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Biomedical subjects

D E Redmond

Publications and source records attributed to D E Redmond.

155 records · Page 9Linked to original sources
PubMedDate not supplied

Menstrual cycle and ovarian hormone effects on plasma and platelet monoamine oxidase (MAO) and plasma dopamine-beta-hydroxylase (DBH) activities in the rhesus monkey.

Dopamine-B-hydroxylase (DBH) and monoamine oxidase (MAO) in plasma and platelets were studied in six female rhesus monkeys during three complete menstrual cycles. The same monoamine enzymes of seven bilaterally ovariectomized females were compared with a group of controls. A difference was found in platelet MAO between a mid-menstrual-cycle peak and a perimenstrual trough in these animals, while plasma MAO was unchanged. DBH showed an inverted cyclical variation to that demonstrated by platelet MAO. The ovariectomized females showed significant differences from the controls, confirming the effects of the ovarian sex steroid hormones on platelet MAO and plasma DBH. The variation in these peripheral enzymes may be reflective of changes in brain monoamine systems, which may play some role in the behavioral changes observed during the menstrual cycle in primates.

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The effects of testosterone on plasma and platelet monoamine oxidase (MAO) an plasma dopamine-beta-hydroxylase (DBH) activities in the male rhesus monkey.

Dopamine-beta-hydroxylase (DBH) and monoamine oxidase (MAO) in plasma and platelets were studied in male rhesus monkeys to evaluate the effects of changes in endogenous testosterone on the activity of these enzymes. High plasma testosterone concentrations attained at the end of the mating season were associated with relatively low levels of platelet MAO activity. When testosterone levels fell, platelet MAO increased significantly. Mean differences in platelet MAO activity between a group of castrated and control males were in the direction expected, with the highest MAO activity in the castrated monkeys, but these differences did not attain statistical significance. No significant mating season or castration effects were seen in plasma DBH or MAO enzyme activities. These data support the hypothesis of a link between testosterone and some monoamine systems, and possibly the monoamine-related behaviors linked to testosterone in primates.

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PubMedDate not supplied

Sham surgery does not ameliorate MPTP-induced behavioral deficits in monkeys.

Parkinsonism has been reported to improve following transplantation of fetal mesencephalic tissue into the striatum of MPTP-exposed monkeys and humans and in patients with idiopathic Parkinson's disease. While there is good evidence for the survival of grafted tyrosine hydroxylase (TH)-positive cells in animal studies, it is not known whether they produce neuronal effects that account for behavioral improvement after transplantation or whether spontaneous or graft-induced changes in the host striatum are at least partly responsible. Are neuronal synaptic connections and dopamine release necessary, or would "toenails and talcum powder" do the job equally well? We have addressed these questions by studying several types of implantation surgeries, including sham surgery, the implantation of cerebellar tissue, and the implantation of mesencephalic TH-positive fetal tissue of various gestational ages into the striatum. Adult male African green monkeys received systemic MPTP administration (cumulative doses of 2.0-2.5 mg/kg) prior to these stereotaxic surgical manipulations. Subjects were matched for quantitative behavioral deficits prior to surgery. Subjects were examined and assessments made by "blinded" observers who scored individual spontaneous and elicited behaviors. Observers were trained and tested repeatedly for inter-rater reliability. A "parkinsonian summary score" derived and determined using a principal component factor analysis of a large sample of data from MPTP-treated and normal monkeys of the same species was used to assess behavior. Postmortem brain tissue was prepared for biochemical analysis of dopamine concentrations and TH immunohistochemical studies. The most dramatic improvement was seen in monkeys with "early" (< 4 cm fetal crown rump length) surviving substantia nigra grafts in the caudate nucleus. Some behavioral improvements were seen in MPTP-treated sham-operated monkeys, cerebellar-grafted monkeys, and "later" (> 14 cm fetal crown rump length) substantia nigra-grafted monkeys. These changes in monkeys which did not have surviving dopamine-producing grafts probably represent the recovery capacity of MPTP-treated host brain during this time interval since un-operated subjects showed similar changes. More variable effects were seen with substantia nigra grafts in the putamen. The most consistent correlate of behavioral improvement in all experimental groups was elevation in dopamine concentrations near the grafts compared with a distant striatal location which is believed to represent the depletion without the effects of the grafts. While these data do not establish the precise mechanism of action, they point to a hierarchy of factors which provide increasingly larger restorative effects, including sprouting of host neurons and increased dopamine production by grafted fetal dopamine neurons. Sham surgery appears to be significantly less effective than early fetal mesencephalic tissue which survives and releases dopamine.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Restoration of dopamine transporter density in the striatum of fetal ventral mesencephalon-grafted, but not sham-grafted, MPTP-treated parkinsonian monkeys.

Transplantation of fetal dopamine neurons to the adult striatum potentially offers a means to reverse the striatal dopamine deficiency that characterizes Parkinson's disease. Many investigations in rodents have supported the hope that neural grafting may be a useful treatment for parkinsonism. However, clinical studies have generally produced more modest improvements in motor abnormalities than observed in lower species. It is possible that the number of fetal dopamine neurons that survive transplantation is insufficient to restore dopaminergic innervation of the large human striatum to a level where striking recovery is obtained. In fact, there has been no quantitative study of graft outgrowth to indicate what portion of the dopamine-depleted striatum might be reinnervated with present techniques. Furthermore, it has been speculated that regeneration of the host dopamine system in response to the implantation surgery may play an important role in the beneficial effects of neural grafting in primates. The present study used nine 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP)-treated parkinsonian monkeys to investigate these issues. Sham implantation procedures produced no increase in either dopamine transporter density (measured by quantitative autoradiography) or tissue dopamine concentration (measured by HPLC) in the striatum of MPTP-treated monkeys. In sham-grafted and nonimplanted MPTP-treated monkeys, the striatal dopamine concentration was reduced by 99%, based on analysis of 16 sampled sites in the caudate nucleus and putamen of each monkey. No behavioral recovery was seen in the sham-grafted and nonimplanted MPTP-treated groups. In contrast, transplantation of fetal dopamine neurons to the caudate nucleus or putamen of MPTP-treated monkeys resulted in a significant elevation of dopamine transporter density and dopamine levels in the grafted striatal nucleus. Each grafted MPTP-treated monkey received ventral mesencephalon dopamine neurons from one donor harvested during putative neurogenesis. Donor ventral mesencephalon was divided equally and implanted into six sites either in the caudate nucleus or putamen. One graft site in each monkey was examined by dopamine transporter autoradiography. In sections in which graft fibers were present, a mean of one-third of the volume of the grafted nucleus was occupied by an elevated density of dopamine transporters. This increase in dopamine transporter density was defined to be at least 5-10% of the control density. However, full behavioral recovery was not observed in the grafted MPTP-treated group. These data provide no support for the hypothesis that regeneration of the host dopamine system occurs in response to a sham implantation procedure in severely parkinsonian monkeys. The current study illustrates the power of the applied techniques for delineating the relationship between the level of host dopamine depletion, the extent of graft-induced dopaminergic restoration, and behavioral recovery.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Metabolic energy capacity of dopaminergic grafts and the implanted striatum in parkinsonian nonhuman primates as visualized with cytochrome oxidase histochemistry.

Histochemistry for visualization of the mitochondrial enzyme cytochrome oxidase has been detect cellular and regional differences in brain metabolism. We have examined the pattern of cytochrome oxidase (CO) staining in grafts of embryonic ventral mesencephalic tissue, and in the implanted striatum, of MPTP-treated monkeys as one index of the functional activity of grafted tissue and its influence on the host brain. Four monkeys were selected for study based on interesting variations in dopamine (DA) neuron content of their bilateral grafts as demonstrated with tyrosine-hydroxylase (TH) immunocytochemistry. The results suggest that grafts rich in DA neurons increase the metabolic activity of the implanted striatum of DA-depleted monkeys, and that this improvement of local energy metabolism is greater in the vicinity of grafts containing greater numbers of DA neurons. In addition, the pattern of CO staining within tissue transplants indicates that DA neurons exhibit the highest rate of metabolic activity among all cell types contained in the ventral mesencephalic grafts, and that the transplants receive metabolically active innervation from outside or within the grafted tissue.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMedDate not supplied

Intrastriatal grafts from multiple donors do not result in a proportional increase in survival of dopamine neurons in nonhuman primates.

We examined the potential for "double grafts," i.e., grafts from two donors in each recipient, to enhance the total number of ventral mesencephalic dopamine neurons that survive grafting in adult African green monkeys. Because dopamine cell survival in grafts represents a small percentage of the total number of neurons grafted, several human clinical trials recently have employed grafts of tissue from multiple donors (e.g., from two to eight embryos per host recipient) in attempts to increase the total number of dopamine neurons that survive in grafts. Presumably, this is intended to elevate dopamine levels by providing more dopamine neurons to the damaged brain to alleviate the symptoms of parkinsonism. While well-developed grafts with several thousand dopamine neurons were found in most recipient animals, we observed a reduced total number of tyrosine hydroxylase positive neurons in the grafts in spite of the presence of some double grafts that were larger than normal. The overall growth of the grafts was impressive; some grafts were so large that they spanned the full dorsoventral extent of the caudate nucleus, probably reflecting the fact that twice as much tissue was implanted in each drop site in comparison to our standard protocol. However, some animals revealed atypical patterns of neurite outgrowth that appeared limited to the grafted tissue, and at least one monkey revealed "amorphous" grafts generally lacking in cellular structure, which suggests a possible rejection phenomenon. These findings raise questions about the use of multiple donors and suggest that the likelihood of rejection and/or cell death may be enhanced, which is of potential importance in the design of grafting strategies for clinical applications.

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