Intracerebral adrenal medulla grafts: A review

Abstract

This review summarizes basic and clinical research on intracerebral adrenal medulla grafts, emphasizing potential applications to Parkinson's disease. Properties of intraventricular and intraparenchymal grafts are described, and cell survival and functional effects are compared. It is clear that adrenal medulla allografts survive poorly in the parenchyma of the corpus striatum and better in the lateral ventricle. Nerve growth factor (NGF) may improve the survival of adrenal medulla grafts. In the absence of added NGF even adrenal medulla grafts in the ventricle survive irregularly, and the factors required for graft survival in the ventricle are not well understood. In the 6-hydroxydopamine-lesioned rat model most evidence suggests, not surprisingly, that adrenal medulla grafts produce functional effects only when they survive. These effects may be related to production of catecholamines by the transplanted cells. In addition, adrenal medulla grafts may produce trophic effects on host brain. These effects are most evident in animals with MPTP-induced damage to dopaminergic systems and may be nonspecific, possibly related in part to the brain injury that is induced by graft implantation. Trophic effects may contribute to the functional effects of adrenal medulla grafts: For intraparenchymal grafts, trophic effects that do not require cell survival may contribute small functional changes, while additional behavioral effects may require substantial chromaffin cell survival. The evidence for direct dopamine-mediated effects as compared to trophic mechanisms of action for these grafts in animal models for Parkinson's disease is presented. Clinical studies of adrenal medulla grafts in human patients are examined and compared in detail. When inspected closely, the various clinical studies are in general agreement on most points, although there are differences in the degree of improvement found, both across different studies and individual patients. It is concluded that some beneficial clinical effects occur, with small to modest changes in most patients and substantial improvement in a minority of patients. There also seem to be larger or more consistent changes in durations of "on" and "off" times in -dihydroxyphenylalanine-treated patients. There are substantial side effects, and it is not clear that the clinical changes are sufficient to justify performing adrenal medulla transplantation in human patients as a routine procedure. The findings of clinical studies are generally consistent with the predictions that would have been made from animal studies; however, it is not clear whether some of the clinical effects could be nonspecific consequences of lesioning or surgery. Additional basic research would be required to develop a consistently effective clinical procedure. Remaining unanswered questions include the relative contributions of dopamine production and trophic changes to the functional effects of adrenal medulla grafts, the factors required for adrenal medulla graft survival, and the factors responsible for the substantial improvement that has been seen in some patients. The review concludes with a series of recommendations for future basic and clinical research on adrenal medulla transplantation.