Dr. Donald Miller
Professor
Department of Pharmacology & Therapeutics
Faculty of Medicine, University of Manitoba
Tel:  204.789.3278    Fax:  204.789.3932
Email: donald.miller@med.umanitoba.ca

General Research Themes: Neuropharmacology; blood-brain barrier function; drug delivery

The brain capillaries that form the blood-brain barrier (BBB) have a unique, and often under appreciated role in brain function.  Under normal conditions, the BBB restricts the passage of most compounds between the blood and the brain extracellular fluid, thus ensuring a proper environment for the receiving, processing and sending of neuronal signals.  However, in many neurological conditions such as multiple sclerosis, neuro-AIDS, stroke, brain tumors and brain trauma, the BBB becomes compromised.  Understanding the cellular mechanisms involved in the altered BBB permeability observed during these pathophysiological conditions may provide insight into better treatments for these diseases.  In addition, while the BBB has a protective role, restricting passage of compounds from the blood into the brain, it represents an obstacle for many potential therapeutic agents.  Thus, identification of strategies for enhancing drug transport and permeability in the BBB is necessary to optimize the efficacy of drugs for treating central nervous system diseases.  And finally, as the cellular interface between the blood and the extracellular environment of the brain, the brain capillaries represent an important relay point for the transfer of chemical signals from the periphery to the brain. 

Research in my laboratory encompasses all three of the aspects identified above.  Examples of ongoing research projects include:

-Examination of blood-brain barrier changes during brain tumor development and identification of methods for increasing the delivery of chemotherapeutic agents in the brain.

-Identification and characterization of drug efflux transport proteins in the blood-brain barrier and their impact on drug delivery to the brain

-Effect of inflammatory stimuli on the activation of brain microvessel endothelial cells

Laboratory Capabilities:

Cell culture, biochemical, molecular and functional assessment of brain endothelial cell function, in vitro and in vivo imaging techniques

Representative Publications (selected from over 50 peer-reviewed publications)

Chakravarthi, S.S., De, S., Miller, D.W., and Robinson, D.H.  (2010) Comparison of anti-tumor efficacy of paclitaxel delivered in PLGA nanospheres and microspheres.  Intl. J. Pharm. 383, 37-44.

Gufford, B.T., Sriraghavan, K., Miller, N.J., Gu, X., Miller, D.W., Vennerstrom J.L., and Robinson D.R. (2010) Physicochemical characterization of creatine N-methylguanidinium salts.  J. Dietary Supplements 7, 240-252.

Wang, T., Hasinof, B., Miller, D.W. and Gu, X.  (2010) Percutaneous permeation comparison of repellents Picaridin and DEET in concurrent use with sunscreen Oxybenzone from commercially available preparations. Pharmazie (in press). 

Mitchell, R.W., Edmundson, C., Miller, D.W., and Hatch, G.M.  (2009) On the mechanism of oleate transport across human brain microvessel endothelial cells. J. Neurochem. 110, 1049-1057. 

Bachmeier, C., Trickler, W.J., and Miller, D.W. “Comparison of drug efflux transport kinetics in various blood-brain barrier models.” Drug Metab. Dist. 34:998-1003, 2006.

Wang, G., Li, Y., Li, X., Han, H-Y., and Miller, D.W. “ Structure and activity of LL-37 fragments and TOCSY-based identification of a core antimicrobial and anticancer peptide.” J. Am. Chem. Soc. 128:5776-5785, 2006. 

McGuire, T.R., Trickler, W.J., Smith, L., Hoie, E.B., and Miller, D.W.  “Release of TNF-alpha and IL-1beta from porcine brain endothelium corresponds to the pyrogenic potential of three marketed formulations of amphotericin.” Inflamm. Res. 54:375-379, 2005.

4.   Trickler, W.J., Mayhan, W. and Miller, D.W. “TNF-induced increases in brain microvessel endothelial cell permeability involve the activation of NFkB signal transduction system.” Brain Res. 1048:24-31, 2005.

5.   Bachmeier, C., and Miller, D.W. “A fluorometric screening assay for drug efflux transporter activity in the blood-brain barrier.” Pharm. Res. 22:113-121, 2005.

6.   Zhang, Y., Elmquist, W.F., Schuetz, J., and Miller, D.W. “Plasma membrane localization of multidrug resistance-associated protein (MRP) homologues in brain capillary endothelial cells.” J. Pharmacol. Exp. Ther. 311:449-455, 2004.

7.   Zhang, Y., Bachmeier, C., and Miller, D.W. “In Vitro and In Vivo Models for Assessing Drug Efflux Transporter Activity.” Adv. Drug Del. Rev. 55:31-51, 2003.

8.   Mark, K.S., Trickler, W.J., and Miller, D.W. “Role of cyclooxygenase-2 and prostaglandins in the TNF-ainduced changes in brain microvessel endothelial cell permeability.” J. Pharmacol. Exp. Ther. 297:1051-1058, 2001.