Brain Chemistry and Strategies of Delivery of Drug into the CNS

PHAR 402, Dr. Lu

Handout # 1                          Central Nervous System – Blood-Brain Barrier

Location:         The tightly jointed endothelial cells of the brain capillary.

Function:        It behaves as a stringent gatekeeper between blood and brain to maintain homeostasis, i.e., the brain must be kept isolated from any transient changes in the blood particularly after meals or exercises.

  Astrocyte Foot Processes almost completely surround the brain capillary.  Because of this relation it was once thought that the astrocytes form the blood-brain barrier.  It is now known that the endothelial cells constitute the barrier.  Endothelial cells selectively transport nutrients into the brain and their many mitochondrias probably provide energy for transport. The endothelial cells of the brain have few pinocytotic vesicles.  In other organs such vesicles may provide relatively unselective transport across the capillary walls.

PHAR 402, Dr. Lu  

Handout #2

Function of Blood-Brain Barrier

 As ‘Metabolic’ Blood-brain Barrier: 

The metabolic barrier consists of enzymatic steps by which compounds are modified in the endothelium and rendered unable to enter the brain.  For example, L-DOPA, an amino acid that is a precursor of several neurotransmitters, enters and leaves the brain by means of the carrier for L-phenylalanine.  Once in the endothelium, however, L-DOPA may be converted into dopamine and DOPAC in successive steps by the enzymes L-aromatic amino acid decarboxylase and MAO.  Although dopamine can leave the brain by means of its own carrier, neither dopamine nor DOPAC can cross the antiluminal membrane into the brain.  Hence the enzymatic conversion can serve as a means of controlling how much L-DOPA reaches the brain.

 Complex System of Transporters (Asymmetric Barrier)

These transporters enable the brain capillary to control movement of nutrients into and out of the brain tissues.  Some of the transporters merely facilitate osmotic diffusion (light color); others are “active” mechanisms requiring a source of energy (dark color).  D-glucose and large neutral amino acids such as phenylalanine reach the brain by means of transporters found in both membranes of the endothelial cells. These substances flow into as well as out of the brain.  Potassium and small neutral amino acids such as glycine move only from brain to blood.  They are pumped out of the brain by active transporters found merely in the antiluminal membrane.  The inward movement of glycine is coupled with that of sodium, which provides the needed energy.

PHAR 402, Dr. Lu

Handout # 3

Various Interrelationships among Compounds of Neurochemical Interest

Note:  In the brain, all chemical compounds are synthesized from D-glucose or from the essential amino acids as illustrated in the scheme depicted below.  The only exceptions are the vitamins, insulin, and minerals, which are transported into the brain via a specific transporter.

LEGEND: No direct conversion is necessarily implied by the arrows in this figure.

             Electrophysiological activity:  CAPITAL-LETTERED NAMES

             Compounds occurring in concentration > 3mM:  Italic names

             Compounds related to behavior changes: Underlined names

PHAR 402, Dr. Lu

Handout # 4                Physiological-based Strategies

The physiological-based strategies for drug delivery derived from the understanding of the basic physiology of transport systems at the blood-brain barrier (BBB) for transporting nutrients such D-glucose, essential amino acids, vitamins, and certain neuroactive peptides.  These water-soluble nutrients cross blood-brain barrier via carrier-mediated or receptor-mediated transcytosis.

Ex. 1       D-glucose transporter

Note: Chloralose crosses BBB via D-glucose transporter due to structural similarity to D-glucose

Ex. 2       Combination of L-DOPA and Carbidopa (Sinemetâ) for the treatment of Parkinson’s disease

Note: L-DOPA will cross BBB via Phe/Trp-L-aromatic acid transporters while Carbidopa stays in the periphery and protects decarboxylation of L-DOPA. Thus this drug combination will enhance brain uptake of L-DOPA and increase DA levels in the brain.

Ex. 3        g-Vinyl GABA versus GABA

Note: isoleucine, an essential amino acid enters the brain via its transporter.  Can you see why g-Vinyl- GABA has greater brain penetration than GABA?

Ex. 4    Neuroactive peptides such as TRH, enkephalin will not cross the blood-brain barrier, but when coupled to insulin or insulin-like growth factors, their penetration into the brain is greatly enhanced via carrier-mediated transcytosis.  What potential limitations or drawback can you envision, utilizing this strategy for target delivery of drugs into the brain? (Can you use insulin itself as carrier? Why or Why not?)