Research

I am interested to understand the structure and function of the blood-brain barrier (BBB), particularly passage of molecules across the BBB and changes to the BBB in pathological conditions. The BBB is formed by cerebral microvessel endothelium and plays an important role to regulate molecular traffic between the circulating blood and the brain. The regulation involves different levels of barriers including the tight junction that seals inter-endothelial space, and the polarized expressions of membrane transporters that are either facilitating or impeding transport of molecules. Though the regulation of passage of molecules by the BBB protects the microenvironment of the brain, the BBB also imposes a significant challenge in the central nervous system (CNS) drug development as delivery of therapeutic molecules are hampered.

At CDR, we have established a cell-based BBB model using primary brain endothelial cells. The model allows us to investigate BBB permeation of CNS lead compounds and different formulations or constructs to improve delivery. Improvements of the cell-based model to better resembles the BBB, and development of a pathological cell-based model are always of interests to me. As the BBB is dynamic in nature, we also used animal models that mimic pathological state e.g. in cerebral hypoperfusion, to explore potential changes to the BBB in such state. The knowledge gained may lead to better therapeutic strategies for CNS disorders.

Current Research Projects:

• The pathophysiology of the BBB in animal model of cerebral hypoperfusion
• Application of in vitro model of the BBB to investigate  detailed permeability mechanisms of Mitragyna speciosa (ketum) alkaloids

People

• Hema A/P Sekaran
• Mahathir Mohd Uzid

Current MSc student (as main supervisor)

• Liyana Mohd Nazri

Publications

1. Yusof, S.R., Mohd Uzid, M., Teh, E.H., Hanapi, N.A., Mohideen, M., Mohamad Arshad, A.S., Mordi, M.N., Loryan, I., Hammarlund-Udenaes, M. (2018) Rate and extent of mitragynine and 7-hydroxymitragynine blood-brain barrier transport and their intra-brain distribution: the missing link in pharmacodynamic studies. Addict Biol. 2018 Aug 8. doi: 10.1111/adb.12661. [Epub ahead of print]
2. Nielsen, S.S.E.,  Siupka, P., Georgian, A., Preston, J.E., Tóth, A.E., Yusof, S.R., Abbott, N.J., Nielsen, M.S. (2017) Improved method for the establishment of an in vitro blood-brain barrier model based on porcine brain endothelial cells. J Vis Exp., 127, e56277.
3. Yusof, S.R., Abbott, N.J., Avdeef, A. (2017) Impact of capillary flow hydrodynamics on carrier-mediated transport of opioid derivatives at the blood-brain barrier, based on pH-dependent Michaelis-Menten and Crone-Renkin analyses. Eur J Pharm Sci., 106, 274-286.
4. Liew K.F., Hanapi, N.A., Chan, K.L., Yusof, S.R., Lee, C.Y. (2017) Assessment of the blood-brain barrier permeability of potential neuroprotective aurones in PAMPA and porcine brain endothelial cell models. J Pharm Sci., 106 (2), 502-510.
5. Yusof, S.R., Avdeef, A., Abbott, N.J. (2014) In vitro porcine blood-brain barrier model for permeability studies: pCEL-X software pK_a^FLUX method for aqueous boundary layer correction and detailed data analysis. Eur J Pharm Sci., 65C, 98.
6. Dickens, D., Yusof, S.R., Abbott, N.J., Weksler, B., Romero, I.A., Couraud, P.O., Alfirevic, A., Pirmohamed, A., Owen, A. (2013) A multi-system approach assessing the interaction of anticonvulsants with P-gp. PLoS One, 8, e64854.
7. Teow, H.M., Zhou, Z., Najlah, M., Yusof, S.R., Abbott, N.J., D’Emanuele, A. (2013) Delivery of paclitaxel across cellular barriers using a dendrimer-based nanocarrier. Int. J. Pharm., 441, 701-711.
8. Abbott, N.J., Patabendige, A.A. Dolman, D.E., Yusof, S.R., Begley, D.J. (2010) Structure and function of the blood-brain barrier. Neurobiol. Dis., 37, 13-25.

Chapter in Book

1. Abbott, N.J., Dolman, D.E.M., Yusof, S.R., Reichel A. (2014) In vitro models of blood-brain barriers, in Drug Delivery to the Brain, Physiological Concepts, Methodologies and Approaches, (Hammarlund-Udenaes M., de Lange E. and Thorne R., (eds.), Vol. 10, pp. 163-197, Springer New York.

Published Abstract

1. Mohd Uzid M, Hanapi N, Mansor S, Yusof S (2016) Mitragynine and 7-hydroxymitragynine: In vitro blood-brain barrier permeability studies. Front. Cell. Neurosci. Conference Abstract: 14^th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00145.
2. Sekaran H, Hassan Z, Yusof S (2016) Regional extravasation of Evans blue dye in the brain across the blood-brain barrier during cerebral hypoperfusion. Front. Cell. Neurosci. Conference Abstract: 14^th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00162.
3. Hanapi N, Yusof S, Adenan M, Tengku Muhammad T (2016) Blood-brain barrier permeability studies of Centella asiatica extract as potential neuroprotective agent. Front. Cell. Neurosci. Conference Abstract: 14^th Meeting of the Asian-Pacific Society for Neurochemistry. doi: 10.3389/conf.fncel.2016.36.00142.
4. Mahathir Mohd. Uzid, Nur Aziah Hanapi, Siti Rafidah Yusof (2014) Development of in vitro blood-brain barrier models using primary brain endothelial cells. Archives of Pharmacy Practice, 5 Supplement 1, S9.