Bob from Houston
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At 12:02 AM -0500 11/3/98, Automatic digest processor wrote:
>Date: Mon, 2 Nov 1998 00:05:24 EST
>From: Susan Pendleton <DTXNEWS(AT)AOL.COM>
>Subject: Re: Chop Busting/Remyelination
>
>That's the way I understand it. If you already have the neurons and the
axons
>that extend from them, then it seems to me that the missing piece here is
>myelin sheathing to allow conductivity. But if you cover a hole into the
cord
>with just the myelin sheath and you're missing neurons.....no amount of
myelin
>will fix that problem. This is why I tend to believe that remyelination may
>come before other therapies. There are a lot of demyelinating conditions out
>there and the scientists connected with these diseases have been studying
>this particular problem for decades. A good source for this area is
><A HREF="http://www.myelin.org/">THE MYELIN PROJECT</A> .
>
>I need to go over my tapes of Dr Young's speech to get all he said on this
but
>he did mention a term I hadn't heard before.......dismyelination. If I
>remember correctly, it meant the myelin was actually scrapped back and down
an
>axon. Kind of like rolling a stocking down to your ankle. Much different
>thing than a totally demyelinated axon it appears.
>
>Anyone who can explain this stuff better and I'm sure there are
>several........please do. I find this stuff incredibly interesting but very
>confusing.
>
>Sue
Sue, you are such a good explainer. I think that the missing piece of
information that may be confusing you is why myelin is important for
conduction and why it prevents regeneration. Let me give that a shot.
First, a little axonal anatomy and physiology. Myelin covers the axon in
segments. So, a spinal axon is myelinated by many oligodendroglia along
its length. Each myelin "segment" may be several mm long. Between the
myelin segments, there are small exposed sections of the axon called the
"nodes of Ranvier". These nodes contain the sodium channels that are
required for generating the ionic currents responsible for nerve impulses
or action potentials. When an action potential occurs, ionic (sodium)
current enters the axon at the node of Ranvier and passes inside the axon
to "depolarize" and activate the next node. Thus, in myelinated axons,
nerve impulses skip from node to node, allowing the myelinated axon to
conduct much faster than a non-myelinated axon. The fastest myelinated
axons conduct at velocities of 100 meters/sec while unmyelinated axons
conduct at velocities of 1-5 meters/sec.
Injury damages not only axons but oligodendroglia (the cells that myelinate
the axons). In the spinal cord, a single oligodendroglia cell can myelinate
as many as 40 axons! Of course, each axon is myelinated by many
oligodendroglia along its length and so injury causes demyelination only at
the injury site. Within 2-3 weeks after injury, the remaining
oligodendroglia struggle to remyelinate the surviving axons. The
remyelination is often incomplete and this is called dysmyelination. Injury
damages both oligodendroglia and myelin. Remyelination occurs after
injury. Much depends on the severity and spatial distribution of the
injury. Because there may not be enough oligodendroglia around to
remyelinate the axons completely, the nodes of Ranvier are longer; the
myelin (Sue, I really love your analogy) are like stockings that have been
rolled back. This is "dysmyelination". A majority of people with spinal
cord injury continue to have some surviving axons. Not all axons are
dysmyelinated. Some are demyelinated. And, you really need only about 10%
of the axons functioning to have substantial motor and sensory function.
I am often amazed that people know more about their modem transmission than
their spinal cord transmission. So, for the more technologically oriented
members of the group, I offer the following information. Underneath the
myelin, axons have potassium channels. The potassium channels increase the
conductance of the axonal membrane underneath the myelin. Myelin is an
insulating material and has high electrical capacitance. As you may
remember from your physics or electronics courses, high resistance and high
capacitance together result in slow voltage rises. Thus, nature evolved
potassium channels in axonal membranes underneath the myelin to "shunt" the
capacitance of the myelin, thereby allowing voltage pulses to pass from
node to node with minimal capacitative loss. When an axon is remyelinated
after injury, there may not be enough oligodendroglia to cover the original
myelinated zones and axonal membranes containing potassium channels are
exposed. These potassium channels oppose sodium channels and reduce the
excitability of the nodes of Ranvier. 4-AP blocks the potassium channels,
increases the duration of action potentials, and raises the excitability of
dysmyelinated axons. While 4-AP has little or no effect on conduction of
normal myelinated axons, 4-AP does block potassium channels at axon
terminals (where the axons contact other neurons) and increase the amount
of neurotransmitter released per axonal impulse. This is the main reason
why 4-AP may produce seizure activities in the brain when taken in high
doses. By the way, increasing temperature is not good for axonal
conduction. This is because the action potential shorten at higher
temperatures. The shorter duration action potentials produce less current
to activate the next node of Ranvier. For this reason, fevers or hot baths
cause increased weakness and sensory loss in some people with spinal cord
injury and multiple sclerosis.
It is important to emphasize that axons conduct trains of impulses and that
the information content is contained in the number and frequency of the
impulses. A single impulse or action potential is usually not sufficient
to convey a sensation or stimulate a motoneuron to activate a muscle. So,
it is essential that the axons be able to conduct high frequency trains of
impulses. Many dysmyelinated axons can conduct several impulses but
"fatigues" rapidly. One of the beneficial effects of 4-AP is that it
increases the strength of weak muscles or muscles that fatigue rapidly.
Some people experience sensation more clearly. Finally, much of the
descending signals from the brain to the spinal cord is inhibitory rather
than excitatory, one of the reasons why spinal cord injury causes
spasticity or increased excitability in the part of the spinal cord
disconnected from the brain. By restoring the ability of axons to conduct
and inhibit the spinal cord, 4-AP reduces spasticity.
Mature myelin paradoxically express a protein that inhibit axonal growth.
This may because nature does not want axons to grow any more after they
have been myelinated. By the way, myelination occurs relatively late
during development. For example, rat spinal cords are not fully myelinated
until 4-6 weeks after birth. Human spinal cords are probably not fully
myelinated until 5-6 years of age. Have you ever tossed a ball to a kid
under 6 years of age? The ball usually hits his/her chest because the
kid's reflexes are slow. They cannot catch the ball. All of a sudden,
around age 7-8, they can catch the ball. Some of that is due to
myelination. I have done somatosensory evoked potentials in kids
(stimulating the leg and recording from the brain) and it often takes over
100 milliseconds for an impulse to go from the leg to the brain in a 3 year
old, even though a 2-feet tall kid has a much shorter conduction distance
than an adult. By contrast, the typical 6-feet tall adult usually can
conduct a signal from the leg to the brain in less than 35 milliseconds.
Because of the destruction of myelin at the injury site, there is often
substantial growth and sprouting of injured spinal axons at the injury site
for several weeks after injury. The sprouted axons, unfortunately, usually
fail to penetrate into the other side of the injury site, probably because
of the uninjured myelin present in the cord surrounding the injury site.
Several researchers have in fact used radiation to treat injured spinal
cords. Oligodendroglia are exquisitely sensitive to x-rays. This is of
course why people who have been irradiated for cancer often suffer from
"radiation myelopathy" and become paralyzed. There have been reports that
radiation will enhance regeneration in injured spinal cords but this is
something that needs to be investigated very carefully. Obviously too much
radiation causes permanent paralysis and one of the problems that one must
consider is that radiation will also reduce remyelination after spinal cord
injury. Note that if we had the ability to remyelinate the spinal cord
either by transplantation of oligodendroglia or Schwann cells, it may be
possible to stimulate regeneration by first getting rid of the myelin with
radiation or some toxin and then remyelinating the spinal cord. In fact,
some of the basis for recent use of inflammatory therapies such as CM101 or
implantation of activated macrophages to enhance regeneration of the spinal
cord comes from the possibility that these toxins and activated
inflammatory cells break down myelin and thereby enhance regeneration.
I hope that this is not too complicated.
Wise.
(This is the Dr. Wise from the other LIST)