The Nervous System

• The human nervous system can be divided into two parts: the central nervous system (CNS) and the peripheral nervous system (PNS)

• http://pennhealth.com/health_info/animationplayer/nerve_conduction.html

Central Nervous SystemDrugs that affect the CNS can:•Selectively relieve pain•Reduce fever•Suppress disordered movement•Induce sleep or arousal•Reduce appetite•Allay the tendency to vomit•Be used to treat anxiety, depression, schizophrenia, Parkinson’s Disease, Alzheimer’s Disease, epilepsy, migraine, etc.

How do drugs work in the CNS?• “A central underlying concept of

neuropharmacology is that drugs that influence behavior and improve the functional status of patients with neurological or psychiatric diseases act by enhancing or blunting the effectiveness of specific combinations of synaptic transmitter actions.”

Blood Brain Barrier (BBB)

• A physiological mechanism that alters the permeability of brain capillaries, so that some substances, such as certain drugs, are prevented from entering brain tissue, while other substances are allowed to enter freely.

• The separation of the brain, which is bathed in a clear cerebrospinal fluid, from the bloodstream. The cells near the capillary beds external to the brain selectively filter the molecules that are allowed to enter the brain, creating a more stable, nearly pathogen-free environment.

Diagram of a cerebral capillary enclosed in astrocyte end-feet. Characteristics of the blood-brain barrier are indicated: (1) tight junctions that seal the pathway between the capillary (endothelial) cells; (2) the lipid nature of the cell membranes of the capillary wall which makes it a barrier towater-soluble molecules; (3), (4), and (5) represent some of the carriers and ion channels; (6) the 'enzymatic barrier'that removes molecules from the blood; (7) the efflux pumps which extrude fat-soluble molecules that have crossed into the cells

Blood-Brain-Barrier

• Oxygen, glucose, and white blood cells are molecules that are able to pass through this barrier. Red blood cells cannot.

Blood Brain Barrier

• The blood-brain barrier (abbreviated BBB) is composed of endothelial cells packed tightly in brain capillaries that more greatly restrict passage of substances from the bloodstream than do endothelial cells in capillaries elsewhere in the body.

• Processes from astrocytes surround the epithelial cells of the BBB providing biochemical support to the epithelial cells.

• The BBB should not be confused with the blood-cerebrospinal fluid barrier (BCB), a function of the choroid plexus.

History of the BBB

• The existence of such a barrier was first noticed in experiments by Paul Ehrlich in the late-19th century. Ehrlich was a bacteriologist who was studying staining, used for many studies to make fine structures visible. Some of these dyes, notably the aniline dyes that were then popular, would stain all of the organs of an animal except the brain when injected. At the time, Ehrlich attributed this to the brain simply not picking up as much of the dye.

• However, in a later experiment in 1913, Edwin Goldmann (one of Ehrlich's students) injected the dye into the spinal fluid of the brain directly.

• He found that in this case the brain would become dyed, but the rest of the body remained dye-free. This clearly demonstrated the existence of some sort of barrier between the two sections of the body.

History of the BBB

• At the time, it was thought that the blood vessels themselves were responsible for the barrier, as there was no obvious membrane that could be found.

• It was not until the introduction of the scanning electron microscope to the medical research fields in the 1960s that this could be demonstrated. The concept of the blood-brain (then termed hematoencephalic) barrier was proposed by Lina Stern in 1921.

What is the purpose of the BBB?

• The blood-brain barrier protects the brain from the many chemicals flowing around the body.

• For example, many bodily functions are controlled by hormones, which are detected by receptors on the plasma membranes of targeted cells throughout the body.

• The secretion of many hormones are controlled by the brain, but these hormones generally do not penetrate the brain from the blood, so in order to control the rate of hormone secretion effectively, there are specialized sites where neurons can "sample" the composition of the circulating blood.

• At these sites, the blood-brain barrier is 'leaky'; these sites include three important 'circumventricular organs', the subfornical organ, the area postrema and the organum vasculosum of the lamina terminalis (OVLT).

• The blood-brain barrier is also an effective way to protect the brain from common infections. Thus infections of the brain are very rare; however, as antibodies are too large to cross the blood-brain barrier, when infections of the brain do occur they can be very serious and difficult to treat.

How does the BBB affect the design of therapeutic agents?

• Mechanisms for drug targeting in the brain involve going either "through" or "behind" the BBB.

• Modalities for drug delivery through the BBB entail disruption of the BBB by osmotic means, biochemically by the use of vasoactive substances such as bradykinin, or even by localized exposure to high intensity focused ultrasound (HIFU).

• The potential for using BBB opening to target specific agents to brain tumors has just begun to be explored.

The Blood Brain Barrier

• http://www.clinicaloptions.com/HIV/Management%20Series/NeuroAIDS/Animation/Blood%20Brain%20Barrier.aspx