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. P., Tome, M., & Schaefer, C. (2017). Chronic morphine exposure potentiates p-glycoprotein trafficking from nuclear reservoirs in cortical brain microvessels .. PloSOne, Submitted, Submitted.
Davis, T., Ronaldson, P. T., & Davis, T. P. (2013). Targeted drug delivery to treat pain and cerebral hypoxia. Pharmacological reviews, 65(1).

Limited drug penetration is an obstacle that is often encountered in treatment of central nervous system (CNS) diseases including pain and cerebral hypoxia. Over the past several years, biochemical characteristics of the brain (i.e., tight junction protein complexes at brain barrier sites, expression of influx and efflux transporters) have been shown to be directly involved in determining CNS permeation of therapeutic agents; however, the vast majority of these studies have focused on understanding those mechanisms that prevent drugs from entering the CNS. Recently, this paradigm has shifted toward identifying and characterizing brain targets that facilitate CNS drug delivery. Such targets include the organic anion-transporting polypeptides (OATPs in humans; Oatps in rodents), a family of sodium-independent transporters that are endogenously expressed in the brain and are involved in drug uptake. OATP/Oatp substrates include drugs that are efficacious in treatment of pain and/or cerebral hypoxia (i.e., opioid analgesic peptides, 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors). This clearly suggests that OATP/Oatp isoforms are viable transporter targets that can be exploited for optimization of drug delivery to the brain and, therefore, improved treatment of CNS diseases. This review summarizes recent knowledge in this area and emphasizes the potential that therapeutic targeting of OATP/Oatp isoforms may have in facilitating CNS drug delivery and distribution. Additionally, information presented in this review will point to novel strategies that can be used for treatment of pain and cerebral hypoxia.

Davis, T., Huber, J. D., Hau, V. S., Mark, K. S., Brown, R. C., Campos, C. R., & Davis, T. P. (2002). Viability of microvascular endothelial cells to direct exposure of formalin, lambda-carrageenan, and complete Freund's adjuvant. European journal of pharmacology, 450(3).

We investigated three inflammatory agents to establish if these substances elicit a direct effect on the functional and structural integrity of the blood-brain barrier. Cellular cytotoxicity and paracellular permeability were assessed in vitro using primary bovine brain microvascular endothelial cells exposed to formalin, lambda-carrageenan, or complete Freund's adjuvant for 1, 3, or 72 h, respectively. Results showed that only the highest concentration (0.025%) of formalin produced a decrease in cell viability (approximately 34%) and a significant increase in cell permeability to [(14)C]sucrose at 120 min (approximately 137%). Brain perfusion using female Sprague-Dawley rats showed no difference in paracellular permeability to [(14)C]sucrose for any inflammatory agent. Western blot analyses were performed on isolated rat brain microvessels to assess the structural integrity of blood-brain barrier tight junctions. Results indicate that expression of zonula occludens-1, occludin, claudin-1, and actin remain unchanged following intravenous exposure to inflammatory agents. This study confirms that changes seen at the blood-brain barrier following a peripheral inflammation are due to physiological responses to the given inflammatory agent and not to any direct interaction between the inflammatory agent and the brain microvasculature.

Davis, T., Hawkins, B. T., Egleton, R. D., & Davis, T. P. (2005). Modulation of cerebral microvascular permeability by endothelial nicotinic acetylcholine receptors. American journal of physiology. Heart and circulatory physiology, 289(1).

Nicotine increases the permeability of the blood-brain barrier in vivo. This implies a possible role for nicotinic acetylcholine receptors in the regulation of cerebral microvascular permeability. Expression of nicotinic acetylcholine receptor subunits in cerebral microvessels was investigated with immunofluorescence microscopy. Positive immunoreactivity was found for receptor subunits alpha3, alpha5, alpha7, and beta2, but not subunits alpha4, beta3, or beta4. Blood-brain barrier permeability was assessed via in situ brain perfusion with [14C]sucrose. Nicotine increased the rate of sucrose entry into the brain from 0.3 +/- 0.1 to 1.1 +/- 0.2 microl.g(-1).min(-1), as previously described. This nicotine-induced increase in blood-brain barrier permeability was significantly attenuated by both the blood-brain barrier-permeant nicotinic antagonist mecamylamine and the blood-brain barrier-impermeant nicotinic antagonist hexamethonium to 0.5 +/- 0.2 and 0.3 +/- 0.2 microl.g(-1).min(-1), respectively. These data suggest that nicotinic acetylcholine receptors expressed on the cerebral microvascular endothelium mediate nicotine-induced changes in blood-brain barrier permeability.

Davis, T., Fleegal, M. A., Hom, S., Borg, L. K., & Davis, T. P. (2005). Activation of PKC modulates blood-brain barrier endothelial cell permeability changes induced by hypoxia and posthypoxic reoxygenation. American journal of physiology. Heart and circulatory physiology, 289(5).

The blood-brain barrier (BBB) is a metabolic and physiological barrier important for maintaining brain homeostasis. The aim of this study was to determine the role of PKC activation in BBB paracellular permeability changes induced by hypoxia and posthypoxic reoxygenation using in vitro and in vivo BBB models. In rat brain microvessel endothelial cells (RMECs) exposed to hypoxia (1% O2-99% N2; 24 h), a significant increase in total PKC activity was observed, and this was reduced by posthypoxic reoxygenation (95% room air-5% CO2) for 2 h. The expression of PKC-betaII, PKC-gamma, PKC-eta, PKC-mu, and PKC-lambda also increased following hypoxia (1% O2-99% N2; 24 h), and these protein levels remained elevated following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Increases in the expression of PKC-epsilon and PKC-zeta were also observed following posthypoxic reoxygenation (95% room air-5% CO2; 2 h). Moreover, inhibition of PKC with chelerythrine chloride (10 microM) attenuated the hypoxia-induced increases in [14C]sucrose permeability. Similar to what was observed in RMECs, total PKC activity was also stimulated in cerebral microvessels isolated from rats exposed to hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min). In contrast, hypoxia (6% O2-94% N2; 1 h) and posthypoxic reoxygenation (room air; 10 min) significantly increased the expression levels of only PKC-gamma and PKC-theta in the in vivo hypoxia model. These data demonstrate that hypoxia-induced BBB paracellular permeability changes occur via a PKC-dependent mechanism, possibly by differentially regulating the protein expression of the 11 PKC isozymes.