There are however a few places in the brain that are
leakier of terms of the blood-brain barrier than others.
And these are areas that we term circumventricular
organs. And this occur very close to ventricles such as
the lateral ventricle, the 3rd ventricle, the 4th ventricle.
And these areas are such as the subfornical organ,
the median eminence, the posterior pituitary,
the pineal gland, the OVLT, and finally the area postrema.
These are all areas in which the blood-brain barrier is
leakier. The ones that will focus on for fever, however,
are likely the subfornical organ and the OVLT. Why?
Because they are on close proximity to the hypothalamus.
You need to get the signal to the hypothalamus or
otherwise, a fever will not occur.
So those other circumventricular organs would be less
important for a fever transduction mechanism.
So how do you get the signal across the blood-brain barrier?
For thinking about this, we probably need to discuss
the blood-brain barrier to a greater degree.
So you have a good feel about what things can pass and
what things cannot.
First thing to think about is there endothelial cells in the
Blood - brain barrier and this form very tight junctions
which repel most substances from crossing the blood-brain
Gases are one thing that can cross and this it does
occur for things like oxygen, carbon dioxide.
There are some solutes that can transport across a blood-brain
barrier, but they'll require a specific transport.
Finally, besides the endothelial layer, you also have an
astrocyte layer. And that astrocyte layer forms tight
junctions around that endothelial layer, and these are often
times known as foot like projections.
And the next slide will demonstrate that better.
So these astrocytes provide both mechanical support, as well
as regulate some passage of certain ions and nutrients.
In green here, they show these nice foot like projections
that almost form kind of an armored plate around
any individual capillary or endothelial cell.
The capillary itself though, is what will be transferring
that prostaglandin signal to a certain portion of the brain.
The astrocyte foot like projections could be resisting that
flow of information going from the capillary to the brain.
Now, I've talked a lot about prostaglandins. So we need to
spend a minute or so and discuss what exactly is
a prostaglandin,and what is this COX or cyclooxygenase
enzyme that we've discussed in our previous slides.
The first things to think about, when you talk about this COX
pathway is Arachidonic acid,
which is the top portion of this particular slide.
Here, Arachidonic acid is a 20 carbon fat or fatty acid. COX or
cyclooxygenase will breakdown that into another
prostaglandin, PGH2, but it is the PGE2 that we're most concern
about cause this is the fever resulting molecule.
So why do we have to think about that pathway?
Well, antipyretic therapy such as aspirin or Tylenol
block COX enzymes.
If you block the COX enzyme, you get less PGE2 formed.
What is it about PGE2 that is so important?
PGE2 signals EP3 receptors on specific neurons that are
located on the preoptic and to your hypothalamus.
So this is the signaling mechanism, by which a prostaglandin
will stimulate a certain neuron
and that neuron then will cause the fever response.
So this is PGE2 located on the slide. This will bind to an
EP3 receptor, which is part of the G coupled protein
receptor superfamily. And these are all the different kind of
signaling molecules of the prostaglandin family.
You will target a very specific EP receptor and that's EP3.
And let me show you what there are some EP3 receptors
throughout the body and then will concentrate on the brain itself.
So this is an example of the various types of prostaglandin
receptors. And the four primary types of receptors.
And those are EP1, 2, 3, and 4. They choose a slightly different
second messenger-signaling pathway
but EP3s are what we want to concentrate on.
You can see that as the bond here. You'll noticed that EP3
receptors are located throughout the body,
whether it will be in the kidneys or some in the stomach.
But we want to focus on as what occurs in the brain.
You can see the only type of receptor for prostaglandin E2
that is located either E1, 2, EP3 or EP4,
only EP3 is expressed in the brain.