Nigral and adrenal grafts in parkinsonism: recent basic and clinical studies.
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1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Biomedical subjects
L Olson
Publications and source records attributed to L Olson.
Cadaveric renal transplantation after pulsatile perfusion, histocompatibility matching, and conversion to cyclosporine therapy.
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Antilymphocyte Serum↗
Human fetal substantia nigra grafted to the dopamine-denervated striatum of immunosuppressed rats: evidence for functional reinnervation.
Human fetal substantia nigra tissue, obtained following therapeutic termination of first trimester pregnancies, was grafted to cavities overlying the striatum in ciclosporin-treated rats whose nigrostriatal dopamine system had been removed unilaterally by 6-hydroxydopamine. Tyrosine hydroxylase (TH) immunocytochemistry revealed large numbers of surviving human substantia nigra neurons that matured and formed TH-positive nerve fibers reinnervating the host rat striatum. Apomorphine-induced rotational behavior in grafted animals was reduced by 70-80% in optimal cases 3-5 months after grafting. Thus human fetal dopamine neurons can correct functional deficits in dopamine-denervated rat hosts.
Animals↗
Short- and long-term consequences of intracranial injections of the excitotoxin, quinolinic acid, as evidenced by GFA immunohistochemistry of astrocytes.
Astroglial reactions to intrastriatal and intrahypothalamic injections of the endogenous excitotoxin quinolinic acid (50 micrograms in 1 microliter) were studied in adult rats, using immunohistochemistry with antiserum to glial fibrillary acidic protein. Animals were sacrificed 6 h, 24 h, 3, 7 and 30 days or 1 year after the injection. Six and 24 h after quinolinic acid, the amount of glial fibrillary acidic protein-like immunoreactivity in the injected striatum was lower than in controls but returned to a normal level at 3 days. Not until 7 days was a clear striatal gliosis apparent, as evidenced by an increased density of glial fibrillary acidic protein-positive structures and brightly fluorescent, clearly hypertrophic cells. This gliosis was even more developed in animals sacrificed 30 days postoperatively. A weak astrocytic reaction was also observed in the ipsilateral corpus callosum at 6 h after quinolinic acid. By 3 days, a marked gliosis restricted to the injected hemisphere was present throughout corpus callosum and cortex cerebri. In animals sacrificed 30 days after quinolinic acid the extrastriatal astrocytic reaction was clearly diminished, although the striatal gliosis was still prominent. One year postinjection, no obvious gliosis could be observed in cortex cerebri or corpus callosum while striatal tissue, now markedly reduced in volume, was clearly gliotic. Using neurofilament antiserum, increased fluorescence intensity was noted in striatal nerve bundles during the first day after an intrastriatal quinolinic acid injection and persisted 1 year postoperatively. Controls were similarly injected with an equimolar amount of nicotinic acid, the non-excitatory, non-neurotoxic decarboxylation product of quinolinic acid. No changes in immunoreactivity of glial fibrillary acidic protein or neurofilament were found in these animals. In animals treated intrahypothalamically, a spherical central area almost devoid of glial fibrillary acidic protein-immunoreactivity was noted around the injection site 7 days after quinolinic acid administration. Around this area, gliosis was observed. Apart from a very restricted gliotic reaction around the needle tract, no astrocytic reaction was observed in nicotinic acid-injected control animals. We conclude that quinolinic acid causes both reversible and long-lasting gliosis when injected into the rat striatum. As a natural brain metabolite, quinolinic acid may constitute a particularly valuable tool for the elucidation of a possible role of glia in neurodegenerative disorders.
Animals↗
Laminin immunohistochemistry: a simple method to visualize and quantitate vascular structures in the mammalian brain.
Immunohistochemistry using antiserum against the basement membrane glycoprotein laminin, was shown to be an excellent marker for brain blood vessels. Throughout the brain of mice, rats, guinea pigs, monkeys and humans, the basement membrane of the vascular structures were strongly laminin-positive. The neuropil itself was laminin-negative, whereas a positive reaction was observed in the meaninges. When the laminin antiserum was preabsorbed with its proper antigen, no specific fluorescence was observed. Using India ink perfusion as a comparative method, it was found that probably all vascular structures were also visualized with laminin immunohistochemistry. Laminin immunofluorescence was found well-suited for computer-assisted quantitative image analysis of brain vascularity. As expected in the periphery, the basement membrane of many other structures except blood vessels such as endoneurium, epithelium and smooth muscle cells were laminin-positive. Although the vascular network was also strongly laminin-immunoreactive, it was difficult to differentiate between blood vessels and non-vascular structures in the periphery as compared to the central nervous system. In conclusion, laminin immunohistochemistry has proven to be a simple, useful and specific method to study vascular structures in the central nervous system and an excellent alternative to more conventional and laborious methods such as perfusion with India ink.
Animals↗
Growth and development of intraocular fetal cortex cerebri grafts in rats of different ages.
Cortex cerebri pieces from fetal donors were homologously and bilaterally grafted to the anterior chamber of the eye of 1.5-, 3.0- and 7.5-month-old rats. Repeated stereoscopic in vivo measurements revealed that the grafts in the young group grew to a size twice as large as those in the older two groups. The degree of gliosis was studied immunohistochemically using antibodies against glial fibrillary acidic protein. Both grafts to young and to older hosts were clearly gliotic as compared to normal cerebral cortex. However, the gliosis was significantly more pronounced in grafts to 3.0- and 7.5-month-old hosts as compared to grafts to 1.5-month-old hosts. The vascular component was evaluated using antibodies against laminin. We found laminin immunofluorescence to be an excellent marker of brain tissue vascularization, particularly at the capillary level, revealing the entire capillary tree and endothelial budding. The density of the vascular plexus and the average thickness of the capillaries of cortex cerebri grafted to the youngest recipients was remarkably similar to normal cerebral cortex. In marked contrast, grafts to the older hosts had a clearly pathological vascular network characterized by few, thick-walled blood vessels and very few normal-looking capillaries. We conclude that host age factors profoundly influence development and growth of intraocular brain tissue grafts.
Animals↗
Raphe dorsalis-spinal cord cografts in oculo: electrophysiological evidence for an excitatory serotonergic innervation of transplanted spinal neurons.
Intraocular replicas of descending serotonergic bulbospinal pathways were constructed by means of sequential intraocular grafting of nucleus raphe dorsalis and spinal cord. Using extracellular recordings we have studied the functional connections between such double grafts. Superfusion of single spinal cord grafts with serotonin causes an increase in spontaneous activity. This excitation is reversibly blocked by the specific 5-hydroxytryptamine (5-HT) antagonist metergoline. Stimulation of the raphe part of nucleus raphe dorsalis-spinal cord double grafts causes a long-lasting excitation of the spinal neurons similar to that seen in single spinal cord grafts given serotonin. The electrically induced excitation could also be reversibly blocked with metergoline. It is concluded that serotonin-containing nerves from grafts of nucleus raphe dorsalis are not only morphologically organotypic, but also form functional contacts with neurons in cografted spinal cord. The results further support an excitatory or modulatory role of the descending spinal serotonergic pathways and demonstrate that functional contacts can be established between isolated CNS grafts when 5-HT fibers invade immature or mature spinal cord tissue.
Animals↗
Astrocyte responses to dopaminergic denervations by 6-hydroxydopamine and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine as evidenced by glial fibrillary acidic protein immunohistochemistry.
Astrocytic responses to dopaminergic denervation by two widely used dopamine neurotoxins, 6-hydroxydopamine (6-OHDA) and 1-methyl-4-phenyl-1,2,3,6-tetrahydropyridine (MPTP) were monitored using immunofluorescence with antibodies against glial fibrillary acidic protein (GFA) while neurofilament (NF) antibodies were used to monitor neuronal disturbances. Following stereotaxic injection of 6-OHDA into the nigrostriatal dopamine bundle in rats, an increased amount of GFA-immunoreactivity in striatum was detectable after 24 hours and remained after one month. Retrograde degeneration of nigral neurons led to gliosis in the cell body area. At the site of injection, astrocytes were destroyed and NF-immunoreactivity increased. New astrocytes invaded the injection area during the first month after injection. MPTP given systemically to mice in a dose that causes marked dopaminergic denervation of striatum also caused marked increases of GFA-immunoreactivity in striatum. These changes were larger in C57 BL/6 mice, known to be more sensitive to MPTP, than in N.M.R.I. mice, which are less sensitive to MPTP. The glial responses to MPTP-induced dopaminergic denervation did not occur when the dopamine neurotoxic effects were prevented by pretreatment with nomifensine or pargyline. It is concluded that dopaminergic denervation by neurotoxins causes rapid and profound changes in striatal astrocytes characterized by increased GFA-immunoreactivity. These changes remained up to a month after denervation and should be taken into account when functional consequences of dopaminergic denervations are discussed.
1-Methyl-4-phenyl-1,2,3,6-tetrahydropyridine↗
Thy-1-like immunoreactivity in human brain during development.
Thy-1-like immunoreactivity was found in several areas of the immature and adult human brain, using indirect immunofluorescence techniques. In the fetal brain (31 gestational weeks) most immunoreactivity was located in the white matter with an overall granular diffuse distribution and stray fluorescent fibrous structures radiating into grey matter. At 2 months postnatally, the large axon bundles of the internal capsule traversing the caudate nucleus were strongly positive, whereas surrounding neuropil seemed to be negative. In the adult caudate nucleus no such fluorescent fibre bundles could be observed. At 8 months of age, both cerebellum and frontal cerebral cortex contained large numbers of fibrous structures in the grey matter in addition to white matter fluorescence. The molecular layer of both areas was negative. The 8-month-old cerebellum had a Thy-1 distribution similar to the adult, while in the frontal cortex cerebri the density of fluorescent structures increased gradually until adulthood. However, in the 5-year-old frontal cortex the immature granular appearance of 2-month-old cortex could still be seen, but with a greater number of radiating fluorescent bundles. In the adult brain, cerebellum contained a dense pattern of thick, fibrous fluorescent structures in white matter and the internal granular layer and in the frontal cortex thick bundles radiated into grey matter to form a plexus of coarse individual fibres in layers II and III. The hippocampal formation of the 31-week-old fetus contained a network of thin varicose fibres, ascending from the white matter. Stratum radiatum at this stage contained numerous small spots of Thy-1-like immunoreactivity, but no visible fluorescent fibres.(ABSTRACT TRUNCATED AT 250 WORDS)
Adult↗
Increased lead concentration in brain and potentiation of lead-induced neuronal depression in rats after combined treatment with lead and disulfiram.
The effects of disulfiram (tetraethylthiuram disulfide) on blood and brain lead levels and on lead-induced changes in growth and cerebellar Purkinje neuron excitability were assessed in adult Sprague-Dawley rats. Disulfiram is metabolized to diethyldithiocarbamate, which forms a lipophilic complex with lead, and can thereby influence the tissue distribution of lead. Pregnant rats were exposed to 0.25% lead acetate or an equimolar amount of sodium acetate in the drinking water, and these treatments were continued for 4 weeks after birth. Half of the mothers from each group were given 0.1 mmole/kg disulfiram orally twice a week until parturition, after which the treatment was continued for 4 weeks in the respective pups in the form of subcutaneous injections. Although lead exposure markedly increased blood lead levels, the increase in brain lead levels was much more modest. Disulfiram markedly increased brain lead levels while blood lead levels in this group were only slightly elevated as compared to animals receiving lead alone. In addition, the lead + disulfiram group had depressed weight gain during maturation, and Purkinje neuron firing rates were reduced. The lead alone and disulfiram alone groups were not different from controls in these respects. These data suggest that disulfiram potentiates the adverse effects of lead on growth rates and on cerebellar Purkinje neuron function by facilitating the accumulation of lead in brain tissue.
Animals↗
Coexistence of neuronal messengers--an overview.
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Animals↗
Development and regional expression of beta nerve growth factor messenger RNA and protein in the rat central nervous system.
The presence of nerve growth factor (NGF) mRNA and protein in the rat central nervous system is documented. Blot-hybridization analysis showed an abundance of NGF mRNA in the hippocampus, cerebral cortex, and olfactory bulb. Enzyme immunoassay confirmed significant levels of a NGF-like protein in the hippocampus and cerebral cortex. Bioassay of a NGF-like immunoaffinity-purified protein from these regions was physiologically indistinguishable from NGF. Immunohistochemistry revealed a widespread distribution of NGF-like reactivity in the adult brain, preferentially in fiber tracts. NGF mRNA accumulation began at birth, with adult levels reached 3 weeks postnatally. Enzyme immunoassay detected the presence of a NGF-like protein in the embryonic rat brain. Postnatally, the level of NGF-like protein reached a maximum at 3 weeks. Additionally, a distinct fetal form of NGF may exist.
Animals↗
epsilon-N-trimethyllysine availability regulates the rate of carnitine biosynthesis in the growing rat.
Rates of carnitine biosynthesis in mammals depend on the availability of substrates and the activity of enzymes subserving the pathway. This study was undertaken to test the hypothesis that the availability of epsilon-N-trimethyllysine is rate-limiting for synthesis of carnitine in the growing rat and to evaluate diet as a source of this precursor for carnitine biosynthesis. Rats apparently absorbed greater than 90% of a tracer dose of [methyl-3H]epsilon-N-trimethyllysine, and approximately 30% of that was incorporated into tissues as [3H]carnitine. Rats given oral supplements of epsilon-N-trimethyllysine (0.5-20 mg/d), but no dietary carnitine, excreted more carnitine than control animals receiving no dietary epsilon-N-trimethyllysine or carnitine. Rates of carnitine excretion increased in a dose-dependent manner. Tissue and serum levels of carnitine also increased with dietary epsilon-N-trimethyllysine supplementation. There was no evidence that the capacity for carnitine biosynthesis was saturated even at the highest level of oral epsilon-N-trimethyllysine supplementation. Common dietary proteins (casein, soy protein and wheat gluten) were found to be poor sources of epsilon-N-trimethyllysine for carnitine biosynthesis. The results of this study indicate that the availability of epsilon-N-trimethyllysine limits the rate of carnitine biosynthesis in the growing rat.
Administration, Oral↗
Enkephalin and capsaicin-resistant substance P-like immunoreactivities in intra-ocular grafts of different fetal spinal cord areas.
Fetal spinal cord tissue was grafted to the anterior chamber of the eye of adult rats in order to evaluate survival and distribution of substance P- and enkephalin-immunoreactive neurons. Capsaicin treatment was used to evaluate any possible contribution of host iris-derived substance P fibres to the innervation of the grafts and to check for capsaicin sensitivity of graft substance P-positive systems. Substance P- and enkephalin-immunoreactive nerve fibres were present in grafts of half-transverse segments of the spinal cord and were clearly co-distributed throughout the grafts. Areas with a high density of substance P- and enkephalin-positive fibres resembling substantia gelatinosa were seen. Grafts of the dorsal horn alone had a moderate to high density of substance P- and enkephalin-positive fibres, while ventral horn grafts contained a low amount of such fibres. Capsaicin eliminated the substance P innervation of the host iris and the dorsal root ganglion-derived substance P innervation of the host spinal cord, while sparing the intrinsic substance P innervation of both host spinal cord and spinal cord grafts. These experiments show that intra-ocular grafts of defined spinal cord areas express relatively organotypic amounts of substance P- and enkephalin-positive nerve fibres, and thus emphasize the importance of intrinsic genetic determinants for spinal cord development.
Animals↗
Natural history of intrahepatic canine islet cell autografts.
We have serially followed the function of intrahepatic canine islet autografts in 15 beagle dogs for up to 24 mo. Of these, only 20% sustained normal levels of fasting blood glucose for greater than 15 mo posttransplant. Failure of autograft function was accompanied by a preferential loss of well-granulated beta cells in the engrafted islets. The chronic stimulation of an initially marginal intrahepatic beta-cell mass ultimately resulted in metabolic deterioration and loss of beta cells below the minimal threshold required to maintain normal fasting blood glucose levels. It is possible that transplantation of a larger mass of islets would result in indefinite graft function in dogs. However, it remains to be demonstrated in larger mammals, including humans, whether an islet cell mass that is initially adequate in a heterotropic site such as the liver can remain functionally competent over a prolonged period.
Animals↗
On the localization of Thy-1-like immunoreactivity in the rodent and human nervous system.
The neuronal localisation of the surface glycoprotein Thy-1 was studied using the adult mouse iris whole-mount preparation. Polyclonal antibodies to Thy-1 and indirect immunohistochemical techniques were used on fixed tissues. In the adult intact mouse iris a plexus of delicate bundles and fibres was found in both the dilator and sphincter regions. Ovoid negative spots along the bundles were numerous, probably indicating the location of supportive cells. The ciliary body contained strongly immunoreactive bundles oriented in radial and circular patterns. Numerous Thy-1-positive mast cells were found in the irides. All Thy-1-immunoreactive fibres disappeared in intraocular iris transplants after 4 days, leaving only the Thy-1-positive mast cells. A Thy-1-positive fibre plexus reappeared in intraocular iris transplants after 4 weeks, strongly indicating that Thy-1-immunoreactive fibres in adult mouse irides are associated with the nerve fibres and not with their supportive tissue. Distribution of Thy-1-like immunoreactivity in the developing human nervous system is presented for the first time, and its temporal changes are followed from the eighth gestational week to adulthood. At eight weeks the spinal cord and lower brain stem seemed to show virtually no immunoreactivity. At 10 and 31 weeks gestational age immunoreactivity was found preferentially in white matter areas with a granular appearance, becoming more densely aggregated at the later stage. Two months postnatally the internal capsule was strongly positive in an otherwise negative neuropil, only to disappear completely in the adult brain.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Relationship of mitogen reactivity to type D retrovirus infection in Celebes black macaques (Macaca nigra).
The Celebes black macaque (Macaca nigra) colony at the Oregon Regional Primate Research Center has a high incidence of an immunodeficiency syndrome characterized by recurrent diarrhea and the development of retroperitoneal fibromatosis (RF). We have examined the relationship of type D viral infection to the immunodeficiency syndrome by surveying the colony for viral infection and for mitogen reactivity. Type D virus-positive monkeys (28% of the colony) have a higher prevalence of diarrhea, splenomegaly, lymphadenopathy and weight loss than do virus-negative monkeys, and RF has been found to occur only in virus-positive animals. Comparison of the concanavalin A (con-A) and phytohemagglutinin reactivities of the virus-positive and -negative populations has revealed no significant difference. However, within the virus-positive population, those with RF have reduced con-A reactivity and there are both high and low mitogen responders in the groups lacking RF. Thirty-two percent of the virus-positive monkeys are free of clinical symptoms, 40% have clinical symptoms but no RF, and 27% have clinical symptoms and RF. Five of the six monkeys with RF are older than the RF-free monkeys but monkeys are susceptible to type D retrovirus infection regardless of age or sex. The progressive nature of this immunodeficiency syndrome, its broad age range, and the probability that the etiological agent is also a type D retrovirus and the similarity of RF to Kaposi's sarcoma make this a potentially useful model for human AIDS.
Acquired Immunodeficiency Syndrome↗
Cyclosporine therapy and other adjuncts in the perioperative period with cadaveric and living related donor kidney transplantation.
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Cadaver↗