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PubMed1993

Comparative pathology of recombinant murine interferon-gamma in mice and recombinant human interferon-gamma in cynomolgus monkeys.

Interferon-gamma is a highly species-specific cytokine and has the most restricted host range of activity of the interferons. Recombinant human IFN-gamma was one of the first species-specific recombinant proteins to be thoroughly assessed in conventional safety models used for xenobiotics. Acute single-dose intravenous toxicity studies with rHuIFN-gamma were performed in rats, marmosets, and squirrel monkeys with no indications of toxicity. A complete series of subchronic toxicity studies and segment I and II reproductive studies in the rat revealed no evidence of toxicity at any of the doses tested. These results suggested that studies conducted in pharmacologically nonresponsive species may not be predictive of clinical toxicity. Human IFN-gamma is active on nonhuman primate cells, though not at the same level as on human cells. Multidose studies in cynomolgus monkeys with rHuIFN-gamma for 28 or 90 days were predictive of many of the dose-limiting clinical toxicities. Qualitative similarity was observed between toxicity studies employing rHuIFN-gamma in the cynomolgus monkey and rMuIFN-gamma in the mouse. The adverse effects seen in toxicity studies with cytokines and growth factors are often exaggerated pharmacological effects of the molecules, and therefore can only be studied in a responsive species. In situations in which a high degree of species specificity is encountered, studies employing a recombinant protein in a homologous species may provide a useful test system for preclinical safety assessment.

Abnormalities, Drug-Induced↗
PubMed2006

Immunogenicity of a chimeric hepatitis A virus (HAV) carrying the HIV gp41 epitope 2F5.

Its stable particle structure combined with its high immunogenicity makes the hepatitis A virus (HAV) a perfect carrier to expose foreign epitopes to the host immune system. In an earlier report [Beneduce, F., Kusov, Y., Klinger, M., Gauss-Müller, V., Morace, G., 2002. Chimeric hepatitis A virus particles presenting a foreign epitope (HIV gp41) at their surface. Antiviral Res. 55, 369-377] chimeric virus-like particles (HAV-gp41) were described that carried at their surface the dominant gp41 epitope 2F5 (2F5e) of the human immunodeficiency virus HIV-1. Extending this work, we now report that chimeric virus HAV-gp41 replicates in HAV-susceptible cells as well as in non-human primates. Infected marmosets developed both an anti-HAV and anti-2F5 epitope immune response. Furthermore, an HIV-neutralizing antibody response was elicited in guinea pigs immunized with HAV-gp41 chimeric particles. The results demonstrate that the replication-competent chimeric HAV-gp41 can serve as either a live or a subunit vaccine for eliciting of antibodies directed against a foreign antigenic epitope.

AIDS Vaccines↗
PubMed2004

Role of lipid interactions in autoimmune demyelination.

A morphological transformation involving loss of adhesion between myelin lamellae and formation of myelin vesicles has been described as a mechanism for demyelination in multiple sclerosis and marmoset experimental allergic encephalomyelitis (EAE). Although protein interactions are involved in maintaining normal myelin structure, we describe here how lipids contribute to myelin stability and how lipid changes in EAE, including increases in lipid polyunsaturation and negatively charged phosphatidylserine (PS), promote demyelination. Three physico-chemical techniques were used to identify these changes: (1) Langmuir monolayer isotherms indicated that EAE white matter lipids were significantly more "expanded" (fluid) than controls. (2) NMR spectroscopy indicated that EAE myelin lipids were more polyunsaturated than controls. (3) High-performance liquid chromatography (HPLC) with an evaporative light scattering detector indicated increased PS in EAE compared to controls, while sphingomyelin (SM), sulfatides and phosphatidylcholine (PC) were decreased. We present a physical model considering electrostatic, van der Waals and undulation forces to quantify the effect of these changes on myelin adhesion at the extracellular interface. Taken together, the isotherm, NMR, HPLC and modeling results support a mechanism for autoimmune demyelination whereby the composition of myelin lipids is altered in a manner that increases myelin fluidity, decreases myelin adhesion, increases membrane curvature, and promotes vesiculation.

Animals↗
PubMed2005

Postural changes after lesions of the substantia nigra pars reticulata in hemiparkinsonian monkeys.

Current neurosurgical strategies target overactive brain regions including the subthalamic nucleus, globus pallidus and thalamus to control various symptoms of Parkinson's disease. Subthalamotomy improves akinesia and can induce postural deficits in both parkinsonian humans and animals, pallidotomy improves limb dyskinesia and more variably, distal bradykinesia whilst thalamotomy improves tremor. Because the SNr also becomes overactive in PD and there are few surgical studies in parkinsonian primates, we therefore evaluated the effects of lesioning the SNr in hemiparkinsonian marmosets to establish the effects on symptomatology. Nine monkeys received unilateral 6-hydroxydopamine (6-OHDA) lesions. Seven weeks later, four received kainic acid lesions of the SNr. Behavioural tests were performed prior to 6-OHDA surgery and then fortnightly for 14 weeks. Unilateral 6-OHDA lesions induced ipsilateral postural bias, ipsilateral rotation after amphetamine injection and bradykinesia. Whilst, SNr lesions significantly altered the direction of head position and amphetamine-induced rotation relative to 6-OHDA lesions, there was no improvement in 6-OHDA-induced reaching deficits or sensorimotor neglect. Unbiased quantitation of the nigral lesions showed on average 88% loss of dopaminergic neurons after 6-OHDA lesions and 77% loss of non-dopaminergic neurons after SNr lesions. Our results demonstrate that the SNr is important in body orientation changes in parkinsonism.

Adrenergic Agents↗
PubMed2005

Neglect of memory after dopaminergic lesions in monkeys.

Crossed unilateral dopaminergic lesions of the nigrostriatal bundle and unilateral inferotemporal cortex ablations (DA x IT lesions) in marmoset monkeys produced impaired retention of object discriminations first learnt before, or after, the DA lesion but no impairment on new learning of the same type of task. Retention testing of a pre-operatively learned task was given after new learning of a different task so impairment cannot be attributed to improvement with practice or spontaneous recovery. We argue that the DA lesion produces a form of intentional neglect, a defect of volition, which is the mnemonic counterpart of the volitional neglect of directional hypokinesia, which animals with this lesion also exhibit. The DA lesion was unilateral (for welfare reasons) so the information to be retrieved had to be confined to that hemisphere by the use of an IT ablation in the other hemisphere. Unilateral DA lesion compromises the competence of ipsilateral fronto-striatal interactions and our results parallel those found in monkeys with crossed IT x frontal lesions that are impaired on complex tasks requiring effortful implementation of a cognitive strategy but are not impaired on discrimination learning. Parkinsonian patients with sub-total but bilateral DA loss may lack 'top-down' conative mechanisms as well as 'top-down' movement initiation mechanisms. They may fail to initiate retrieval strategies, although they may not exhibit retrograde amnesia under test conditions that provoke retrieval. Failure to self-initiate retrieval of relevant knowledge may contribute to the paucity of cognitive style and loss of executive skills exhibited by some patients with Parkinson's disease.

Analysis of Variance↗
PubMed2004

Cloning and functional expression of a novel marmoset cytochrome P450 2D enzyme, CYP2D30: comparison with the known marmoset CYP2D19.

Using a primer set designed on the cDNA encoding the known marmoset cytochrome P450 2D19 (CYP2D19), a cDNA encoding a novel CYP2D enzyme (CYP2D30) was cloned from the liver of a female marmoset bred at Kyoto University (KYU). In addition, a cDNA encoding CYP2D19 was cloned from the liver of a female marmoset bred at Kagoshima University (KAU). CYP2D30 and CYP2D19 showed homologies of 93.6 and 93.4% in their nucleotide and amino acid sequences, respectively. Reverse transcription polymerase chain reaction (RT-PCR) and digestion with NdeI demonstrated that the KYU-marmoset liver contained mainly mRNA for CYP2D30, while the KAU-marmoset liver contained mainly mRNA for CYP2D19. Marmoset CYP2D30, like human CYP2D6, exhibited high debrisoquine (DB) 4-hydroxylase activity and relatively low DB 5-, 6-, 7- and 8-hydroxylase activities, whereas CYP2D19 lacked DB 4-hydroxylase but exhibited marked 5-, 6-, 7- and 8-hydroxylase activities. The two marmoset recombinant enzymes showed enantioselective bufuralol (BF) 1"-hydroxylase activities, similar to CYP2D6. BF 1"-hydroxylation by CYP2D30 exhibited product-enantioselectivity of (1"R-OH-BF << 1"S-OH-BF), similar to that observed with human CYP2D6, whereas CYP2D19 showed a reversed selectivity of (1"R-OH-BF > or = 1"S-OH-BF). BF 1"-hydroxylation in marmoset liver microsomes from both sources was inhibited by antibodies raised against rat CYP2D1 in a concentration-dependent manner. A known inhibitor of CYP2D6, quinidine, effectively inhibited the BF 1"-hydroxylation activities in liver microsomal fractions prepared from KYU- and KAU-marmosets. These results suggest that CYP2D19 and CYP2D30 proteins can be expressed as functional enzymes in marmoset livers, although it is unresolved whether both enzymes coexist in the same marmoset liver.

Alcohol Oxidoreductases↗
PubMed2006

Cloning of a cDNA encoding a novel marmoset CYP2C enzyme, expression in yeast cells and characterization of its enzymatic functions.

We cloned a cDNA encoding a novel CYP2C enzyme, called P450 M-2C, from a marmoset liver. The deduced amino acid sequence showed high identities to those of human CYP2C8 (87%), CYP2C9 (78%) and CYP2C19 (77%). The P450 M-2C enzyme expressed in yeast cells catalyzed p-methylhydroxylation of only tolbutamide among four substrates tested, paclitaxel as a CYP2C8 substrate, diclofenac and tolbutamide as CYP2C9 substrates and S-mephenytoin as a CYP2C19 substrate. p-Methylhydroxylation of tolbutamide by marmoset liver microsomes showed monophasic kinetics, and the apparent K(m) value (1.2 mM) for the substrate was similar to that of the recombinant P450 M-2C (1.8 mM). Although all of the recombinant human CYP2C8, CYP2C9 and CYP2C19 expressed in yeast cells catalyzed tolbutamide p-methylhydroxylation, the kinetic profile of CYP2C8 was most similar to that of P450 M-2C. Tolbutamide oxidation by the marmoset liver microsomes and the recombinant P450 M-2C was inhibited most effectively by quercetin, a CYP2C8 inhibitor, followed by omeprazole, a CYP2C19 inhibitor, whereas sulfaphenazole, a CYP2C9 inhibitor, was less potent under the conditions used. These results indicate that P450 M-2C is the major tolbutamide p-methylhydroxylase in the marmoset liver.

Amino Acid Sequence↗
PubMed2004

Neurovirulence of mumps virus: intraspinal inoculation test in marmosets.

An intraspinal inoculation test of mumps virus using marmosets was performed in order to develop a neurovirulence test of mumps vaccines. In the group inoculated with non-neurovirulent Jeryl Lynn vaccine strain at 10(2.0) pfu/dose, there were only minimal histopathological changes in 3 of the 5 marmosets. In contrast, all marmosets inoculated with neurovirulent Urabe and NK-M46 vaccine strains developed extensive encephalitis and meningitis. Thus, this marmoset model, which can distinguish between non-neurovirulent and neurovirulent vaccine strains, is useful for evaluating neurovirulence of vaccine strains and elucidating the molecular pathogenesis of mumps.

Animals↗
PubMed2004

Deprivation of parenting disrupts development of homeostatic and reward systems in marmoset monkey offspring.

BACKGROUND: Early environment is a major determinant of long-term mental health, evidenced by the relationship between early-life neglect or abuse and chronically increased vulnerability to developmental psychopathology, including major depressive disorder (MDD). Animal studies can increase understanding of environmentally mediated causal risk processes. We describe how daily deprivation of biological parenting in primate infants disrupts development of homeostatic and reward systems central to MDD. METHODS: Nine breeding pairs of marmoset monkeys provided control twins (CON) and early-deprived twins (ED); the latter were socially isolated for 30-120 min/day on days 2-28. During the first year of life, basal urinary norepinephrine (NE) titers and cardiophysiologic activity were measured. At the end of year 1 (adolescence), automated neuropsychologic tests were conducted to measure responsiveness to changes in stimulus-reward association (simple/reversed visual discrimination learning) and to reward per se (progressive ratio [PR] reinforcement schedule). RESULTS: The ED monkeys exhibited increased basal urinary NE titers and increased systolic blood pressure relative to CON siblings. The ED monkeys required more sessions to reinstate stimulus-oriented behavior following reversal, suggesting increased vulnerability to perceived loss of environmental control; ED monkeys also performed less PR operant responses, indicating that reward was less of an incentive and that they were mildly anhedonic relative to CON. CONCLUSIONS: In marmoset monkeys, neglect-like manipulation of ED leads to chronic changes in homeostatic systems, similar to those in children and adolescents exposed to early-life adversity and in MDD, and to responses to environmental stimuli similar to those that characterize MDD.

Animals↗
PubMed2006

Diminished cortisol levels in subordinate female marmosets are associated with altered central drive to the hypothalamic-pituitary-adrenal axis.

BACKGROUND: Female marmosets offer a promising primate model of stress-related hypocortisolism, as they undergo chronic reductions in circulating cortisol after becoming subordinate in a social group. In this study, we treated dominant and subordinate female marmosets with the cortisol synthesis inhibitor metyrapone and corticotropin-releasing factor (CRF) to characterize the effects of subordination on central regulation of the hypothalamic-pituitary-adrenal (HPA) axis. METHODS: Seven dominant and six subordinate female marmosets received CRF (6 microg/kg, intravenous [IV]), following pretreatment with metyrapone (75 mg/kg, by mouth [PO]) or water. Plasma adrenocorticotropic hormone (ACTH) and cortisol concentrations were determined before metyrapone or water treatment and before, 1 hour after, and 2 hours after CRF treatment. RESULTS: Following metyrapone treatment, subordinates had similar cortisol levels to dominants but significantly higher ACTH levels. During CRF challenges, cortisol concentrations were lower and ACTH concentrations higher in subordinates, although net integrated responses to CRF did not differ. Cortisol-to-ACTH ratios were consistently lower in subordinates. CONCLUSIONS: These results confirm previous findings of low cortisol concentrations and blunted adrenal responsiveness in subordinates and suggest that when differences in cortisol levels are eliminated, subordinates exhibit exaggerated hypothalamic drive to the pituitary. These neuroendocrine alterations in subordinate marmosets resemble those in posttraumatic stress disorder patients and adult survivors of child abuse.

Adrenocorticotropic Hormone↗
PubMed2003

Pharmacokinetics of L-dopa in plasma and extracellular fluid of striatum in common marmosets.

L-3, 4-Dihydroxyphenylalanine (L-dopa) has been widely used for the treatment of Parkinson's disease (PD), but its pharmacokinetics in the striatum have hardly been investigated, especially in primates. In this study, we examined the concentration of L-dopa in plasma and in the extracellular fluid (ECF) of the striatum in common marmosets using microdialysis and high-performance liquid chromatography (HPLC) with electrochemical detection. With a clinically therapeutic dosage of L-dopa/benserazide (20/5 mg/kg, p.o.), the t(max) of L-dopa was 30 min in plasma and 60-90 min in ECF of striatum. Mean C(max) was 20.3 microM in plasma and 442.9 nM in ECF of striatum, which is about 2.2% of that in plasma. The L-dopa concentration in ECF is much lower than those previously applied during in vivo studies for L-dopa toxicity.

Animals↗
PubMed2004

Autologous transplantation of expanded neural precursor cells into the demyelinated monkey spinal cord.

The objective of this study was to establish if neural precursor cells could safely be developed from biopsy of the subventricular zone (SVZ) in the non-human primate (marmoset), and to determine their myelinating potential after autologous transplantation into a demyelinated lesion. Small amounts of tissue were safely collected from the subventricular-subependymal zone of the adult primate brain under ultrasonography without any neurological deficit. Neural precursor cells were isolated and expanded in the presence of mitogen in vitro. The dorsal columns of the adult marmoset spinal cord were demyelinated by X-irradiation and intraspinal injections of ethidium bromide in the center of the radiation field. Cell suspensions of the neural precursors were microinjected through a micropipette into the demyelinated lesion site in the spinal cord. Lesions were histologically examined 3 weeks after transplantation. Light and electron microscopic examination of plastic embedded sections revealed a significant number of myelinating profiles in the transplantation zone; no myelination was observed in control lesions. The myelinated axons had predominantly peripheral patterns of myelination. These results demonstrate that autologous transplantation of neural precursor cells in the adult nonhuman primate can remyelinate demyelinated central nervous system (CNS) axons, thus suggesting the potential utility of such an approach in demyelinating lesions in humans.

Animals↗
PubMed2006

Osteopontin expression in substantia nigra in MPTP-treated primates and in Parkinson's disease.

Parkinson's disease (PD) is characterised by the loss of dopaminergic neurones in the substantia nigra (SN) but the pathogenic mechanism remains unknown. Cell death involves oxidative stress and inflammatory mechanisms, and these may be altered by the actions of the glycosylated phosphoprotein osteopontin (OPN). OPN is present in the rat SN, but its presence in human and non-human primate brain has not been extensively studied. Both OPN mRNA and protein were present in the normal marmoset SN, and OPN protein was localised to nigral neurones although these were not dopaminergic cells and it was not present in glial cells. In contrast, OPN protein was found in dopaminergic neurones in the normal human SN but again not in glial cells with some accumulation in the extracellular matrix. Following MPTP treatment of common marmosets, OPN protein expression was decreased, although its mRNA levels were unchanged and it was not present in either activated microglia or astrocytes. In the SN in PD, OPN protein expression was decreased in the remaining dopaminergic neurones and it was present in activated microglia but not in astrocytes. This was not specific to PD as OPN protein expression was also decreased in the SN in multiple system atrophy and progressive supranuclear palsy with an identical localisation of the protein. The presence of OPN in the normal human and non-human primate SN coupled to its decreased expression following nigral cell degeneration suggests that it may play an important role in dopaminergic neurone survival.

Aged↗
PubMed2005

Further analysis of the effects of immunotoxic lesions of the basal nucleus of Meynert reveals substantial impairment on visual discrimination learning in monkeys.

In this paper we undertake a combined analysis of several studies in which marmoset monkeys received immunotoxic lesions of the cortical cholinergic projections from the basal nucleus of Meynert (NBM) bilaterally and/or in combination with immunotoxic lesions of other parts of the cholinergic system or ablations of the target inferotemporal neocortical area. Analysis of the mean learning scores across all visual discriminations learning tasks for each lesion combination revealed highly significant impairments where the NBM was lesioned bilaterally or where an NBM lesion in one hemisphere was crossed with an inferotemporal cortical ablation in the other hemisphere. This demonstrates that the cholinergic projection from the NBM to the major target area of neocortex involved in visual discrimination learning, i.e. the inferotemporal cortex, makes an important contribution to the perceptuo-mnemonic processes necessary for this type of learning. A new study demonstrates a significant effect of a subtotal bilateral cholinergic lesion confined to the NBM on a concurrent object-reward association task using black objects which is perceptually and mnemonically demanding. These results do not preclude the possibility that cholinergic projections from the NBM to other parts of the neocortex make a contribution to other cortical functions which are not mnemonic. It is well established that lesions of the cholinergic projection from the diagonal band of Broca disrupts the mnemonic functions of the hippocampus. The results described here suggest that degeneration of the cholinergic projections in Alzheimer's disease and other dementias will contribute to the loss of those mnemonic functions which are dependent on the neocortex.

Analysis of Variance↗
PubMed2005

Elucidating coding of taste qualities with the taste modifier miraculin in the common marmoset.

To investigate the relationships between the activity in different types of taste fibers and the gustatory behavior in marmosets, we used the taste modifier miraculin, which in humans adds a sweet taste quality to sour stimuli. In behavioral experiments, we measured marmosets' consumption of acids before and after tongue application of miraculin. In electrophysiological experiments responses of single taste fibers in chorda tympani and glossopharyngeal nerves were recorded before and after tongue application of miraculin. We found that after miraculin marmosets consumed acids more readily. Taste nerve recordings showed that after miraculin taste fibers which usually respond only to sweeteners, S fibers, became responsive to acids. These results further support our hypothesis that the activity in S fibers is translated into a hedonically positive behavioral response.

Animals↗
PubMed2006

siRNA targeting LMP1-induced apoptosis in EBV-positive lymphoma cells is associated with inhibition of telomerase activity and expression.

Epstein-Barr Virus (EBV) is closely associated with B cell malignancies. However, whether EBV appears to be absolutely required for cell proliferation and survival in lymphoma cells is still unknown. In this study, small interfering RNA (siRNA) targeting LMP1 was employed to investigate the effect of LMP1 on cell proliferation in EBV-positive lymphoblastoid B-cell line. A plasmid stable encoding 21-nt small RNA specifically and efficiently interfering LMP1 was constructed, resulting in a substantial loss of LMP1 mRNA and a significantly decreased LMP1 protein expression. Our data demonstrated that cell proliferation was completely inhibited and apoptosis was induced after knockdown of LMP1 gene in lymphoblastoid B-cell line. Also, we found that suppression of LMP1 caused downregulation of telomerase protein expression and decreased telomerase activity in lymphoma cells. In EBV-negative NPC cell line, transfection of plasmid expressing LMP1 greatly enhanced telomerase protein expression. Our results suggested that siRNA targeting LMP1 can induce apoptosis in EBV-positive lymphoma cells and is associated with inhibition of telomerase activity and expression. siRNA-directed LMP1 silencing may be of the therapeutic value for preventing and treating those EBV-associated tumors.

Animals↗
PubMed2005

Molecular cloning and functional analysis of cytochrome P450 1A2 from Japanese monkey liver: comparison with marmoset cytochrome P450 1A2.

A cDNA encoding a novel cytochrome P450 1A2 (CYP1A2) was cloned from the liver of an adult female Japanese monkey. The CYP1A2 protein was expressed in yeast cells and its enzymatic properties were compared with those of marmoset CYP1A2 using ethoxyresorufin (ER) and phenacetin (PN) as substrates. The nucleotide sequence of Japanese monkey CYP1A2 revealed 94.7, 99.5 and 93.5% identities to those of human, cynomolgus monkey and marmoset monkey CYP1A2, respectively. Multiple amino acid sequence alignment of Japanese monkey CYP1A2 with CYP1A2 of humans, cynomolgus monkeys and marmosets showed that Japanese monkey CYP1A2 had 92.4, 99.0 and 91.9% identities to the human, cynomolgus monkey and marmoset enzymes, respectively. Kinetic studies demonstrated that the enzymatic properties as ER and PN O-deethylases were considerably different between the Japanese monkey and the marmoset CYP1A2. Furthermore, both of these reactions in liver microsomal fractions from the Japanese monkey and marmoset showed biphasic kinetics. On the basis of the kinetic parameters, it is suggested that Japanese monkey CYP1A2 is a high-K(m) enzyme in both ER and PN O-deethylations, whereas marmoset CYP1A2 is a high-K(m) and low-K(m) enzyme in ER and PN O-deethylations, respectively. alpha-Naphthoflavone, an inhibitor of human CYP1A1 and CYP1A2, did not completely inhibit the liver microsomal oxidations of ER and PN even at the highest concentration (50muM), supporting the notion that CYP1A2 enzymes are not the sole ER or PN O-deethylase in Japanese monkey and marmoset liver microsomes. Inhibitory effects of furafylline, an inhibitor of human CYP1A2, on ER O-deethylation by recombinant CYP1A2 enzymes were much lower than those of alpha-naphthoflavone, but marmoset CYP1A2 was more sensitive to furafylline than Japanese monkey CYP1A2. These results indicate that the properties of Japanese monkey CYP1A2 are considerably different from those of marmoset CYP1A2.

Adult↗