Thomas P Davis
Professor, BIO5 Institute
Professor, Neuroscience - GIDP
Professor, Pharmacology
Professor, Pharmacology and Toxicology
Professor, Physiological Sciences - GIDP
Primary Department
Department Affiliations
(951) 858-5720
Research Interest
Thomas Davis, PhD, and his lab continue its long-term CNS biodistribution research program, funded by NIH since 1981, by studying the mechanisms involved in delivering drugs across the blood-brain barrier to the C.N.S. during pathological disease states. Recently, Dr. Davis and his lab discovered specifica drug transporters which can be targeted to enhance delivery. They are also interested in studying the effect of hypoxia/aglycemia/inflammatory pain on endothelial cell permeability and structure at the blood-brain barrier. Dr. Davis has recently shown that short-term hypoxia/aglycemia leads to significant alterations in permeability which can be reversed by specific calcium channel antagonists. This work has significant consequences to the study of stroke. Additionally, he has discovered that peripheral pain has significant effects on BBB tight junction protein cytoarchitecture leading to variations in the delivery of analgesics to the CNS.

Publications

Davis, T., Brown, R. C., Egleton, R. D., & Davis, T. P. (2004). Mannitol opening of the blood-brain barrier: regional variation in the permeability of sucrose, but not 86Rb+ or albumin. Brain research, 1014(1-2).

Clinically, infusion of hyperosmolar solutions is used to enhance chemotherapeutic drug penetration of the blood-brain barrier (BBB) in patients with malignant brain tumors or metastases. We examined the effect of hyperosmolar BBB disruption on brain permeability of three compounds, 86Rb+, a marker for K+ permeability and transport, [14C]sucrose and Evans blue albumin, using a rat in situ perfusion model. 86Rb+ and [14C]sucrose had increased permeability 20 min after BBB disruption with 1.6 M mannitol. There was no change in Evans blue albumin permeability. Only [14C]sucrose showed regional variation in permeability after mannitol-induced BBB disruption, with the cortex and midbrain having higher sucrose permeability then either the cerebellum or brainstem. These data suggest that the clinical efficacy of hyperosmolar disruption therapy in conjunction with chemotherapeutic agents, of a similar molecular weight to sucrose, may be affected by the location of the tumor within the brain.

Davis, T., Hau, V. S., Huber, J. D., Campos, C. R., Lipkowski, A. W., Misicka, A., & Davis, T. P. (2002). Effect of guanidino modification and proline substitution on the in vitro stability and blood-brain barrier permeability of endomorphin II. Journal of pharmaceutical sciences, 91(10).

Endomorphin II (ENDII), an endogenous ligand for the mu-opioid receptor, was investigated as a possible analgesic with fewer side effects than morphine. To improve CNS entry of END II, structural modification was also examined to determine whether Pro(4) substitution and cationization affected physico-chemical characteristics, blood-brain barrier (BBB) transport, and analgesic profile. END II and its Pro(4)-substituted analog, Morphiceptin (MOR), were cationized by guanidino (GU)-addition. MOR was seven times less lipophilic than END II, whereas GU-addition decreased lipophilicity of both peptides. MOR did not affect in vitro BBB permeability; however, GU-addition increased permeability of MOR by 31%. MOR decreased protein binding by 23% compared to END II, whereas GU-addition increased protein binding of both peptides by 71 and 113%, respectively. MOR increased brain t(1/2) compared to END II. GU-addition significantly increased t(1/2) of MOR and END II in both brain (sixfold and 10-fold, respectively) and serum (over 10-fold). Pro(4)-substitution and GU-addition enhanced the in vivo analgesia profiles of i.v. administered END II and MOR, but decreased i.c.v. analgesia profiles. This study demonstrates Pro(4)-substitution decreases protein binding and enhances brain stability while cationization enhances both brain and serum stability with variable effects on BBB permeability. The analgesic profiles show that both Pro(4)-substitution and cationization enhance i.v. analgesia and thus, are promising structural modifications for the development of successful opioid drugs.

Davis, T., Brown, R. C., & Davis, T. P. (2002). Calcium modulation of adherens and tight junction function: a potential mechanism for blood-brain barrier disruption after stroke. Stroke; a journal of cerebral circulation, 33(6).

This review deals with the role of calcium in endothelial cell junctions of the blood-brain barrier (BBB). Calcium is critical for adherens junction function, but it appears that calcium is also important in regulating tight junction function necessary for the barrier characteristics of cerebral microvessels.

Davis, T., Ronaldson, P. T., & Davis, T. P. (2012). Blood-brain barrier integrity and glial support: mechanisms that can be targeted for novel therapeutic approaches in stroke. Current pharmaceutical design, 18(25).

The blood-brain barrier (BBB) is a critical regulator of brain homeostasis. Additionally, the BBB is the most significant obstacle to effective CNS drug delivery. It possesses specific charcteristics (i.e., tight junction protein complexes, influx and efflux transporters) that control permeation of circulating solutes including therapeutic agents. In order to form this "barrier," brain microvascular endothelial cells require support of adjacent astrocytes and microglia. This intricate relationship also occurs between endothelial cells and other cell types and structures of the CNS (i.e., pericytes, neurons, extracellular matrix), which implies existence of a "neurovascular unit." Ischemic stroke can disrupt the neurovascular unit at both the structural and functional level, which leads to an increase in leak across the BBB. Recent studies have identified several pathophysiological mechanisms (i.e., oxidative stress, activation of cytokine-mediated intracellular signaling systems) that mediate changes in the neurovascular unit during ischemic stroke. This review summarizes current knowledge in this area and emphasizes pathways (i.e., oxidative stress, cytokine-mediated intracellular signaling, glial-expressed receptors/targets) that can be manipulated pharmacologically for i) preservation of BBB and glial integrity during ischemic stroke and ii) control of drug permeation and/or transport across the BBB. Targeting these pathways present a novel opportunity for optimization of CNS delivery of therapeutics in the setting of ischemic stroke.

Davis, T., Witt, K. A., Mark, K. S., Hom, S., & Davis, T. P. (2003). Effects of hypoxia-reoxygenation on rat blood-brain barrier permeability and tight junctional protein expression. American journal of physiology. Heart and circulatory physiology, 285(6).

Cerebral microvessel endothelial cells that form the blood-brain barrier (BBB) have tight junctions (TJs) that are critical for maintaining brain homeostasis. The effects of initial reoxygenation after a hypoxic insult (H/R) on functional and molecular properties of the BBB and TJs remain unclear. In situ brain perfusion and Western blot analyses were performed to assess in vivo BBB integrity on reoxygenation after a hypoxic insult of 6% O2 for 1 h. Model conditions [blood pressure, blood gas chemistries, cerebral blood flow (CBF), and brain ATP concentration] were also assessed to ensure consistent levels and criteria for insult. In situ brain perfusion revealed that initial reoxygenation (10 min) significantly increased the uptake of [14C]sucrose into brain parenchyma. Capillary depletion and CBF analyses indicated the perturbations were due to increased paracellular permeability rather than vascular volume changes. Hypoxia with reoxygenation (10 min) produced an increase in BBB permeability with associated alterations in tight junctional protein expression. These results suggest that H/R leads to reorganization of TJs and increased paracellular diffusion at the BBB, which is not a result of increased CBF, vascular volume change, or endothelial uptake of marker. Additionally, the tight junctional protein occludin had a shift in bands that correlated with functional changes (i.e., increased permeability) without significant change in expression of claudin-3, zonula occludens-1, or actin. H/R-induced changes in the BBB may result in edema and/or associated pathological outcomes.