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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. --------------------------------------------------------------------- úÿ [ Continued In Next Message... ]