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The neurorestorative effects of exogenous neurturin (NTN) delivered directly into the putamen via multiport catheters were studied in 10 MPTP-lesioned rhesus monkeys expressing stable parkinsonism. The parkinsonian animals were blindly assigned to receive coded solutions containing either vehicle (n = 5) or NTN (n = 5, 30 μg/day). Both solutions were coinfused with heparin using convection-enhanced delivery for 3 months. The NTN recipients showed a significant and sustained behavioral improvement in their parkinsonian features during the treatment period, an effect not seen in the vehicle-treated animals. At study termination, locomotor activity levels were increased by 50% in the NTN versus vehicle recipients. Also, DOPAC levels were significantly increased by 150% ipsilateral (right) to NTN infusion in the globus pallidus, while HVA levels were elevated bilaterally in the NTN-treated animals by 10% on the left and 67% on the right hemisphere. No significant changes in DA function were seen in the putamen. Volumetric analysis of putamenal NTN labeling showed between-subject variation, with tissue distribution ranging from 214 to 744 mm3, approximately equivalent to 27–93% of area coverage. Our results support the concept that intraparenchymal delivery of NTN protein may be effective for the treatment of PD. More studies are needed to determine strategies that would enhance tissue distribution of exogenous NTN protein, which could contribute to optimize its trophic effects in the parkinsonian brain.

Slowing of motor movements in human aging is a well-known occurrence, but its biologic basis is poorly understood. Reliable quantitation may refine observations of this phenomenon to better aid research on this entity.

We describe the methods and rationale for using rats with a partial unilateral lesion of the nigrostriatal system as an animal model for studying neural plasticity in both young and aged brains. The rats are lesioned with 6-hydroxydopamine injected into the substantia nigra or the medial forebrain bundle. Amphetamine- and apomorphine-induced rotational behaviors are tested 3 and 4 weeks following the lesion. Based on the rotational responses to amphetamine and apomorphine administration, animals can be classified into one of three groups: unaffected, partially lesioned, or severely lesioned. Animals classified as displaying unaffected rotational behavior are those that do not respond to either amphetamine or apomorphine stimulation. Partially lesioned animals rotate ipsilateral to the lesioned side upon amphetamine injection, but do not display a significant number of rotations in response to apomorphine administration. In contrast, severely lesioned rats rotate after both amphetamine and apomorphine injections. Cell counts reveal that the mean number of dopamine neurons in the ventral mesencephalon of partially lesioned animals is reduced to 40% of that of the intact side. Also in partially lesioned animals, dopamine concentrations on the lesion side are even more severely depleted, averaging about 20% of levels in the contralateral intact striatum. Striatal dopamine concentrations correlate well with the number of surviving dopamine neurons in the ventral mesencephalon (r2 = 0.66, P < 0.05). Amphetamine-induced rotation rates also show a moderate correlation with both striatal dopamine concentrations and mesencephalic dopamine neuron cell counts. Therefore, rotational behavior induced by amphetamine and apomorphine stimulation can be used to identify partially lesioned rats following unilateral 6-hydroxydopamine lesions. It is also possible to estimate the extent of nigrostriatal system damage from the rate of amphetamine-induced rotation.Copyright 1994, 1999 Academic Press

Quinolinic acid (QA) and related excitotoxins produce a pattern of neuronal loss and neurochemical changes in the rat striatum similar to that of patients suffering from Huntington's disease, suggesting neurotoxicity is important in the etiology of that disease. Thus, strategies for limiting excitotoxin-induced striatal damage, like that caused by QA, may be of great benefit to these individuals. Accordingly, we tested the ability of both neural and non-neural tissue implants to protect the rat striatum against a subsequent QA challenge. Our results demonstrated that recipients of fetal striatal grafts were significantly less affected by striatal injections of QA than non-grafted animals. In contrast to the latter, fetal striatal tissue recipients did not exhibit apomorphine-induced rotation behavior and showed a sparing of cholinergic and enkephalinergic systems normally lost following QA injections. Animals grafted with adult rat sciatic nerve, adrenal medulla or adipose tissue all showed a less dramatic behavioral protection and sparing of cholinergic and enkephalinergic systems. These results suggest that fetal striatal tissue exerts an optimal, and perhaps specific protective influence on the host brain.

In order to maintain a chronic supply of growth factor for medulla cells in vitro, chromaffin cells from rat, African green monkeys and man were co-cultured with C6 glioma cells, which secrete growth factors that sustain sympathetic neurons in vitro. The response of chromaffin cells to coculture was compared to treatment of medullary cells with nerve growth factor (NGF) alone. Dispersed chromaffin cell preparations were obtained by a trypsin-collagenase procedure, and subjected to differential plating on collagen-coated surfaces. With both human and monkey tissue, non-chromaffin cells did attach to the culture plates and an enriched chromaffin cell population could be replated. Rat adrenal medulla cells survived very poorly in vitro and were not enriched in this procedure. Cultured human and monkey chromaffin cells survived as epithelial cells (50%) and showed neuritic outgrowth on 55 to 66% of the cells after eight days when treated with nerve growth factor (NGF). These cells showed strong catecholamine histofluorescence, tyrosine hydroxylase (TH) and dopamine beta hydroxylase (DBH) immunoreactivity. In contrast, only ten percent of adult rat chromaffin cells survived in culture, although NGF treatment rescued an additional 20% of the cells and induced neuritic outgrowth after one week in vitro. C6 glioma cells were treated with mitomycin C bromodeoxyuridine to inhibit mitosis and were plated with the various medulla cells in a one to one ratio. Both human and monkey chromaffin cells expressed extensive and enhanced neuritic arborization within eight days of co-culture, (64–82% respectively) and exhibited intimate contact with the glioma cells as seen at the ultrastructural level. Importantly, survival of adult rat adrenal medulla cells was enhanced to 50% or more with 40% of the cells extending neurites when co-cultured with glioma cells for seven days. Chromaffin cells from all three species reacted for TH, DBH and PNMT in co-culture and were histofluorescent. The majority of these cells were also immunoreactive for serotonin and enkephalin, while only 37% of chromaffin cells indicated the presence of NPY. These data indicate that adrenal medulla can be maintained in vitro as the neuronal phenotype when co-cultured with growth factor producing cells and that this strategy may be useful for in vivo transplantation studies.

The antidiuretic activity of oxytocin (OT) was measured in Brattleboro rats with congenital diabetes insipidus. A dose dependent antidiuretic response was found in animals receiving chronic infusions of 0.1 μg/h, 1.0 μg/h, and 5 μg/h of OT. OT infused at the rate of 5 μg/h over a 7-day period completely reversed the symptoms of diabetes insipidus. The results support the concept that OT serves as a weak agonist of vasopressin at the level of the kidney and at pharmacological levels exhibits antidiuretic activity.

Intratesticular grafts of pituitary primordia from 11–13-day-old rat embryos developed in 6 weeks into round nodules approximately 1 mm in diameter. The nodules were principally composed of well differentiated glandular and nervous tissues.