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Krzysztof S. Bankiewicz, Meg Palmatier, Robert J. Plunkett, Alex Cummins and Edward H. Oldfield

✓ Although recent animal and human experiments suggest that tissue implantation can ameliorate parkinsonism, there is controversy about what mechanism underlies recovery. Secretion of dopamine from the graft seems unlikely to be the sole restorative factor. Regenerative sprouting by the host brain may also underlie behavioral recovery. Fetal amnion and term amnion, which were shown to produce and secrete a factor that supports the outgrowth of neurite processes in vitro, were implanted in hemiparkinsonian monkeys. Fetal amnion implants induced sprouting of dopaminergic fibers from the host brain and behavioral improvement, despite failure of the grafts to survive. Animals implanted with term amnion also had some sprouted dopaminergic fibers and behavioral improvement, but these were limited and were similar to the recovery, in prior experiments using the same primate model of parkinsonism, of animals that received surgical cavitation only.

Recovery after central nervous system grafting with fetal amnion, a fetal accessory tissue, does not require secretion of a deficient neurotransmitter(s) from the graft and occurs despite the failure of graft survival. Recovery after cerebral implantation of fetal tissues appears to depend more on the regenerative and recuperative processes of the host brain than on graft replacement of deficient neurotransmitters or development of functional synaptic connections between the graft and the host brain.

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Intrastriatal implantation of interleukin-1

Reduction of parkinsonism in rats by enhancing neuronal sprouting from residual dopaminergic neurons in the ventral tegmental area of the midbrain

Jin Wang, Krzysztof S. Bankiewicz, Robert J. Plunkett and Edward H. Oldfield

✓ Intrastriatal implantation with dopaminergic or nondopaminergic tissue can elicit behavioral recovery in parkinsonian animals. Because in these animals, especially in 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine-lesioned monkeys, there are still considerable numbers of dopaminergic neurons left in the mesencephalon, implantation-induced trophic effects on host residual dopaminergic neurons have been suggested as a mechanism underlying the behavioral recovery. Gliosis around the graft is a universal finding in any implantation procedure and is probably mediated by interleukin-1 (IL-1); in addition, activated astrocytes secrete several neurotrophic factors in vitro. Therefore, the authors postulated that trophic effects from IL-1-induced gliosis may be a “final common pathway” for recovery in parkinsonian animals after implantation.

Hemiparkinsonism was induced in rats by injection of 6-hydroxydopamine either directly into the substantia nigra or into the median forebrain bundle. The substantia nigra-lesioned rats showed complete depletion of dopaminergic neurons in the substantia nigra but sparing of those in the ventral tegmental area, whereas the median forebrain bundle-lesioned animals had depletion of dopaminergic cells in the substantia nigra and the ventral tegmental area. Polymer pellets containing either slow-released IL-1 alpha and beta or placebo pellets were implanted in the caudate nucleus on the lesioned side in both groups. The rats' rotational response to amphetamine was tested weekly for 8 weeks. Selective substantia nigra-lesioned rats with implantation of IL-1 pellets had a 45% reduction in amphetamine-induced rotation, whereas placebo-implanted substantia nigra-lesioned rats had a 14% reduction in rotation. In the median forebrain bundle-lesioned group, neither IL-1 nor placebo implantation elicited any effect on turning. Immunohistochemical staining for glial fibrillary acidic protein was markedly increased surrounding the IL-1 pellets compared to the placebo pellets. In the selective substantia nigra-lesioned rats with IL-1 pellets implanted in the caudate nucleus, a considerable number of tyrosine hydroxylase immunoreactive (TH-IR) fibers were observed in the medial and middle portions of the caudate nucleus. Fewer TH-IR fibers were seen in the rats with placebo-bearing pellets.

These results suggest that neurotrophic activities mediated by IL-1 and reactive astrocytes might be a common path through which tissue trauma and some tissue transplants exert their beneficial effects in parkinsonian animals. Furthermore, most of the sprouted dopaminergic fibers induced by IL-1 in the caudate nucleus come from dopaminergic neurons in the ventral tegmental area.

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Krzysztof S. Bankiewicz, Robert J. Plunkett, David M. Jacobowitz, Irwin J. Kopin and Edward H. Oldfield

✓ Implantation of fetal dopamine-containing tissue into preformed cavities in the caudate nucleus of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-induced parkinsonian monkeys leads to behavioral recovery. Recovery may be related to two sources of dopamine: the grafted cells and/or the sprouted fibers from host dopaminergic neurons. The authors undertook this study to determine whether behavioral recovery requires release of dopamine by the implanted tissue, and to establish if nondopaminergic fetal central nervous system implants can induce sprouting of dopamine fibers in the primate brain and cause behavioral recovery.

Rhesus monkeys with MPTP-induced hemiparkinsonism or full parkinsonism and a stable neurological deficit were used for this study. Cavities were created in the caudate nuclei anterior to the foramen of Monro via an open microsurgical approach. Fetal cerebellum or spinal cord was implanted into the preformed cavities of three monkeys. Control parkinsonian monkeys showed no recovery. However, implant-induced improvement was stable for up to 6 months after implantation. Sprouted dopaminergic fibers oriented from the ventral striatum and nucleus accumbens were found in the area of the tissue implant in the animals that received fetal grafts but were not present in the control monkeys.

It is concluded that brain implants do not need to contain dopamine to induce functional recovery in MPTP-induced parkinsonian primates. Implant-induced and trophic factor-mediated dopaminergic sprouting by the host brain plays a role in the behavioral recovery and may well be responsible for the clinical improvement seen in parkinsonian patients after brain implants.

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Robert J. Plunkett, Krysztof S. Bankiewicz, Alex C. Cummins, Robert S. Miletich, Joan P. Schwartz and Edward H. Oldfield

✓ Autografts of adrenal medulla were implanted into preformed cavities in the caudate nuclei of four rhesus monkeys with hemiparkinsonism induced by l-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP). Five other hemiparkinsonian monkeys underwent caudate cavitation, but received no tissue implant. All of the animals had marked bradykinesia of the affected arm and stable apomorphine-induced turning before cavitation or implantation.

Moderate behavioral recovery was seen in all five monkeys with cavitation and two of the three monkeys with long-term adrenal autografts (the fourth adrenal recipient was sacrificed 10 days after grafting). The improvement occurred months after the procedure and was not as early or as complete as that seen after fetal dopaminergic grafts. Surviving adrenal tissue was found only in the animal that showed no behavioral recovery. The other two adrenal autograft recipients (with no surviving adrenal medulla) and all of the animals with cavitation had ingrowth of dopaminergic fibers from the area olfactoria and nucleus accumbens into the caudate, oriented toward the cavity.

These findings show that the mechanism of improvement after adrenal medullary implants for parkinsonism is not dopamine secretion by chromaffin cells, but may be related to the sprouted host fibers. The results also indicate that the limited recovery after adrenal implants in parkinsonian patients may be a result of the cavitation, and not necessarily the result of tissue implantation.

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Krzysztof S. Bankiewicz, Robert J. Plunkett, David M. Jacobowitz, Linda Porrino, Umberto di Porzio, William T. London, Irwin J. Kopin and Edward H. Oldfield

✓ Parkinsonism or hemiparkinsonism was induced by administration of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) in four rhesus monkeys, which then received homologous fetal mesencephalon implants into the caudate nuclei. Cavities were prepared in the medial caudate nucleus 2 to 5 weeks before the fetal grafts were implanted. Control studies were conducted in unoperated MPTP-treated animals. Significant behavioral improvement, which occurred within weeks of implantation of fetal mesencephalon, was sustained for up to 7 months. No recovery was seen in the unoperated control animals. Histological examination revealed numerous surviving tyrosine hydroxylase (TH)-immunoreactive cell bodies. In addition to the graft, abundant TH-immunoreactive fibers were observed in the host caudate nucleus ventral to the region of the implanted and the nonimplanted cavities. Since TH-immunoreactive cell bodies of the substantia nigra compacta (A-9 cells) were destroyed by MPTP treatment and the ventral tegmental area (A-10) remained intact, it is concluded that sprouting of remaining host dopaminergic fibers occurs. These newly formed fibers appeared to emanate from the mesolimbic projection to the striatum. It is likely that the newly sprouted dopaminergic fibers account for the motor improvement elicited by precavitation and fetal mesencephalon implantation.

These results suggest that the mechanism of recovery of parkinsonian primates after implantation of fetal dopaminergic tissue into the caudate nucleus is by stimulation of sprouting from host neurons. They also suggest that, with identification of the factors responsible for the formation of the new dopaminergic neuronal processes and with further development, tissue implantation may be an effective therapy for Parkinson's disease in humans.

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Stereotaxic implantation of dispersed cell suspensions into brain

A systematic appraisal of cell placement and survival

Robert J. Plunkett, Richard J. Weber and Edward H. Oldfield

✓ The application of several recent advances in cell biology, brain implantation, and cell-mediated tumor immunotherapy requires successful and reproducible placement of viable cell suspensions into brain. Stereotaxic implantation is being used to inject cytotoxic lymphocytes into gliomas and to replace dopaminergic cells in parkinsonian models. Systematic assessment of the factors that influence success in implantation of cell suspensions into solid tissues is needed.

A model was developed for investigation of stereotaxic implantation using radiolabeled rat lymphokine-activated killer (LAK) cells. Anesthetized rats received microliter injections of cell suspension into the right caudate nucleus. The injection volume, cell concentration, infusion rate, and needle size were varied systematically. The animals were sacrificed 1 hour after injection; the brain was removed and sectioned, and the radioactivity was counted. Three aliquots of the suspension were injected into counting tubes for control analysis. Recovery of radioactivity was expressed as the percent of mean counts per minute (cpm) in the right frontal lobe/mean cpm in the three control tubes. To assess the viability of implanted cells, the right frontal region was mechanically dissociated in media and centrifuged, and the pellet and supernatant were counted. By using small needles and slow infusion of volumes of 10 µl or less, 85% to 90% of the radioactivity was recovered in the caudate nucleus. At least half of the implanted cells were viable. Consistent, accurate implantation of dispersed cells into brain over a range of volumes, cell concentrations, infusion rates, and needle sizes was achieved.

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Edward H. Oldfield, Robert J. Plunkett, William A. Nylander Jr. and William F. Meacham

✓ Ischemia is the pathophysiological mechanism in many types of spinal cord injury. In the present study, the infrarenal segment of the aorta was occluded for 25 minutes to produce spinal cord infarction in rabbits. Paraplegia occurred in 100% of control animals. Thiopental administered before aortic occlusion resulted in paraplegia in only 40% of animals so treated (p < 0.01). Histological study of the spinal cord demonstrated infarction of the gray matter in all paraplegic animals, whereas the microscopic appearance was normal in animals without neurological deficit. The protective influence of thiopental therapy in spinal cord ischemia was demonstrated.