Transplanted dopaminergic neurons: more or less?
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Biomedical subjects
Publications and source records attributed to S Dunnett.
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We have used a polyclonal antibody to the biosynthetic adrenocortical enzyme, 3-beta-hydroxysteroid dehydrogenase, to demonstrate rat adrenal cortical tissue in situ, in vitro, and in intracerebral adrenal suspension grafts. This technique provides a means of identifying the degree to which adrenal medulla grafts are in practice contaminated by adrenal cortical cells and allows analysis of the extent to which the presence of cortical cells influences the viability, differentiation, and functional efficacy of intracerebral adrenal grafts.
Rat chromaffin cells display phenotypic plasticity postnatally. In the presence of glucocorticoids, they retain a chromaffin cell phenotype, whilst in the presence of nerve growth factor and the absence of glucocorticoids they adopt a sympathetic neuronal phenotype. The tachykinins have some of the characteristics of a neurotrophic factor and are present in the form of a substance P afferent input in the rat adrenal medulla. We investigated the effects of stable NK1 and NK2 tachykinin receptor agonists, Ava[L-Pro,N-Me-Leu-10]SP7-11 (GR73632) and [Lys-3,Gly-8,R-Lac-Leu-9]NKA3-10 (GR64349), respectively, on the survival and phenotype of P5-7 rat chromaffin cells in vitro. GR73632 promoted neurite outgrowth, characteristic of the sympathetic neuronal phenotype, in the absence of NGF and glucocorticoids, but was without effect on survival after 2 weeks in culture. GR64349 was without effect.
Neural grafts rich in cholinergic neurones can survive transplantation to the neocortex or hippocampus in rats. Such grafts have the capacity to ameliorate a variety of functional deficits associated both with explicit lesions that deafferent the neocortex or hippocampus and with natural ageing. The transplantation technique enhances our understanding of the involvement of forebrain cholinergic systems in normal cognitive functions (including memory) and of the role of cholinergic degeneration in the dysfunctions associated with ageing. It is unlikely, however, that these observations will extend to a therapeutic strategy for dementia using neural transplantation, because the human diseases (at least in the case of Alzheimer's disease and multi-infarct dementia) involve widespread degeneration of other populations of cortical neurones that are not so amenable to functional transplantation as the diffuse forebrain cholinergic systems.
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The effects of reducing brain serotonin (5-HT) levels by means of intracerebral-ventricular injections of the tryptophan antagonist p-chlorophenylalanine (PCPA) were investigated in male rats. Six days after the operation, PCPA-treated rats, either fed ad libitum or pair-fed to the food intake of control rats, showed decreased thermogenic activity and capacity in their interscapular brown adipose tissue (BAT) and also increased fat storage in their white adipose tissue (WAT). These results indicate that serotonergic synapses might play a regulatory role in the sympathetic control of BAT thermogenesis and in the rate of WAT deposition (by an as yet unidentified mechanism), in addition to their well established role in controlling food intake.
Electrophysiological recordings were made from grafts of embryonic ventral mesencephalon transplanted into the neocortex, overlying the host neostriatum of rats in which the intrinsic striatal dopamine (DA) innervation had been removed by a unilateral 6-hydroxydopamine (6-OHDA) lesion. Whereas all rats had surviving grafts, half of the rats showed recovery from amphetamine-induced rotational asymmetry induced by the 6-OHDA lesions ('compensation'), indicating a functional dopaminergic reinnervation of the host striatum by the graft. The electrophysiological recordings revealed: neurons within all grafts which could be antidromically activated from host striatum, and which had faster conduction velocities and narrower action potentials than is characteristic of DA neurons in the intact substantia nigra, neurons only within the grafts of compensated rats which had properties characteristic of normal nigral DA neurons, and neurons within the grafts which responded to stimulation of the frontal cortex and lower brainstem of the host. The data support the view that the grafts can establish physiologically functional afferent and efferent connections with the host brain.
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The catecholamine containing chromaffin cells of the adrenal medulla have recently been employed as intracerebral grafts in man and animals with lesions of the nigrostriatal dopaminergic system. This review outlines the basic biology of the chromaffin cell with reference to its efficacy as a source of dopamine in the grafted state. This is followed by an evaluation of the use of these grafts in experimentally lesioned animals and in patients with Parkinson's disease.