Page 48 - Human Lyme Neuroborreliosis

32 David S. Younger

the cytoplasm and exocytosis at the opposite side of the cell [30] and via the
formation of caveolae or vesicle formation for the transport of macromolecules
[31]. Transmigration of cellular elements across endothelial cells of the BBB
during inflammation including leukocytes, neoplastic cells, and pathogenic
viruses, bacteria and yeasts, investigated in experimental animal models
utilizing HRP, highlighted the role of caveolae as mini-transporters of the CNS
[31]. Unique systems of modified caveolae that fuse together forming
transendothelial cell channels and later vesiculo-canalicular or vesiculo-
tubular structures (VTS) or vesiculo-vacuolar organelles (VVO), appear to be
an important gateway to the CNS in damaged endothelial cell populations
[31]. Transportation of potentially toxic endogenous or xenobiotic lipid-
soluble nonpolar molecules from the brain to the blood are accomplished by
transporters located along the luminal membrane such as the ATP binding
cassette (ABC) transporter P-glycoprotein 1 (P-gp or Pgp) (multidrug
resistance protein 1 [MDR1] or ATP-binding cassette sub-family B member 1
[ABCB1]) respectively important in the distribution of CNS tumor drug
therapy [32] and the active efflux of the anti-human immunodeficiency virus
type 1 (HIV1) nucleoside drug abacavir at the BBB [33-35]; and breast-cancer
resistance protein (BCRP) and multidrug resistance related protein (MRP) 1, 2,
4 and 5 efflux transporter pumps that serve as defense mechanisms and
determinate bioavailability and concentration of many CNS drugs important in
the treatment of CNS cancers [36] such as the novel tyrosine kinase inhibitor
dasatinib [37], and the efflux transportation of the protease inhibitor lopinavir
that contributes to its poor oral bioavailability in the treatment of HIV1 [38].
The neuroinflammation and progression of damage associated with focal
cerebral ischemia appears to be modulated by upregulation of other MRP
protein molecules that activate Toll-like receptor (TLR) signaling contributing
to neuroinflammation and progression of ischemic cerebral damage [39].

Transendothelial migration of circulating leukocytes involves a multistep
process. Leukocyte adhesion molecules (LAM) expressed on the surface of EC
initiate binding of leukocytes as a beginning step in the in their entry in brain
tissue which later includes rolling adhesion to EC, firm adhesion, and
transmigration. Although less well understood, the molecular mechanism is
believed to involve endothelial CAM including CD99, platelet ECAM
(PECAM-1)/CD31, vascular CAM-1 (VCAM-1) (important in firm adhesion);
junctional adhesion molecule-1; and expression of leukocyte adhesion
molecules E- and P-selectin (rolling adhesion); cytokine responsiveness so
noted in situ and in cell culture [40, 41] and expression of the integrins alpha4-
and beta-2. Inflamed capillary endothelia support transmigration of different

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