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PubMed2005

Assessment of GDNF in primate models of Parkinson's disease: comparison with human studies.

Potential future treatments for Parkinson's disease (PD) include those that not only provide symptomatic relief to patients but are also neuroprotective and/or neurorestorative. Glial cell line-derived neurotrophic factor (GDNF) may be a valuable candidate in this regard. Positive results using monkeys have encouraged the use of GDNF in human trials. These trials have unfortunately shown mixed results, illustrating the influence that various parameters of administration can have on clinical outcome. The aim of this review is to compare the findings of these clinical studies with available primate data. While bolus intraventricular injections of GDNF in primates have shown some behavioural efficacy, there was no clinical benefit in the first human trial using this method, which was most likely a result of inefficient GDNF distribution in the striatal parenchyma. In primates, however, continuous (rather than bolus) delivery of GDNF into the ventricles results in significant distribution in the striatum. While chronic delivery of GDNF into the ventricles has not been assessed in humans, intraputamenal protein delivery in two Phase I trials have demonstrated that GDNF considerably reduces PD symptoms, suggesting that the putamen is the optimal location for delivery. Primate studies have shown that vector mediated delivery of GDNF may provide a suitable means for long-term intraputamenal delivery. However, the possibility of high levels of GDNF resulting in widespread distribution of GDNF to non-targeted areas is a cause of concern, and vectors with transgene regulation are needed. The development of these vectors may be the way forward for GDNF treatment.

Animals↗
PubMed2005

Reward-spatial view representations and learning in the primate hippocampus.

The primate anterior hippocampus (which corresponds to the rodent ventral hippocampus) receives inputs from brain regions involved in reward processing, such as the amygdala and orbitofrontal cortex. To investigate how this affective input may be incorporated into primate hippocampal function, we recorded neuronal activity while rhesus macaques performed a reward-place association task in which each spatial scene shown on a video monitor had one location that, if touched, yielded a preferred fruit juice reward and a second location that yielded a less-preferred juice reward. Each scene had different locations for the different rewards. Of 312 neurons analyzed in the hippocampus, 18% responded more to the location of the preferred reward in different scenes, and 5% responded to the location of the less-preferred reward. When the locations of the preferred rewards in the scenes were reversed, 60% of 44 hippocampal neurons tested reversed the location to which they responded, showing that the reward-place associations could be altered by new learning in a few trials. The majority (82%) of these 44 hippocampal neurons tested did not respond to reward associations in a visual discrimination, object-reward association task. Thus, the primate hippocampus contains a representation of the reward associations of places "out there" being viewed. By associating places with the rewards available, the concept that the primate hippocampus is involved in object-place event memory is now extended to remembering goals available at different spatial locations. This is an important type of association memory.

Animals↗
PubMed2004

Mapping dopamine function in primates using pharmacologic magnetic resonance imaging.

Dopamine (DA) receptors play a central role in such diverse pathologies as Parkinson's disease, schizophrenia, and drug abuse. We used an amphetamine challenge combined with pharmacologic magnetic resonance imaging (phMRI) to map DA-associated circuitry in nonhuman primates with high sensitivity and spatial resolution. Seven control cynomolgous monkeys and 10 MPTP (1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine)-treated parkinsonian primates were studied longitudinally using both positron emission tomography (PET) and phMRI. Amphetamine challenge (2.5 mg/kg, i.v.) in control monkeys increased relative cerebral blood volume (rCBV) in a number of brain regions not described previously, such as parafascicular thalamus, precentral gyrus, and dentate nucleus of the cerebellum. With the high spatial resolution, we were also able to readily identify changes in rCBV in the anterior cingulate, substantia nigra, ventral tegmental area, caudate (tail and head), putamen, and nucleus accumbens. Amphetamine induced decreases in rCBV in occipital and posterior parietal cortices. Parkinsonian primates had a prominent loss of response to amphetamine, with relative sparing of the nucleus accumbens and parafascicular thalamus. There was a significant correlation between rCBV loss in the substantia nigra and both PET imaging of dopamine transporters and behavioral measures. Monkeys with partial lesions as defined by 2beta-carbomethoxy-3beta-(4-fluorophenyl) tropane binding to dopamine transporters showed recruitment of premotor and motor cortex after amphetamine stimulus similar to what has been noted in Parkinson's patients during motor tasks. These data indicate that phMRI is a powerful tool for assessment of dynamic changes associated with normal and dysfunctional DA brain circuitry in primates.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed2000

In vitro manipulation of nonhuman primate gametes for embryo production and embryo transfer.

Since nonhuman primates are closely related to humans and share many physical similarities, they are important for use in research areas such as human infectious diseases, reproduction, physiology, endocrinology, metabolism, neurology and longevity. To develop and maintain these animals, we must establish techniques for in vitro manipulation of spermatozoa and eggs. For a decade my research group has been conducting basic research to establish embryo manipulation techniques and to clarify the reproductive phenomena in nonhuman primates. This article summarizes the past research on in vitro manipulation of nonhuman primate gametes, from collection of reproductive cells and in vitro fertilization to the birth of offspring after embryo transfer, as well as the current status of these research areas. The studies summarized here will directly lead to the development of standard techniques for practical and comprehensive use in nonhuman primates.

Animals↗
PubMed2004

Cloning of oestrogen receptor beta from Old and New World primates: identification of splice variants and functional analysis.

Oestrogens have a major impact on reproductive function in both males and females. Two oestrogen receptor genes known as ERalpha (ESR1NR3A1) and ERbeta (ESR2NR3A2) have been cloned. Splice variant isoforms of the ERbeta gene have been identified in human, bovine and rodents and it has been suggested that the existence of these forms can influence oestrogen responsiveness. In the human, splicing of an alternative eighth exon results in the formation of a C-terminal variant called hERbetacx, or hERbeta2, but this isoform has not been identified in other species. The aim of the present study was to clone ERbeta cDNAs from primates so as to determine how closely they resembled the ERbeta isoforms found in the human. The two species studied were the stump-tailed macaque (Macaca arctoides), an Old World primate, and the common marmoset (Callithrix jacchus jacchus), a New World primate. Full length ERbeta (wild type, ERbeta1) cDNAs were cloned from macaque and marmoset; they encoded proteins of similar size to those found in human (59 and 54 kDa, long and short forms respectively) and shared significant sequence homology (97.5% in macaque and 93.8% in marmoset) with the human peptide sequence. Full length cDNAs homologous to the hERbeta2 variant were identified in both primates. Marmoset ERbeta2 was slightly shorter than that of human ERbeta2 (54 kDa compared with 55 kDa) and did not contain the peptide sequence used to raise an anti-hERbeta2 antibody. All the macaque ERbeta2 cDNAs contained 56 bp of intronic sequence which included an in-frame stop codon resulting in translation of a truncated protein ( approximately 35 kDa). In all three species, truncated, alternatively spliced mRNAs lacking exon 5 were isolated on multiple occasions from all tissue extracts. In transient transfection assays, ERbeta2-containing constructs were unable to induce transcription of an oestrogen response element (ERE) reporter plasmid in the presence of oestradiol. ERbeta1 from human, macaque and marmoset exhibited minor differences in their ability to induce transcription of the ERE reporter when incubated with different ligands (oestradiol, PPT, DPN, 5-alpha-androstane-3-beta, 17beta-diol (3betaAdiol), genistein) and this may be due to amino acid substitutions within their ligand binding domains. In conclusion, we have identified and cloned wild type ERbeta (ERbeta1) from macaque and marmoset and demonstrated that splice variant mRNAs homologous to hERbeta2 are formed in both species. The marmoset monkey, therefore, provides a suitable animal model in which to investigate the impact of ERbeta variant expression on tissue responsiveness to oestrogens.

Alternative Splicing↗
PubMed1989

Control of inhibin production by primate granulosa cells.

In-vitro data from experiments on rats implicate granulosa cells as primary sites of hormone-dependent ovarian inhibin biosynthesis, but no equivalent data exist for primates. We have used the common marmoset (Callithrix jacchus) to investigate inhibin biosynthesis in primate granulosa cells in vitro and to determine its relationship to preovulatory follicular development. To relate the production of immunoactive inhibin to follicular maturity, we studied primary granulosa cell cultures from follicles at progressive stages of preovulatory development. Granulosa cells from 'large' (greater than or equal to 2.0 mm diameter) follicles expressed high rates of inhibin production and steroidogenesis (progesterone), and were positively regulated by human (h)LH in vitro. Less mature granulosa cells from 'medium' (1.1-1.9 mm) and 'small' (less than or equal to 1.0 mm) follicles expressed proportionately lower rates of inhibin production and steroidogenesis, but each parameter was stimulated in a dose- and time-dependent manner by hFSH in vitro. The stimulatory action of hFSH on immunoreactive inhibin was augmented by the presence of testosterone or oestradiol; testosterone (but not oestradiol) also augmented the steroidogenic response to hFSH. Marmoset luteal tissue also produced inhibin in vitro and expressed an approximately 1.5 kb inhibin alpha-subunit mRNA, confirming the corpus luteum as a source of ovarian inhibin in primates. These results provide direct experimental evidence that primate granulosa cells produce inhibin. They suggest that production of inhibin by immature granulosa cells is initially induced by FSH and subject to modulation by follicular steroids.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1982

Nonhuman primates as models for the study of human diabetes mellitus.

Nonhuman primates have been used for a variety of studies on diabetes mellitus. Spontaneous, natural forms of diabetes have been well documented in several species; there are limited data on numerous other species that indicate diabetes or a diabetes-like syndrome. The causes and manifestations of spontaneous diabetes, their prevalence, and their severity vary among species. Diabetes has also been induced in nonhuman primates with streptozotocin, alloxan, hypothalamic lesions, or pancreatectomy. The extent and severity of metabolic and hormonal abnormalities vary according to the method of induction, the individual monkey, and the species. Metabolic, hormonal, and pathologic abnormalities present in human diabetics also occur in monkeys with either spontaneous or induced diabetes. Hyperglycemia and impaired glucose clearance are common, lipid concentrations are elevated, and hemoglobin A1c concentrations are increased in hyperglycemic monkeys. Monkeys may have fasting hypo- or hyperinsulinemia; insulin responses are often impaired in glucose tolerance tests. Glucagon concentrations may be increased. Aortic atherosclerosis, muscle capillary microangiopathies, cataracts, and glomerulosclerosis have been documented. Primate size and longevity allow longitudinal studies with procedures that may not be feasible in smaller animals or in human beings. Nonhuman primates may be the models of choice for studies on selected aspects of diabetes and its secondary complications.

Animals↗
PubMed1995

Oral kinetics of dexfenfluramine and dexnorfenfluramine in non-human primates.

1. Large doses of dexfenfluramine in animals cause a decrease of serotoninergic markers but none of the species so far investigated shows sufficient kinetic and metabolic similarity with man to be a valid model for safety studies. The plasma kinetics of dexfenfluramine and its active metabolite dexnorfenfluramine were therefore studied in baboon, rhesus and cynomolgus monkeys given dexfenfluramine hydrochloride orally (2 mg/kg) in order to investigate whether any of these primates have a biodisposition particularly similar to man. 2. The drug was rapidly N-deethylated to dexnorfenfluramine achieving comparatively low mean maximum plasma levels (Cmax) of 12-14 ng/ml in all primates, and rapidly disappeared thereafter with half-lives (t1/2) ranging from 2 to 3 h in the baboon and rhesus monkey to 6 h in the cynomolgus monkey. Its normetabolite reached higher mean Cmax (52-97 ng/ml) and the t1/2's were longer, varying from about 11 h in the rhesus monkey to 22 h in the cynomolgus monkey. The metabolite-to-parent drug ratio (14-37), in terms of plasma area under curve (AUC), greatly exceeded that in man (< 1), being higher than in all species investigated so far. 3. Comparative repeat dose simulation in monkey and man indicated that the dosage in primates would need to be increased 10-fold to achieve comparable dexfenfluramine steady-state plasma Cmax, producing nor-metabolite levels several times those in man, whilst for comparable metabolite Cmax, those of the parent drug would be correspondingly too low. 4. In view of the different mechanism of action of dexfenfluramine and dexnorfenfluramine within the serotoninergic system none of these primates is therefore a suitable model for safety assessment in terms of exposure of the active moieties in comparison with man.

Animals↗
PubMed1998

The neurotoxicity of amyloid beta protein in aged primates.

Amyloid beta protein deposition is a universal feature of Alzheimer's disease brain. To investigate the effects of amyloid beta protein in aged primates, intracerebral microinjections of solubilized amyloid beta (A beta (1-40)) and control peptides were made into the frontal cortex of 7 primates under stereotactic guidance. Control injections consisted of vehicle alone, a 37 amino acid non toxic peptide (A37), scrambled peptide (CA4), and reverse peptide (A beta (40-1)). Amyloid beta peptide produced dose-dependent cortical lesions that were significantly larger than those produced by vehicle or by isomolar control peptides (3.28 and 2.20 fold larger respectively) (p = < 0.005). In 5 aged primates, the cortex surrounding the amyloid beta lesions contained argyrophilic, thioflavine S fluorescent, Alz 50 and ubiquitin immunoreactive neurons and perikarya. The number of Alz 50 immunoreactive neurons surrounding the amyloid beta injections was significantly greater (mean 127 +/- 39) than the number found surrounding reverse peptide injections (mean 20 +/- 13) and other control peptides (mean 0.8 +/- 0.3) (p < 0.05). Neuronal and neuritic alterations were not found adjacent to the amyloid beta peptide lesions in young monkeys and control injections produced insignificant Alz 50 neuronal positivity. These findings suggest that amyloid beta peptide is neurotoxic in primate brain and that the cytoskeletal response to amyloid beta protein is specific and age-related.

Age Factors↗
PubMed1989

Implantation of dispersed cells into primate brain.

Although several experimental therapies such as dopaminergic cell implantation in parkinsonian models and intratumoral placement of lymphokine-activated killer cells require intracerebral deposition of dispersed cell suspensions, a successful technique of needle implantation of cells into primate brain has not been demonstrated. The authors have sought to establish a stereotaxic technique to predictably deposit dispersed cells in primate brain. Human lymphocytes were cultured in recombinant interleukin-2, labeled with sodium 51 chromate (51Cr), and stereotaxically injected into the frontal white matter of six anesthetized rhesus monkeys. A 10-microliters aliquot of cell suspension (2 X 10(7) cells/ml) was deposited 16 mm deep to the dura at 5 microliters/min via Hamilton No. 22s or 26s needles. Five control aliquots were counted for each injection. Reflux out of the needle track was absorbed on gauze, and the recovered cells were counted. The animals were sacrificed 1 hour after implantation and the brain was removed and sectioned such that the cortex and white matter along the needle track were separate. The tissue sections were then counted. Recovery was expressed as the percentage of total injected radioactivity (cpm) that was present in each brain section. Two additional injected hemispheres were processed for autoradiography and histological study. Cell recovery in the brain (mean +/- standard deviation) was 87.2% +/- 13.9% (3.3% +/- 4.9% in cortex and 83.9% +/- 15.9% in white matter). The autoradiograms and histological examination showed a dense accumulation of radioactivity (cells) at the target site and minimal radioactivity (cells) in the needle track. Accurate intracerebral deposition of dispersed cells in primates was achieved with the technique described. This knowledge permits reliable stereotaxic implantation of cells into the brains of nonhuman primates and humans for investigation and therapy.

Animals↗
PubMed1975

Urinary metabolites of 2, 5, 2', 5'-tetrachlorobiphenyl in the nonhuman primate.

The metabolism of 2, 5, 2', 5'-tetrachlorobiphenyl (TCB) in nonhuman primates was found to be different from that previously reported in lower species. Monohydroxy TCB (I), the only metabolite in the ether extracts of rat urine, is a minor metabolite in the urine of nonhuman primates. The two major metabolites identified in the urine were dihydroxy TCB (II) and trans-3,4-dihydro-3,4-dihydroxy TCB (III). A second minor metabolite was identified as hydroxy-3,4-dihydro-3,4-dihydroxy TCB (IV). None of the above mentioned metabolites have been reported in primates and only I and III have been identified in lower animals. It is concluded that a likely mechanism for metabolism of TCB in primates is through arene oxide intermediates. This observation is of particular importance in that these types of intermediates are known to alkylate cellular components causing carcinogenic, mutagenic, necrogenic and teratogenic effects.

Animals↗
PubMed2002

Functional domains in dorsal striatum of the nonhuman primate are defined by the dynamic behavior of dopamine.

The dorsal striatum comprises a continuum of distinct functional domains, limbic, associative, and sensorimotor. In the primate it exclusively subdivides further into two nuclei, the putamen and caudate. Dopamine (DA) transmission is differentially affected between these nuclei in neurodegenerative diseases such as Parkinson's and by psychostimulants such as cocaine. Because rodent systems can offer only limited insight into DA systems of the human brain, a fuller appreciation of DA transmission and its role in dysfunction requires direct study in primates. DA behavior was explored in the major functional domains of the caudate nucleus and compared with the putamen, using fast-scan cyclic voltammetry in striatal sections from the marmoset (Callithrix jacchus). There was domain-specific variation in extracellular DA transients [i.e., concentration ([DA](o)) released by a single stimulus and the rate maximum of DA uptake, V(max)]. Across nuclei, functional rather than anatomical regions were differentiated by these dynamics. The largest, fastest DA transients were at motor-associated loci. Evoked [DA](o) at physiological frequencies was differently frequency-sensitive between functional domains but not between anatomical nuclei. In contrast, presynaptic depression was not an index of regional differentiation, recovering with similar kinetics at all loci. Within a given functional domain of dorsal striatum, the dynamics of DA release and uptake are similar for the putamen and the caudate nucleus. Conversely, distinct functional domains are defined by these DA dynamics, in a manner more marked in primates than in rodents. These data from the primate brain highlight differences in DA availability that may be central to DA function and dysfunction in the human.

Animals↗
PubMed1999

Route and method of delivery of DNA vaccine influence immune responses in mice and non-human primates.

BACKGROUND: In spite of the large number of studies that have evaluated DNA-based immunization, few have directly compared the immune responses generated by different routes of immunization, particularly in non-human primates. Here we examine the ability of a hepatitis B surface antigen (HBsAg)-encoding plasmid to induce immune responses in mice and non-human primates (rhesus monkeys: Macaca mulatta) after delivery by a number of routes. MATERIALS AND METHODS: Eight different injected [intraperitoneal (IP), intradermal (ID), intravenous (IV), intramuscular (IM), intraperineal (IPER), subcutaneous (SC), sublingual (SL), vaginal wall (VW)] and six noninjected [intranasal inhalation (INH), intranasal instillation (INS), intrarectal (IR), intravaginal (IVAG), ocular (Oc), oral feeding (oral)] routes and the gene gun (GG) were used to deliver HBsAg-expressing plasmid DNA to BALB/c mice. Sera were assessed for HBsAg-specific antibodies (anti-HBs, IgG, IgG1, IgG2a) and cytotoxic T lymphocyte (CTL) activity measured. Three of the most commonly used routes (IM, ID, GG) were compared in rhesus monkeys, also using HBsAg-expressing vectors. Monkeys were immunized with short (0-, 4- and 8-week) or long (0-, 12- and 24-week) intervals between boosts, and in the case of GG, also with different doses, and their sera were assessed for anti-HBs. RESULTS: In one study, anti-HBs were detected in plasma of mice treated by five of eight of the injected and none of the six noninjected routes. The highest levels of anti-HBs were induced by IM and IV injections, although significant titers were also obtained with SL and ID. Each of these routes also induced CTL, as did IPER and VW and one noninjected route (INH) that failed to induce antibodies. In a second study, GG (1.6 microg) was compared to ID and IM (100 microg) delivery. Significant titers were obtained by all routes after only one boost, with the highest levels detected by IM. Delivery to the skin by GG induced exclusively IgG1 antibodies (Th2-like) at 4 weeks and only very low IgG2a levels at later times; ID-immunized mice had predominantly IgG1 at 4 weeks and this changed to mixed IgG1/IgG2a over time. Responses with IM injection (in the leg or tongue) were predominantly IgG2a (Th1-like) at all times. IV injection gave mixed IgG1/IgG2a responses. In monkeys, in the first experiment, 1 mg DNA IM or ID at 0, 4, and 8 weeks gave equivalent anti-HB titers and 0.4 microg at the same times by GG induced lower titers. In the second experiment, 1 mg DNA IM or ID, or 3.2 microg by GG, at 0, 12, and 24 weeks, gave anti-HB values in the hierarchy of GG > IM > ID. Furthermore, high titers were retained after a single immunization in mice but fell off over time in the monkeys, even after boost. CONCLUSIONS: Route of administration of plasmid DNA vaccines influences the strength and nature of immune responses in mice and non-human primates. However, the results in mice were not always predictive of those in monkeys and this is likely true for humans as well. Optimal dose and immunization schedule will most likely vary between species. It is not clear whether results in non-human primates will be predictive of results in humans, thus additional studies are required. http://link.springer-ny.com/link/service/journals/00020/bibs /5n5p287. html

Administration, Cutaneous↗
PubMed1999

Head-out immersion in the non-human primate: a model of cardiovascular deconditioning during microgravity.

BACKGROUND: Orthostatic intolerance is a common complication associated with spaceflight. It has been speculated that this is due to changes in blood volume and alterations in cardiovascular reflexes. The objective of the current study was to develop a model that would allow us to study the cardiovascular system and the regulation of blood volume during short-term microgravity exposure in the primate with the intent of eventually being able to elucidate those factors responsible for the orthostatic intolerance. HYPOTHESIS: Head-out water immersion in the conscious non-human primate simulates the cardiovascular and volume regulatory responses observed in astronauts during exposure to microgravity. METHODS: Four monkeys were chronically instrumented for measuring BP and heart rate and then conditioned to the primate restraint chair. They were then subjected to 72 h of head-out water immersion (two immersions in three monkeys and one immersion in the fourth) in order to simulate the cardiovascular and renal effects of the microgravity environment. RESULTS: During the immersion, there was an increase in arterial BP (ABP) and central venous pressure (CVP) and a reflex decrease in heart rate (HR). Urine flow (UV) increased and water intake decreased, producing a negative water balance. This was not associated with an alteration in food intake. CVP and UV decreased following de-immersion. There was also resetting of the arterial baroreflex control of HR. Significant tachycardia occurred after the immersion that was associated with a decrease in ABP. CONCLUSION: These results are similar to those observed in astronauts during and after spaceflight, suggesting that head-out water immersion of the non-human primate provides a good model for studying cardiovascular and renal adaptations to spaceflight.

Animals↗
PubMedDate not supplied

Susceptibility of nonhuman primates to carcinogens of human relevance.

Nonhuman primates are a valuable experimental model for the evaluation of human carcinogenic risk but have not been widely used for various reasons, such as high cost and lack of availability. The present review discusses the findings from a long-term carcinogenesis study in nonhuman primates that was carried out under contract by the National Cancer Institute from 1961 to 1997. Among the classes of compounds investigated were model rodent carcinogens, food additives, food and environmental contaminants, heterocyclic amines, N-nitroso compounds, and antineoplastic and immunosuppressives. Of the model rodent carcinogens tested, only urethane was carcinogenic in monkeys. Long-term administration of saccharin or cyclamate did not result in toxicity or carcinogenicity in nonhuman primates, which is commonly seen in rodent models. Similar to rodent models and suspected in the human population, the fungal toxins, aflatoxin B1 and sterimatocystin, induced malignant liver tumors in monkeys. Relatively few animals administered DDT developed malignant tumors, however, hepatic and CNS toxicity was commonly observed. Hepatocellular carcinoma developed in a majority of monkeys administered the heterocyclic amine, IQ but not the structurally similar MeIQx. Resultant toxicity and carcinogenicity from N-nitroso compounds was variable. While diethylnitrosamine proved to be the most potent hepatocarcinogen tested, no malignant tumors were seen in animals administered N-methyl-N-nitro-N-nitrosoquanidine. Susceptibility of nonhuman primates to chemotherapeutic agents was also variable. Only procarbazine and N-methyl-N-nitrosourea were highly carcinogenic, whereas few tumors were seen as a result of cyclophosphamide, Adriamycin, melphalan, or azathioprine.

Animals↗
PubMed2000

Heat shock cognate-70 gene expression declines during normal aging of the primate retina.

PURPOSE: Despite documented age-related changes in retinal function and histology, little is known about the pattern of gene expression during normal aging of the vertebrate retina. This study was undertaken to definitively characterize gene expression in the primate retina during aging. METHODS: Human retina cDNA library clones were arrayed at high density on nylon membranes and screened with mixed cDNA probes generated from young (4-year-old) and old (80-year-old) human retinae. Clones showing a more than twofold difference in intensity were rescreened by dot blot analysis with the same probes and with mixed cDNA probes generated from young (2-3 years) and old (27-35 years) rhesus monkeys. One clone identified by its differential (age-putative) signal, and age-related differential expression was used for analysis of Northern blot analysis of total retinal RNA from human donors (35 weeks to 94 years of age) and two rhesus monkeys (2 and 27 years of age). The identified clone was sequenced and compared with entries in the GenBank/EMBL databases. Western blot analysis was performed on protein isolated from the retina of human donors aged 4 to 64 years and rhesus monkeys aged 18 months and 35 years. RESULTS: Approximately 1.6% of the 55,368 retina-expressed sequences examined show age-related changes between tissues from young and old donors. The mRNA level one clone, identical with heat shock cognate (HSC)70, was altered during normal retinal aging in primates. Regression analysis of Northern blot analysis signals from 23 human donors suggested that there may be a two- to threefold decrease in HSC70 mRNA levels in the human retina by the eighth decade of life. Western blot analysis also showed lower levels of the 70-kDa HSC protein in older tissues of both primates. CONCLUSIONS: HSC70 mRNA levels apparently decline during normal aging of the primate retina. Because the heat shock 70 protein family may play important roles in ocular development and protection from various biologic and environmental stresses, decreased HSC70 levels in the retina during aging may contribute to the apparent increased susceptibility of the retina to age-acquired retinal disease.

Adolescent↗
PubMedDate not supplied

Islet cell transplantation: in vivo and in vitro functional assessment of nonhuman primate pancreatic islets.

Transplantation of pancreatic islets of Langerhans as a therapeutic approach for treatment of type I diabetes offers an alternative to subcutaneous insulin injections. Normalization of blood glucose levels by transplanted islets may prevent the development of diabetes-related complications. Problems related to rejection, recurrence of autoimmunity, and local inflammation upon transplantation of islets into the liver need to be solved before the implementation of islet cell transplantation can be viewed as a justifiable procedure in a large cohort of patients. Islet cell isolation has been quite successful in small animals, but the translation of this approach to nonhuman primates has been less rewarding. One of the main problems encountered in nonhuman primate models is the difficulty of isolating an adequate number of functional islets for transplantation. The aim of the present study was to develop a method for isolating a sufficient number of viable islets from nonhuman primates to allow for reversal of diabetes. By implementing minor modifications in the automated method for human islet isolation we were able to obtain viable, functional islets that responded normally to glucose stimulation in vitro. These islets were also able to reverse diabetes in immunocompromised nude mice, rendered diabetic by streptozotocin. This method of islet cell isolation has enabled us to proceed with protocols of allogeneic islet cell transplantation in preclinical, nonhuman primate models.

Animals↗
PubMed2000

Dopamine release and uptake dynamics within nonhuman primate striatum in vitro.

The putamen of the human striatum is a heterogeneous nucleus that contains the primary site of loss of dopamine (DA) in Parkinson's disease (PD). Furthermore, different functional domains of the putamen are heterogeneously susceptible to DA loss, and yet the dynamic regulation of extracellular DA concentration ([DA](o)) and comparison between domains has not been explored in the primate brain. In these studies, DA was measured in real time using fast-scan cyclic voltammetry at a carbon-fiber microelectrode in vitro in striatal sections from the common marmoset (Callithrix jacchus). [DA](o) released by a single stimulus pulse varied threefold along a ventromedial-dorsolateral axis. DA uptake was via the DA transporter (GBR12909 sensitive, desipramine insensitive). On the basis of data modeling with simulations of Michaelis-Menten kinetics, rate maximum, V(max), varied with region: both [DA](o) and V(max) were greatest in regions most vulnerable in PD. These differences were reflected in part by regional variation in DA content. [DA](o), V(max), and regional variation were two- to threefold greater than in rodent caudatoputamen. In addition, steady-state [DA](o) at physiological firing rates in primate striatum was controlled by depolarization frequency, uptake, and presynaptic autoreceptors. Furthermore, regulation of [DA](o) by these mechanisms differed significantly between limbic- and motor-associated domains. These data indicate interspecies heterogeneity in striatal DA dynamics that must be considered when extrapolating behavioral and drug responses from rodent to the primate brain. Moreover, the heterogeneity demonstrated within the primate putamen in the availability and dynamic regulation of DA may be central to understanding DA function in health, cocaine abuse, and disease.

3,4-Dihydroxyphenylacetic Acid↗