1998 First Web Reports
Neural Transplants in the Treatment of Parkinson's Disease
In the eighteenth century, when biologists were first exploring the various dimensions of experimental and descriptive neuroanatomy, there was much concentration on the brain and the myriad of neural connections that linked different parts of the brain together. The popular belief was that the Central Nervous System could not be repaired after injury because the regenerative capacity of neurons ceased to exist by the time an individual reached maturity. Now, in modern times, although there has been a great advance in technological equipment and a molecularization of the scientific consciousness, the question of rehabilitation within the nervous system still exists. Thus, the drive to answer this enigma is still strong as ever, as recent studies in the developing field of experimental neurosurgery have led researchers to challenge past dogmas. One of these experimental treatments for brain and spinal cord trauma is neural transplantation. So far, neural transplants have led the way as strong contingents for the cure and alleviation of symptoms that are associated with neurodegenerative diseases such as Alzheimer's Disease, Huntington's Disease, and Parkinson's Disease (3).
Parkinson's Disease (PD), the subject of this particular paper, is a condition that results from a chemical imbalance within the brain, which is consequently caused by cell death. The disease affects the part of the brain called the "substantia nigra," which is responsible for producing the chemical, dopamine. Once produced, dopamine moves from the nigra cells to another part of the brain called the striatum. In PD, the brain cells of the substantia nigra begin to disintegrate. This, accordingly, impairs the production of dopamine, for as the cells of the nigra die, a decrease in the secretion of dopamine by one part of the brain results in the decrease of dopamine arriving at another part of the brain, the striatum. The striatum is the center of coordination for many chemicals. Thus, when one of these chemicals is absent or not present in a substantial amount, there is a chemical imbalance. (1) (6)
Dopamine is needed to secure the ability of the brain to carry out the walking and speaking functions of an organism. Thus, the chemical imbalance caused by the death of dopamine-producing cells causes the deterioration of motor functions associated with Parkinson's. Although these symptoms vary from patient to patient, the general characteristics of individuals with this disease are rigidity (stiffness in the extremities), resting tremors (tremors occurring when one is ant rest or sitting quietly), bradykinesia (delay of initiating movements), and loss of postural reflexes (poor balance). Thus, patients become incapable of carrying out normal, daily-life functions. Some of the symptoms of PD also occur as a result of cell death in numerous portions of the brain and the rest of the nervous system. (1) (6)
There are many treatments, some in common use and others in experimental stages, that are available for the alleviation and even cure of PD symptoms. First, there are drug treatments, which usually consist of a dopamine replacement technique. For instance, many patients are given levodopa, which is an overall effective dopamine-enhancing agent. Surgical lesions and deep brain stimulation with electrodes within the thalamus are two other treatments that have been proven to reduce PD symptoms. However, the most interesting and significant research of all has to do with the various advances in nuerosurigical transplants (1). The mechanism behind this treatment is the notion that one can replace damaged brain cells with functioning ones and, thus, compensate for the loss of nerve cell groups. (4)
Two approaches to neural transplantation regarding PD are adrenal medullary and fetal brain grafts (5). The technique of grafting adrenal medulla cells was first experimented on because it was believed that intercerebral grafts, which would replace lost neurotransmitters, could produce large amounts of dopamine. (4) One important experiment, which has helped the credibility of this grafting technique, was reported by a research team lead by J.H. Kordower in 1991. The patient was a 45 yr. old male who had been suffering from PD for 15 years. While this man did not display secondary Parkinsonism degeneration, and was also responding to medications of carbidopa and levodopa, he would experience severe, daily motor fluctuations that would cause him to be bed-ridden or forced into a wheelchair. Since the medications were not effecting these motor difficulties, his adrenal medulla was removed and replaced in a pocket of the caudate nucleus. After this transplantation, the patient's symptoms began to steadily improve. Nevertheless, after 18 months after surgery, his motor functions began to decline. By the time this patient died, 30 months after transplantation, he still showed less PD symptoms than before surgery. Thus, his autopsy supported clinical observations as the substantia nigra of his brain contained melanin with bilateral neuron growth. Tyrosine hydroxylase staining confirmed that there were indeed dopamine-containing cells within the substantia nigra. However, the presence of macrophages incorporated within the neuromelanin pigment also illustrated the process of degeneration within this region. (5)
Thus, although this experiment was somewhat successful in proving the beneficial effects of adrenal medulla grafts, most other studies have disproved this theory. The main problem with the medulla transplants has to do with brain circuitry. This circuitry exists through the connections of nerve cell fibers with other nerve cells at multiple sites. These sites, or synapses, are the main methods of cell-to-cell communication and controllers of neurotransmitter discharge. Adrenal medulla cells are unable to create as much synapses as are needed by the region of the brain that is effected by PD. Thus, this type of graft is generally inefficient at creating favorable conditions in which there is a great amount of synapses and, thus, neurotransmitters. (4)
The second neural transplant approach for the treatment of Parkinson's Disease is the grafting of fetal cells. Embryonic brain tissue grafts are reported to form direct connections to the host brain, which implies that these fetal substantia nigra cells could quickly and easily differentiate to produce neurons that replace damaged ones. In essence, the grafted cells could restore damaged circuitry (something that the adrenal medulla grafts tended to fail to accomplish) which help to cure behavioral dysfuctions. But reciprocal, point-to-point connections between newly grafted and host cells were also found to be sparse and superficial. Therefore, this direct "connectionist" theory is being challenged by other possible mechanisms caused by the transplantation of fetal cells. For example, fetal cells have been proven to be extremely successful as neurotransmitter replacements and stimulators of trophic or survival factors that help strengthen, differentiate, and enlarge cells of both the peripheral and central nervous systems. Yet, in the end, all these mechanisms have been proven to stimulate the secretion of dopamine in the denervated striatum of the brain. (3) The main problem with the application of fetal brain tissue grafts is based more on a moral debate than on a scientific one. The use of human embryonic and fetal material depends largely on the complicated issue of legally induced abortions. If research on fetal grafts picks up sufficient speed and becomes standard therapy, then many raise the question of how to supply this medical demand. Indeed, although it is more than probable that fetal research will not have any pressure on the decisions of women in this country to have an abortion, the legal and ethical issues cannot be completely detached from this particular method. (2) (5)
American Academy of Neurology- Parkinson's Disease.
Ethical Guidelines for the Use of Human Embryonic or Fetal Tissue for Experimental and Clinical Neurotransplantation and Research.
Fetal Brain Tissue Grafts as Therapy for Brain Dysfunctions: Some Practical and Theoretical Issues.
Fetal Nerve Cell Transplantation: Advances in the Treatment
of Parkinson's Disease.
Parkinson's Disease and Tissue Transplants.
Working to Cure Paralysis.