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
A Seiger
Publications and source records attributed to A Seiger.
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↗
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↗
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↗
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↗
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↗
Nerve fiber production by intraocular adrenal medullary grafts: stimulation by nerve growth factor or sympathetic denervation of the host iris.
This study evaluates the production of adrenergic nerve fibers by adrenal medullary tissue of the adult rat grafted to the anterior chamber of the eye of adult recipients. The chromaffin grafts attach to and become vascularized by the host iris. They decrease in size intraocularly during the first 3 weeks. This decrease is somewhat counteracted by sympathetic denervation of the host iris, and better counteracted by sympathetic denervation and addition of nerve growth factor (NGF, given at grafting and 1 and 2 weeks after grafting). Outgrowth of adrenergic nerve fibers from the grafts into the host iris was studied in wholemount preparations by use of the Falck-Hillarp technique 3 weeks after grafting. The innervated area of the host iris was approximately doubled in the chronically sympathectomized group and doubled again in the chronically sympathectomized NGF-supplemented group. Chronic sympathetic denervation had no effect on density of outgrowing nerves, whereas addition of NGF more than doubled nerve density. Since sympathetic denervation causes a slight elevation of NGF activity in the iris, the present experiments are taken as evidence that the level of NGF in the iris regulates formation of nerve fibers by adrenal medullary tissue grafts from adult rats.
Adrenal Medulla↗
On the origin and distribution of vasoactive intestinal polypeptide-, peptide HI-, and cholecystokinin-like-immunoreactive nerve fibers in the rat iris.
The presence and distribution of nerve fibers expressing immunoreactivity to the neuropeptides vasoactive intestinal polypeptide, peptide HI and cholecystokinin was examined in stretch-prepared rat iris whole mounts. By use of antiserum to vasoactive intestinal polypeptide an irregular, relatively sparse network of varicose, intensely fluorescent fibers was observed innervating both the dilator plate and the sphincter area. Positive fibers were present also in the ciliary body and the choroid membrane. Surprisingly, a large variation in the amount of vasoactive intestinal polypeptide-positive nerves was seen among irides. Furthermore, an uneven distribution of fluorescent nerve fibers was observed within individual irides. Thus, some areas had a relatively dense innervation, whereas others were devoid of immunoreactive nerve fibers. A similar fiber system was detected using antiserum to peptide HI. In all probability, vasoactive intestinal polypeptide and peptide HI coexist within the same nerve population. A denser and more regular network of cholecystokinin-positive fibers was found in normal rat irides. Such fibers were also present in the sphincter area and in high density in the choroid membrane. Neither extirpation of the superior cervical nor the ciliary ganglion caused any detectable decrease in amount of either vasoactive intestinal polypeptide/peptide HI- or cholecystokinin-positive fibers. However, capsaicin, which in the iris causes permanent disappearance of substance-P fibers, had a similar effect on cholecystokinin-positive fibers, whereas no effect was noted on the vasoactive intestinal polypeptide/peptide HI fiber network.(ABSTRACT TRUNCATED AT 250 WORDS)
Animals↗
Combined grafts of the ventral tegmental area and nucleus accumbens in oculo. Histochemical and electrophysiological characterization.
Dissection techniques and optimal donor stages have been established for constructing an isolated intraocular model of the ventral tegmental area (VTA)-accumbens system using intraocular sequential grafting. Single grafts including accumbens and VTA respectively survived and developed many organotypic features when taken from 15-17 day fetuses. Falck-Hillarp fluorescence histochemistry showed dopamine neurons and terminals in single VTA grafts, no or almost no catecholamine fibers in single accumbens grafts, and a well-developed VTA-accumbens dopamine pathway in combined grafts where cell bodies in the VTA part provided the accumbens part with a rich terminal network. A similar distribution was found using immunohistochemistry with antibodies directed against tyrosine hydroxylase. CCK-like immunoreactivity had a distribution that mimicked that of the catecholamine-containing system. Enkephalin-like immunoreactivity was found both in single VTA and in single accumbens pieces as well as in both parts of the double grafts. Cells with long-duration action potentials typical of dopamine neurons discharged at approximately 8 Hz in single VTA grafts and below 1 Hz in the VTA part of VTA-accumbens double grafts. Cells in the accumbens portion of double grafts had shorter action potential durations and fired at 10-20 Hz. Haloperidol increased discharge frequency in VTA neurons with long action potential durations while apomorphine reduced discharge markedly. Antidromic activation of putative dopamine neurons in the VTA part was obtained by electrical stimulation of the accumbens part. The indirect dopamine agonist + 3-methyl-phencyclidine slowed firing rates of neurons in the accumbens part of double grafts. Taken together, the histochemical and the electrophysiological data show that the intraocular VTA-accumbens system retains several of its normal structural and functional characteristics. It is proposed that the isolated VTA-accumbens projection can be used as a model to study the cellular mechanism of action of stimulant and opiate drugs of abuse.
Animals↗
Distribution of Thy-1-like immunoreactivity in normal, sympathetically denervated and grafted mouse irides.
The distribution of Thy-1-like immunoreactivity was studied in whole-mounts of adult mouse iris and intraocular iris grafts 4 days and 4 weeks postoperatively. After fixation in picric acid/paraformaldehyde, the irides were incubated with a polyclonal rabbit anti-mouse brain Thy-1 antibody. In the adult mouse iris, a dense network of thin bundles and individual fibres was seen on the dilator plate and in the sphincter. Fluorescence paucities, resembling Schwann cell nuclei, were frequently seen along the bundles. Numerous mast cells, stained specifically with the Thy-1 antibody, were scattered over the entire surface of the iris. The ciliary body contained several brightly fluorescent bundles, and some circularly running individual fibres. In 4-day iris grafts, the Thy-1-like immunoreactivity had disappeared, except in mast cells. After 4 weeks in oculo, a regular plexus of thin fibres had reappeared in the iris grafts. Sympathetic denervation of adult irides did not seem to affect the Thy-1 immunoreactivity in terms of either fluorescence intensity or fibre distribution. The present data suggest a distribution of the glycoprotein Thy-1 along nerve fibres in the iris.
Animals↗
Parasympathetic neurotrophic activity in the rat iris: determination after different denervations.
The iris of the adult rat contains one or several neurotrophic factors that enhance the survival of dissociated parasympathetic neurons (from the embryonic chick ciliary ganglion) in culture. To assay survival activity, iris homogenates were serially diluted with culture medium and the percentage of neurons surviving for 2 days in a collagen matrix in culture determined. The extract induced survival curves that were similar for denervated and normal irides. Similarly no differences in fibre outgrowth from cultured whole ciliary ganglia were found. The results suggest that the apparent level of parasympathetic growth factor(s) is not under strict control of the innervation of the iris.
Animals↗
Immature and mature neurofilament-immunoreactive trigeminal fibers can innervate the iris as studied by intraocular grafting of iris and trigeminal ganglia.
Using immunohistochemistry on stretch-prepared whole mounts of adult rat irides, a dense, well-organized plexus of neurofilament-positive nerves originating in the trigeminal ganglion can be visualized. Such a two-dimensional tissue preparation is well-suited for studies on sensory and autonomic nerve fiber growth. In the present study the growth capacity of such neurofilament-positive nerves has been studied immunohistochemically. In irides homologously transplanted to the anterior eye chamber of adult albino rats, the intrinsic neurofilament-positive network had almost completely disappeared 4 days postoperatively. In whole mounts of iris grafts after 15 days and 4 weeks in oculo a gradually increasing plexus of nerves was observed. After 3.5 months in oculo a dense, regular network of fluorescent fibers had formed in the iris grafts to the same magnitude as in situ. However, whereas large axon bundles constituted a prominent feature of the distribution of neurofilament-positive nerves in situ, only a few and relatively thin axon bundles were seen in the grafts. The growth capacity of the neurofilament-positive trigeminal nerves was also studied by grafting fetal trigeminal ganglia to the anterior eye chamber. As visualized in cryostat sections, trigeminal grafts contained a large number of strongly fluorescent perikarya and a high density of positive fibers after intraocular maturation. Such grafts readily innervated the host iris. In the area immediately adjacent to the grafts, thin, parallel, rather weakly fluorescent fibers radiated out from the ganglia. When mature trigeminal grafts with attached host iris were regrafted to the anterior eye chamber of adult animals for a few days, in order to remove the intrinsic host iris innervation, such irides showed outgrowing fibers, often organized in small axon bundles, at long distances from the ganglion graft. The present report shows that both mature and immature neurofilament-immunoreactive neurons are capable of innervating the iris. Furthermore, this ingrowth can occur both in the presence and absence of normal intrinsic neurofilament-positive nerve fibers.
Animals↗
Substance P-containing sensory nerves in the rat iris. Normal distribution, ontogeny and innervation of intraocular iris grafts.
Trigeminal, substance P-containing nerves have been studied in the stretch-prepared rat iris with immunohistochemical techniques. The normal iris exhibited a slightly irregular plexus of individual fibres in the dilator, intermingled with thin, meandering axon bundles. The sphincter contained more circumferentially oriented fibres. Occasional free nerve endings were present in all parts of the iris; no obvious association with blood vessels was detected. All substance P-positive nerves in the iris disappeared after lesioning the trigeminal nerve. Irides of neonates showed scattered, smooth fibres in a sparse plexus, without visible axon bundles. Over the first two postnatal weeks, the density of innervation developed rapidly, reaching a transiently supranormal level and fluorescence intensity, compared to adulthood. From 3 weeks on, the pattern and density of substance P-containing fibres approached the normal adult appearance. In irides grafted to the anterior eye chamber, the intrinsic substance P nerves degenerated, disappearing completely after 5 days. Reinnervation from the host irides transpired over the next few weeks, approximating normal density after 3 weeks, and organotypic density and distribution from 4 weeks on. No obvious hyperinnervation was encountered after longer postoperative times (3 months). In the host iris, many substance P fibres disappear or exhibit low fluorescence intensity during the first postoperative week, recovering fully during the next 2 weeks. Over longer postoperative periods irregular, moderate hyperinnervation developed with increased numbers of axons in bundles. In conclusion, we show normal distribution and plasticity during ontogeny and maturity of substance P-containing iris nerves in the rat, with a sensitive immunohistochemical technique in iris whole mounts.
Animals↗
Transplantation of monoamine-producing cell systems in oculo and intracranially: experiments in search of a treatment for Parkinson's Disease.
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Adrenal Medulla↗
Transplantation of adrenal medullary tissue to striatum in parkinsonism. First clinical trials.
Autologous adrenal medullary tissue was transplanted to the striatum in two patients with severe parkinsonism. The aim was to provide the striatum with a new cellular source of catecholamines. Some rewarding effects were registered. This is the first time that such tissue has been transplanted in the human brain. The results merit further clinical trials.
Adrenal Medulla↗
Parasympathetic neurons of salivary gland ganglia in the fetal and postnatal rat are substance P-like immunoreactive.
Substance P-like immunoreactivity (SPLI) of neuron cell bodies is described here in the parasympathetic ganglia of salivary glands in rat fetuses. When grafted to the anterior eye chamber of adult rats, outgrowth of SPLI fibers was also observed around fetal and postnatal ganglia. These observations are significant for the understanding of salivation mechanisms. They also imply the importance of substance P or related compounds in parasympathetic peripheral neurons. The graft experiments indicate a substantial morphological plasticity of these SPLI neurons on perturbation.
Animals↗
Adrenergic transmission in hippocampus-locus coeruleus double grafts in oculo: demonstration by in vivo electrochemical detection.
In vivo electrochemical detection was used to study transmitter release from a synaptically or pharmacologically stimulated noradrenergic isolated pathway formed by double in oculo brain tissue grafts. Retinal illumination, which activates cholinergic nerve fibers that grow into intraocular grafts from the autonomic ground plexus of the iris, produced increases in the concentration of electroactive species in the hippocampal portion of intraocular locus coeruleus-hippocampus double grafts. This response was potentiated after cholinesterase inhibition, and mimicked by perfusion of carbachol, a muscarinic agonist. Much smaller increases in the electroactive species were measured in reserpinized animals, and this minimal response was completely eliminated by the subsequent inhibition of catecholamine synthesis with alpha-methyl-p-tyrosine. Taken together, the data suggest that synaptically released transmitter in these isolated brain circuits can be measured using in vivo electrochemical detection techniques, and lend further support to the hypothesis that in oculo locus coeruleus grafts develop a functional catecholaminergic input to sequentially grafted hippocampus.
Animals↗
Regulation of axonal ingrowth into area dentata as studied by sequential, double intraocular brain tissue transplantation.
The anterior eye chamber was used as a model environment to study, in isolation, the interaction of embryonic area dentata transplants with transplants of one of three important sources of in situ innervation: entorhinal cortex, locus coeruleus or septal nuclei. None of these brain regions significantly affected the morphogenesis or in oculo growth of area dentata transplants. All three brain regions innervated the area dentata transplant. Entorhinal cortical transplants sent nerve fibers into a limited, and apparently specific, region of area dentata that was adjacent to the entorhinal transplant. This light innervation contrasts to the predominant innervation of area dentata by entorhinal cortex in situ. The fluorescent, noradrenergic neurons of locus coeruleus provided the area dentata transplant with an abundance of fine varicose nerve fibers. Given about 100 noradrenergic neurons in the locus coeruleus transplant and 4 to 6 months joint survival, the area dentata transplant was noradrenergically hyperinnervated. The cholinergic neurons of the septal nuclei transplant had a prolific ingrowth of acetylcholinesterase (AChE)-positive nerve fibers to the area dentata transplant. There appeared to be a mutual exclusion between the extrinsic AChE-positive fibers and the intrinsic Timm's-positive granule cell mossy fibers in the area dentata transplant. We conclude that isolated replicas of the coeruleo-, septo-, and entorhinal cortico-dentate pathways can be made through sequential intraocular double grafting. The nature of the in oculo connectivity between these replicates offers clues as to the mechanisms that might account for the regulation of nerve growth.
Animals↗