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J R Sladek

Publications and source records attributed to J R Sladek.

At least 73 records · Page 4Linked to original sources
PubMed1987

Intracerebral grafting and culture of cryopreserved primate dopamine neurons.

Dopamine neurons from the ventral midbrain and olfactory bulb of fetal and postnatal African green monkeys were frozen, stored in liquid nitrogen for intervals of 4-28 days, thawed, and tested for viability and growth following intracerebral transplantation into 3 adult monkeys. Well developed tyrosine hydroxylase positive neurons from all donors were seen in intracerebral transplants at 7-50 days after grafting. Freeze-stored neurons also were tested at various intervals by Trypan blue dye exclusion and development in tissue culture. More than 99% of the cryopreserved cells from both pre- and postnatal donors were viable by dye exclusion, and fetal tissue developed neuronal morphology in culture. This evidence further supports the fact that primate neurons survive intracerebral transplantation, even after cryopreservation and storage. The ability to store, transport and verify the transmitter phenotype of neurons offered by this approach is pertinent to possible therapeutic applications.

Animals↗
PubMed1987

Effects of 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) on catecholamines and metabolites in primate brain and CSF.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) administration is able to produce nigrostriatal damage and motor disabilities in primates similar to those seen in Parkinson's disease. Two months after MPTP treatment in African Green monkeys, significant depletions of dopamine (DA) and/or homovanillic acid (HVA) were found in the dorsal ventral tegmental area, and septum, but not in the ventral part of the ventral tegmental area or nucleus accumbens. However, DA losses were greater at all examined sites in the striatum. In putamen and caudate nucleus the decreases in DA and HVA appeared more marked dorsolaterally than ventromedially. After MPTP treatment the ratio HVA/DA was elevated in the septum and all striatal regions; in the striatum the increases in ratio were greater in the dorsolateral than in the ventromedial samples. NE concentration was not significantly altered by MPTP in the mesolimbic system. In control animals the HVA concentration and the ratio HVA/DA were higher in the putamen than in the caudate nucleus. A longitudinal study showed that CSF HVA and 3-methoxy-4-hydroxyphenylglycol were reduced by MPTP and remained below baseline level for 12 months after MPTP treatment. This biochemical study indicates that in the monkey MPTP is able to induce selective damage within both the nigrostriatal and mesolimbic DA systems.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1987

Reinnervation of transplanted hypothalamic neurons by host aminergic fibers in rats.

Fetal mediobasal hypothalamic tissue which receives an extensive noradrenergic innervation in the adult brain, was implanted into the vicinity of the medial forebrain bundle of adult rats to determine whether host noradrenergic fibers would innervate the ectopically placed tissue in an organotypic manner. Tissue from the site of implantation was prepared for light and ultrastructural immunocytochemistry at 6, 12, or 20 weeks postsurgery. Putative host catecholamine fibers formed dense plexuses in localized portions of the grafts and made synaptic contacts with dendrites and somata of transplanted neurons. This suggests that a mature host central nervous system is capable of a region-specific integration of transplanted neurons.

Animals↗
PubMed1987

Effects of lesions of hypothalamic catecholamines on blood pressure, fluid balance, vasopressin and renin in the rat.

Fluid balance, systolic blood pressure (BP) and serum vasopressin (VP) and renin activity (SRA) in the basal state and in response to blood volume depletion were examined in unanesthetized rats previously given intrathecal 6-hydroxydopamine (6-OHDA) to destroy catecholaminergic (CA) input to supraoptic nucleus (SON). Sham-operated rats, unoperated ad libitum hydrated rats and rats undergoing 4 days of water deprivation served as controls. The 6-OHDA lesion resulted in adipsia, a failure to conserve administered fluids and a decrease in systolic BP. Despite decreased blood volume secondary to dehydration, and decreased systolic BP, the 6-OHDA group failed to show the expected increase in serum VP. However, when blood volume was further decreased following intraperitoneal polyethylene glycol, lesioned rats showed robust VP and SRA responses. Thus, CA input to critical target areas in the hypothalamus may be necessary for maintenance of sensitivity to stimuli that normally elicit VP release. Decreased systolic BP following 6-OHDA lesions most likely results from dehydration coupled with inadequate VP responses.

Animals↗
PubMed1987

Differential responsiveness to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine toxicity in sub-regions of the primate substantia nigra and striatum.

After treatment with the neurotoxin, 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP), there was a severe loss of dopamine (DA) at all examined sites in the striatum, both in those monkeys which remained asymptomatic (77-99%) and in one monkey which developed severe parkinsonian disability (94-99%). However, the asymptomatic animals had normal DA concentration in the substantia nigra (SN); yet in the symptomatic animal DA was largely depleted in the central (86%) and medial (94%), but not lateral (8%) regions of the SN. The HVA/DA ratio was raised in the striatum of all MPTP-treated animals. In the SN though, this ratio was elevated only in the symptomatic animal, in the central and medial, but not lateral regions. The contralateral half of these brains were examined for DA histofluorescence. The SN of asymptomatic animals had a slight increase in lipofuscin fluorescence within dopaminergic neurons and a small reduction in the number of dopaminergic cells, while fluorescent intensity of individual neurons was unchanged. The SN of the symptomatic animal displayed a sharp decline in the number of DA neurons along with an increase in autofluorescent pigment granules; these changes were most pronounced in the central and medial regions of the SN. These data suggest that after MPTP the terminals of the nigrostriatal pathway are affected before the cell bodies. In the one symptomatic animal emergence of parkinsonian disability corresponded with a marked loss of DA neurons and DA concentration in the central and medial regions of the SN. In the control monkeys a gradient in the concentration of amines and metabolites was observed within the SN; the lateral region contained the highest and the medial region the lowest concentration.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Diencephalic catecholamine neurons (A-11, A-12, A-13, A-14) show divergent changes in the aged rat.

The effects of aging on diencephalic (A-11, A-12, A-13, A-14) catecholamine neurons in the F344 male rat were examined with Falck-Hillärp histofluorescence. In contrast to the age-related increase in A-12 perikaryal fluorescence intensity previously reported (Hoffman and Sladek: Neurobiol. Aging 1:27-37, '80), incertohypothalamic perikarya showed decreased (A-13) or unchanged (A-11, A-14) fluorescence intensity with age. Cell counts of fluorescent A-12 perikarya disclosed a 47% increase in the number of fluorescent A-12 neurons in 30-month-old F344 rats relative to the 3-month-old controls; numbers of A-11 and A-13 fluorescent perikarya decreased with age, but the declines were not statistically significant. It is unlikely that the age-related increase in number of fluorescent A-12 perikarya is the result of proliferation of neurons in the aged F344 rat. Rather, the greater number of fluorescent A-12 perikarya in 30-month-old F344 rats indicates that some A-12 neurons in 3-month-old F344 rats contain levels of dopamine that are subthreshold for detection with the Falck-Hillärp fluorescence technique, whereas virtually all A-12 perikarya in 30-month-old F344 rats contain detectable quantities of dopamine. These findings suggest that diencephalic catecholamine neurons exhibit divergent changes in transmitter content and cell number that may reflect varying degrees of functional integrity during brain aging.

Animals↗
PubMed1986

Aged mice are more sensitive to 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine treatment than young adults.

Parkinson's disease is a neurodegenerative disorder characterized mainly by damage to the dopaminergic nigrostriatal system. Recently, the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) has been shown to induce damage in the nigrostriatal system, accompanied by Parkinson-like symptoms in humans. We present here evidence that MPTP treatment in aged 21-month-old mice produced a marked reduction in the presence and intensity of fluorescence in noradrenergic neurons of the locus coeruleus and in dopaminergic neurons of the ventral tegmental area in addition to extensive damage to the substantia nigra. Aged mice treated with MPTP also showed physical signs of movement disability characterized by marked akinesia, rigidity of the hind limbs, and an initial resting tremor of the entire body. Such symptoms were less evident in young mice treated with MPTP. These remarkable initial behavioral effects of MPTP treatment in aged mice and evidence of reduced catecholamine fluorescence in the locus coeruleus and ventral tegmental area suggest that aged mice are more sensitive to, and more severely affected by MPTP treatment than young mice. We suggest that these MPTP-treated aged mice provide a useful animal model for studying both anatomical and functional characteristics of Parkinson's disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Preferential vulnerability of A8 dopamine neurons in the primate to the neurotoxin 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine.

Immunohistochemical examination of the midbrain of vervet monkeys treated with MPTP revealed a marked loss of dopaminergic neurons in the lateral, but not medial, region of the A8 dopamine (DA) cell group. In the same animals, the number of DA neurons in the substantia nigra was only slightly decreased. Biochemical assessment revealed a marked (greater than 85%) depletion of DA in the striatum. However, in the DA cell body regions significant decreases in DA and homovanillic acid were observed only in the lateral A8 region, and not in the medial A8 region or substantia nigra. These data suggest that those A8 DA neurons which project to the striatum are preferentially vulnerable to MPTP.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Fetal neuronal grafts in monkeys given methylphenyltetrahydropyridine.

Fetal substantia nigra cells of two different gestational ages were successfully transplanted into the brains of three methylphenyltetrahydropyridine-treated monkeys with severe parkinsonian motor and behavioural deficits. Functional improvement continued for 10 weeks after cell grafts into the striata of two monkeys with substantial numbers of tyrosine-hydroxylase-positive fetal neurons at necropsy. Behavioural improvement was correlated with increases in cerebrospinal fluid (CSF) homovanillic acid (HVA) concentrations after the transplants. A control monkey with inappropriately placed transplanted cells of an earlier gestational age remained severely parkinsonian and died during a similar period. CSF HVA fell slightly in this monkey from the low level seen before the transplants. Fetal dopamine neurons of two different gestational ages appear to survive transplantation in primates and have biochemical and functional effects.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1986

Localization of vasopressin-neurophysin and norepinephrine in the supraoptic nucleus of spontaneously hypertensive rats.

Histological analysis of the catecholaminergic innervation of vasopressin neurons in the supraoptic nucleus (SON) was performed using catecholamine histofluorescence and immunocytochemistry of vasopressin specific neurophysin (VP-NP) in order to determine if spontaneously hypertensive rats (SHR) demonstrate alterations in the relationship between these two types of chemically defined neurons. Chronically hypertensive SHRs showed an increased density of catecholamine fluorescence particularly in the dorsal part of the SON in comparison to age-matched, normotensive, Wistar-Kyoto (WKY) rats, but not in comparison to age-matched Wistar rats. In addition, there was an increase in the area of distribution of VP-NP immunopositive neurons such that they extended into the dorsal portion of the nucleus in the SHR compared to the WKY. Comparator bridge analysis of immunocytochemical staining and catecholamine histofluorescence revealed a precise overlap of the two patterns in SHR. Thus, the more extensive distribution of catecholamine fluorescence in the dorsal SON in the SHR compared to WKY paralleled the more extensive distribution of VP neurons in this region. Quantitative analysis of the relative percentage of SON neurons which were VP-NP positive indicated that the increased representation of VP-NP positive neurons in the dorsal portion of the nucleus reflected a greater distribution of the VP-NP cell population throughout the SON rather than an increase in the number of VP-NP neurons in the SHR. In young SHRs (5 weeks old) the catecholamine fluorescence pattern in the SON was considerably smaller than that observed in older SHRs. This low density pattern, however, was comparable to that observed in young WKYs. Thus, the catecholamine fluorescence in the SON apparently increases in the SHR in parallel with the development of the hypertension. This observation and the finding of comparable catecholamine fluorescence in Wistars and SHRs suggest that the altered catecholamine innervation of VP neurons observed in chronically hypertensive SHRs is not causal to the hypertension but may reflect a response to the elevated blood pressure. A marked increase in the catecholamine innervation of cerebral arteries was also noted.

Age Factors↗
PubMed1986

Survival and growth of fetal catecholamine neurons transplanted into primate brain.

Dopamine and norepinephrine neuroblasts of the ventral mesencephalon, hypothalamus, and dorsolateral pons were transplanted from fetal African green monkeys into multiple brain sites in adult (host) African green monkeys. Tissue was grafted from both early and late gestational age fetuses. Immunohistochemical analysis, with antibodies to tyrosine hydroxylase, a marker of catecholamine-containing neurons, showed large numbers of transplanted catecholamine neurons in host cerebral cortex, corpus striatum and lateral ventricles up to 69 days after transplantation. Serial reconstructions revealed extensive outgrowth of neuronal processes from large numbers of transplanted neurons as well as expansion of the size of transplanted (solid) grafts of fetal brain tissue in the host brain. Some grafts extended from the caudate nucleus into the adjacent lateral ventricles or from the cerebral cortex into the underlying corpus callosum and ventricle. There were dense networks of varicose fibers emanating from the tyrosine hydroxylase positive neurons within intraparenchymal and intraventricular grafts. The size and shape of transplanted neurons retained characteristics common to catecholaminergic neurons from the dissected regions of fetal brain. Thus, a variety of fetal, catecholamine-containing neurons survive transplantation to primate brain and produce extensive neuritic outgrowths. Moreover, rejection of transplanted tissue was not apparent. These findings provide essential information on nerve cell grafting in a species closely related to humans as a prerequisite in the consideration of neural transplants as therapeutic measures in neurological disease.

1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
PubMed1985

Hypothalamic catecholamine histofluorescence in dwarf mice.

Brains of growth hormone (GH)- and prolactin (PRL)-deficient Ames (df/df) and Snell (dw/dw) dwarf mice and normal mice of the same strains were examined for catecholamine (CA) histofluorescence, with particular emphasis upon the hypothalamic tuberoinfundibular (A12) (arcuate nucleus/median eminence) region, which plays a role in the regulation of both GH and PRL. Dwarfs and normal animals of both types also were treated with a drug regimen to deplete sequentially neuronal CA stores (reserpine), inhibit CA oxidation (nialamide) and load dopaminergic A12 cells with exogenous transmitter (norepinephrine), in order to test viability and axonal transport capacity of A12 neurons. In both types of dwarfs, compared with normals, fluorescence was markedly reduced in the zona externa of the median eminence, which is normally rich in terminals from A12 neurons. Fluorescence in the median eminence was particularly weak in Ames dwarfs, and A12 perikarya were difficult to discern in this group. Snell dwarfs showed reduced fluorescence of A12 perikarya when compared with the brightly fluorescent perikarya seen in normal mice. In supraoptic and paraventricular nuclei, and in the zona interna of the median eminence, CA fluorescence attributable to NE was comparable among dwarfs and normals; fluorescence of dopaminergic perikarya in substantia nigra was also unaffected in dwarfs. Exogenously administered NE effected enhanced fluorescence of A12 perikarya in normal mice and in Snell dwarfs; NE treatment in the Ames dwarf, however, failed to increase significantly the faint fluorescence of A12 cell bodies. The results indicate that dopaminergic A12 neurons in Snell dwarf mice are present and viable.(ABSTRACT TRUNCATED AT 250 WORDS)

Animals↗
PubMed1985

Neural transplantation: a review of recent developments and potential applications to the aged brain.

Mammalian neural transplantation has recently been recognized to be a valuable technique for studying normal development and regeneration in the central nervous system. In addition, the ability of grafted neurons to reinnervate damaged regions of the host brain and to ameliorate some neuroendocrine deficits, cognitive disorders and motoric dysfunctions in young adult rodents has suggested that transplantation therapy may be effective in treating human neurodegenerative diseases and neurotransmitter deficiencies related to aging. It is of particular interest that initial studies of neuron transplants in aged rodents indicate that cholinergic, dopaminergic and noradrenergic neurons all integrate to some extent with the aged brain, and that the product of this graft-host interaction is improved behavioral performance of aged subjects. The present paper critically reviews the present domain of neural transplantation, its application to studies on the properties of the aged mammalian brain and discusses the possible therapeutic use of transplants in ameliorating transmitter-specific abnormalities associated with Parkinson's disease and Alzheimer's disease.

Adrenal Medulla↗