GDNF FOR THE TREATMENT OF PARKINSON'S
UPDATE # 68..1996 (EXcERpTS)


NEUROTROPHIC FACTORS PREVENT CELL SUICIDE

All cells, including nerve cells, self-destruct when they are no longer
needed or have become damaged and pose a threat to other cells. This
form of suicide in which cells sacrifice themselves for the common good,
is called APOPTOSIS. It is under the control of a genetic program that
is permanently turned on. In other words, cells commit suicide unless
they are continually told not to by neighbouring cells, and sometimes
even by distant cells. How do cells tell other cells not to commit suicide?
One way is by secreting chemical messengers called TROPHIC FACTORS. Thus
the basic survival law for cells is simple: to survive, they continually
need chemical signals that turns off their apoptosis-suicide program.

In the brain, these survival signals are called NEUROTROPHIC FACTORS.
They were first discovered in the early 1950s by researchers who were
studying the development of the nervous system before birth. As nerve
cells mature, they extend long thread-like pieces called axons. These
grow until they reach their targets. For some developing nerve cells,
the target can be several inches away, and their axons face the daunting
task of finding these targets, through an intricate obstacle course of
other cells and growing axons. The reward is worth the struggle: the
target makes and secretes the neurotrophic factor that the nerve cells
needs to survive. If a nerve cell makes a mistake and sends its axon to
the wrong target, it does not get its neurotrophic factor and dies by
apoptosis. Apoptosis is essential for the developing brain because it
ensures that the right connections between nerve cells are established.

For many years, neurotrophic factors were thought of as substances whose
only function was to drive and organize development of the brain. In the
late 1980s, it became clear that neurotrophic factors were also involved
in survival of adult neuron. For example, if neurotrophic factors were
inactivated or removed in adult animals, certain sets of nerve cells start
undergoing death by apoptosis. The discovery that neurotrophic factors
could promote survival of adult nerve cells, spurred a wave of research
on these factors, especially because apoptosis seemed to be involved in
many  neurodegenerative disorders (including Parkinsons), suggesting that
the cause of such conditions might be related to loss of certain neurotrophic
factors.

There are many such chemical/factors. Two are known to be critical for
the survival of the substantia nigra cells characteristically lost in
Parkinsons. BDNF (brain derived neurotrophic factor) is essential for
the early development of these cells, while GDNF appears to be needed
mainly for their survival during adulthood. This has led scientist to
question whether a disorder of GDNF might contribute to the onset of
Parkinsons. Even if it did not, several experiments show that GDNF can
protect nerve cells from suicide, whatever causes them to commit apoptosis,
suggesting that GDNF could stop the progression of Parkinsons, regardless
of what causes the substantial nigra cells to die.

GDNF Promotes the Survival OF Substantial Nigra Nerve Cells

It has been known for a very long time that cutting axons cause the
entire nerve cell to die. Following the discovery of neurotrophic factors,
this might be explained by the fact that when axons are severed, nerve
cells no longer receive survival messages from their target tissues. In
adult rats, treatment with GDNF at the same time as the axons are cut,
protect most neurons from death. This result indicates that GDNF can
protect adult nerve cells from committing suicide.

In mice, substantial nigra cells can be destroyed by injecting a toxic
called MPTP. This chemical causes brain lesions in both animals and humans
that closely reassemble those noted in Parkinsons. Many scientist believe
that MPTP causes substantial nigra cells to commit apoptosis. GDNF
administered at the same time as MPTP protects most nerve cells from death.
GDNG also seems to have a "rescue" effect. Mice were treated with this
neurotrophic factor after their nerve cells had been injured with MPTP,
and the GDNF still protected a substantial number of substantial nigra
cells. This indicates that GDNF can rescue nerve cells even after they
have turned on the suicide program.

In rats, substantial nigra nerves cells can be destroyed by injecting a
toxic substance called 6-hydroxy dopamine. Animals were given GDNF for
weeks after their nerve cells had been damaged, and were found to develop
normal neurons in the damaged substantial nigra. This suggests that GDNF
not only can protect against damage, but can perhaps cause nerve cells
to grow again after they had been destroyed - or at least rescue cells
that were not quite dead.

GDNF  Treatment for Parkinsons.
GDNF is a big protein that cannot be given by mouth because it is
destroyed by chemicals in the stomach. It cannot be injected intravenously
because it cannot pass the blood-brain barrier to enter the brain. At
present, in the above animal experiments, neurotrophic factors are
administered directly into the brain .....Administration of GDNF to
humans involves the surgical insertion of a device between the skin and
the skull. Once the device is in place, GDNF will be administered through
this device once a month. The first tests were to evaluate the GDNF's safety.
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