Parkinson's disease is a neurological disorder characterized initially by muscular rigidity and slowing of voluntary movements (1). Ultimately, the characteristics are tremor, mask-like faces, decreased spontaneous blinking, flexion posture and sometimes cognitive impairment. The neuropathology of Parkinson's disease generally involves loss of cell bodies in all melanin-containing brain regions and invariably a loss of substantia nigra dopamine-containing neurons (DA). The principal target for dopaminergic neurons located in the substantia nigra is the striatum and the loss of dopaminergic tone in the striatum is thought to produce most of the symptoms of Parkinson's disease.

Since Parkinson's disease is a dopamine deficiency, treatment with L-Dopa, the precursor of dopamine, was successful in treating Parkinson's patients (1). However, these patients taking L-Dopa often develop side effects and in about 50% of the patients, the drug effectiveness is lost. As an alternative to drug therapy, the possibility of grafting dopamine-containing tissue into the brains was proposed. From the proposal, there have been a vast amount of experiments to test transplantation effectiveness.

Work in amphibians and fish were the first to demonstrate the possibilities for neuronal replacement after damage in the central nervous system (2). In these species, especially in the visual system, grafted neurons were substituted both structurally and functionally for damaged axonal connections, and afferent and efferent connections were established with a high degree of specificity between the grafted neurons and the host. Evidence in adult sub-mammalian vertebrates has shown certain type of intracerebral neural grafts can be performed. Evidence on fetal monoaminergic neurons implanted in the host brain could substitute functionally for elements lost or damaged as a result of a lesion. Thus, adult mammalian central nervous system had the potential to incorporate new neuronal elements into already established neuronal circuitry and implanted neurons could modify the functional behavior of the recipient. The ability to transplant monoaminergic neurons is of particular relevance in the context of Parkinson's disease in which the loss of particular neurons are the likely to be related to some of the major symptomology of the disease. In Parkinson's disease, the severe motor disturbances can be related to a loss of about 80 - 90% of the neurons in the nigrostriatal dopamine system.

For rodent experimentation, a lesion of the nigrostriatal DA pathway represent the most widely used model of the principal neuropathology in Parkinson's disease (2). In order for the symptomology of Parkinson's to be reversed via transplantation, reinnervation of the dorsal caudate-putamen is required for alleviation of both spontaneous and drug-induced rotation, reinnervation of ventral and lateral caudate--putamen is required for reinstatement of sensorimotor attention and responsiveness on the contralateral side of the body and reinnervation of the nucleus accumbens and or prefrontal cortex is required for alleviation of the akinesia in bilaterally lesioned rats and normalization of the locomotor response to dopaminergic drugs.

Grafting fetal central nervous tissue requires transplantation of solid pieces of tissue to a surgically prepared transplantation cavity and the graft is placed in direct contact with the enervated striatum (2). Good graft survival is ensured by preparing the cavity in which the graft can be placed on a richly vascularized surface.

In dennervated rodents, the nigrostriatal dopamine neurons survived quite well, however, their fiber outgrowth in the surrounding host tissue varies markedly form one area to another (2). Rich fiber outgrowth was seen into areas normally richly innervated by DA fibers, such as the caudate-putamen and nucleus accumbens. Each DA cell only deposited into a sub-portion of the striatum revealed extensive reinnervation of the striatum required several implants in different sites. Ingrowth and patterning of the axons from implanted neurons are greatly influenced by the target tissue, and regulatory influence exhibit a relative specificity with respect to different types of neurons within the graft. The effects of denervating lesions showed the proliferation and terminal patterning of the reinnervation axons may be related to the filling of vacated terminal space in the denervated target.

For grafted DA neurons, measurements of DA turnover and synthesis rates in vivo indicate that the implanted DA neurons are capable of restoring DA neurotransmission in the initially denervated target (2). The compensation of motor asymmetry induced by solid nigral grafts was highly correlated to the degree of striatal reinnervation. Restoration of as little as 3 - 5% of the normal striatal DA content is sufficient for substantial compensatory effect on behavior.

DA grafting has also been experimentally tested in aged rodents. Aging can result in naturally occurring brain damage, with anatomic, biochemical and behavioral changes that appear to be substantial, yet selective (2). Age-dependent decline in brain function is also seen in aged rodents. The focus on the dopaminergic innervation of the striatum was chosen because, age-related anatomic, biochemical and functional changes have been repeatedly documented for both of these neurochemical systems, and deficits in sensorimotor coordination and swimming abilities in aging rats are similar to those seen after DA-depleting brain lesions and may be reduced by administration of DA-receptor agonists.

Twelve weeks after transplantation of the aged rats with nigral grafts there was a marked improvement in their balance and limb coordination (2). The rats could walk along a bridge without falling, display a gait posture similar to that of young rats and fell less frequently than did the other aged rats. Spatial learning was also assessed. The ability of the rats to use spatial cues for the location of the platform in a pool was assessed by analyzing their search behavior after removal of the platform of the fifth day of testing. In the post-transplantation rats, significant improvement was seen compared to non-grafted controls. Swim distance was increased by 83%. These results demonstrate the ability of intracerebral grafts to lessen age-related impairments in motor and complex cognitive behaviors.

The degree of functional recovery in DA lesioned rats with nigral transplants is directly correlated with the extent of striatal DA reinnervation and the functional recovery is dependent on which area of the striatal complex is reinnervated by the graft. This point is particularly well illustrated in rats with electrodes implanted into the center of intracortical nigral grafts, and then were allowed to self-stimulate via the graft. The results show that the graft can indeed sustain self-stimulation behavior and the rate of lever-pressing is related to the proximity between the electrode tip and the dopamine- containing neurons in the graft. This supports the notion that the implanted DA neurons can transmit behaviorally meaningful and temporally organized information to the host brain via their efferent connections.

Thus far experimental models discussed have focused on induced destruction of the nigrostriatal system. However, animal models with genetically determined degeneration of the substantia nigra have been examined (3). The weaver homozygote mutant mouse has a loss of the cerebellar granule cells and a progressive depletion of striatal dopamine. Thus the weaver mutant mouse can be used as a genetic model in the depletion of striatal dopamine and the effects of transplantation. These mice display instability of gait, fine rapid tremor of the trunk and extremities and poor coordination of the limbs. In these animals, graft transplantation also was effective in overcoming the nigrostriatal degeneration of genetic etiology.

Studies in primates have also been experimented with(4). Parkinson signs were produced in African Green monkeys by the administration of a neurotoxin. Transplantation of fetal neurons from the substantia nigra into monkeys with severe symptoms of hypokinesia, postural and resting tremor, episodes of movement freezing and difficulty in initiating movements, resulted in a reversal of these symptoms. The degree of recovery corresponded with the proportion of positive neurons in the host caudate nucleus and putamen.

Human studies have been implemented on the bases of experimental data. Lindvall et al (5) transplanted ventral mesencephalic tissues from an aborted human fetuses of 8 - 10 weeks gestation and implanted the tissue unilaterally into the striate of two patients with advanced Parkinson's disease. Both patients showed small but significant increases of movement speed for repeated pronation-suppination, fist clenching and foot lifting. One patient had an increased rate of walking. Motor readiness potential increased in both patients post-operatively. Neurophysiological measurements also showed a more rapid performance of simple and complex arm and hand movements of the side contralateral to transplantation in one patient. These results suggest that the fetal nigral implants may have provided a modest improvement in motor function . Freed et al (6) showed a marked improvement in hand speed movement and walking speed after transplantation of the mesencephalic dopamine cells from a seven week aborted human embryo into the caudate and putamen of a man with Parkinson's disease.

Patients receiving transplants from the adrenal medulla have not been as successful. Adrenal medullary autotransplantation for Parkinson's patients was tested. Adrenal medullary tissue was transplanted into the caudate nucleus of 3 patients with advanced Parkinson's disease (7). The first patient had mild improvement in his motor functioning after the operation. However, post-operatively prolonged drowsiness and complex visual hallucinations developed. After his death, biopsy showed necrotic adrenal medullary tissue surrounded by inflammatory cells. The second patient had mild improvements in his symptoms. The third patient initially had a mild improvement; however, soon returned to his preoperative symptoms. Another study (8), using 18 patients, look at the effects of adrenal medullary autotransplantation to the caudate nucleus for Parkinson's patients. This study found no distinctive improvements in the symptomology of the Parkinson's patients.

Overall, experimentation of transplanting fetal brain tissue into the host has been successful in resolving the symptomology of Parkinson's disease in animals. However, success of human studies has not been as promising. Case studies have shown mild to no improvement in resolving the symptomology of Parkinson's disease in humans.

References:

1. Wyatt, R.J., Morihisa, J.M., Nakamura, R.K. and Freed W.J. 1986 Transplanting tissue into the brain for function: Use in a model of Parkinson's disease. Neuropeptides in Neurologic and Psychiatric Disease. pp.199-208.

2. Bjorklund, A. and Gage, F.H. Neural grafting in animal models of neurodegenerative diseases. Annals of the New York Academy of Sciences, 457: 53-81.

3. Triarhou, L.C., Low, W.C. and Ghetti, B., 1986, Transplantation of ventral mesencephalic anlagen to hosts with genetic nigrostriatal dopamine deficiency. Proc. Natl. Acad. Sci. USA, 83: 8789-8793.

4. Sladek,J.R., Redmond, D.E., Collier, T.J., Haber, S.N., Elsworth, J.D., Deutch, A.Y. and Roth, R.H., 1987, Transplantation of fetal dopamine neurons in primate brain reverses MPTP induced Parkinsonism. Progress in Brain Research 71: 309-323.

5. Lindvall, O., Rehncrona, S., Brundin, P. and Gustavii, B., 1989, Human fetal dopamine neurons grafted into the striatum in two patients with severe Parkinson's disease. A detailed account of methodology and a 6-month follow-up. Archives of Neurology 46: 615-631.

6. Freed, C.R., Breeze, R.E., Rosenberg, N.L. and Schneck, S.A., 1990, Transplantation of human fetal dopamine cells for Parkinson's disease. Results at 1 year. 47: 505-512.

7. Jankovic, J., Grossman, R., Goodman, C. and Pirozzolo, F., 1989, Clinical, biochemical and neuropathologic findings following transplantation of adrenal medulla to the caudate nucleus for treatment of Parkinson's disease. Neurology 39: 1227-1234.

8. Allen G.S., Burns, R.S., Tulipan, N.B. and Parker, R.A., 1989, Adrenal medullary transplantation to the caudate nucleus in Parkinson's disease. Initial clinical results in 18 patients. 46: 487-491.