DRUG TRANSPORT IN THE BRAIN - Drug Transporters: Molecular Characterization and Role in Drug Disposition - page 414

processes (e.g., the axon). The conduction of electrical impulses results in the release
of neurotransmitters that further regulate (positively and negatively) nearby neuronal
responses. 25 This enables the brain to maintain a highly complex communication

network.
Glial cells are known to play an instrumental role in the regulation and mainte-
nance of CNS homeostasis and can be classified into two groups: the macroglia and
the microglia. The macroglia include both astrocytes and oligodendrocytes, which
originate from the ectodermal layer of the gastrula and proliferate throughout life,
particularly in response to injury. 26 Astrocytes are the most abundant cell type in
the brain. They possess a stellate (i.e., star-shaped) morphology and contain nu-
merous cytoplasmic fibrils, of which glial acidic fibrillary protein (GFAP) is the
main constituent. 27 Astrocytes possess numerous functions that aid in maintaining
the homeostatic environment of the CNS. These functions include the initiation and
regulation of immune and inflammatory events during injury and infection (i.e., pro-
duction and secretion of cytokines), expression of adhesion molecules for neuronal
development, buffering of excess K + during periods of neuronal hyperactivity, and
secretion of trophic factors required to maintain the integrity of the BBB. 3 , 28 - 30 The
primary function of the other macroglia cell type, oligodendrocytes, is to form the
insulating myelin sheath that surrounds neuronal axons in the CNS. Myelin, an exten-
sion of the oligodendrocyte plasma membrane, is a lipid-rich biological membrane
that forms multilamellar spirally wrapped sheaths around neuronal axons to increase
the resistance for electrical impulses during an action potential. 31
Microglia, are much smaller in size than macroglia and are the primary immune
cells of the brain. Similar to macroglia, microglia may also proliferate in response
to injury. Although a few studies have suggested that microglia originate from the
neuroectoderm, 32 , 33 the most widely accepted view is microglia are derived from
the hematopoietic lineage of the embryonic mesoderm. 34 , 35 Microglia are distributed
ubiquitously within the CNS, with the basal ganglia and cerebellum possessing con-
siderably greater numbers than the cerebral cortex. 36

14.3. DRUG TRANSPORTERS IN THE BRAIN

Pharmacological treatment of CNS disorders requires that drugs attain efficacious
concentrations in the brain. This therapeutic objective requires that drugs are able
to cross the brain barriers successfully (i.e., BBB, BCSF barrier) and in the case
of some diseases, also permeate the cellular compartments of the brain parenchyma
(i.e., astrocytes, microglia, oligodendrocytes, neurons). Although small, nonionic,
lipid-soluble compounds can easily enter the brain by passive diffusion, the CNS per-
meation of larger, water-soluble, and/or ionic substances is less likely to occur by this
mechanism. 37 For many of these compounds, uptake into the brain and extrusion from
the brain is governed by drug transport proteins. Many transport proteins that have
been shown to be involved in the influx and efflux of drugs [i.e., adenosine triphosphate
(ATP)-binding cassette transporters, organic anion and cation transporters, nucleoside
transporters, peptide transporters] have been identified both at the brain barriers and