92(1):2030-214, 2005.
Egleton, R.D. and T.P. Davis. Development of Neuropeptide Drugs that Cross the Blood-Brain Barrier. NeuroRx. Jan:2(1), 44-53, 2005.
Brown, R.C. and T.P. Davis. Hypoxia/Aglycemia alters expression of occludin and actin in brain endothelial cells. Biochemical and Biophysical Research Communications. 327(4):1114-1123, 2005.
Hawkins, B.T., R.D. Egleton and T.P. Davis. Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors. American J. Physiology (Heart and Circulatory) 289(1): H212-H219, 2005.