Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.1.7 (acetylcholinesterase)
 28,390 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

Cocaine, a catecholamine agonist, has been shown to produce a transient induction of the immediate-early gene c-fos and its protein product Fos in the striatum of normal rats. In the present study we report that the expression of Fos can be induced by cocaine challenge in intrastriatal grafts derived from cell suspensions of embryonic striatal primordia. Fos-like immunoreactivity in the nuclei of grafted neurons was detected 2 hr after the injection of 50 mg/kg cocaine into the host rats. Neurons with Fos-immunoreactive nuclei tended to form clusters in the striatal grafts. The Fos-rich clusters were aligned with acetylcholinesterase (AChE)-rich and tyrosine hydroxylase (TH)-rich patches demonstrated in adjoining sections. Previous studies have shown that presynaptic and postsynaptic cellular markers of the dopaminergic system in the striatum, including immunostaining for TH and dopamine- and adenosine 3':5'-monophosphate-regulated phosphoprotein (DARPP-32), and binding for high affinity dopamine uptake sites and for dopamine D1 and D2 receptor sites, are all concentrated in the AChE-rich patch regions (P regions) of such embryonic striatal grafts. The preferential expression of Fos in neurons of the P regions of the grafts thus implies that the induction of Fos was cell-type specific in being concentrated in the parts of the grafts that express striatal phenotype and that are innervated by catecholamine-containing fibers.(ABSTRACT TRUNCATED AT 250 WORDS)
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PMID:Intrastriatal grafts derived from fetal striatal primordia. III. Induction of modular patterns of fos-like immunoreactivity by cocaine. 168 Jul 35

We used immunohistochemical staining with antibodies against the novel protein striatal enriched phosphatase (STEP) to investigate the internal organization of grafts of embryonic striatal tissues implanted in the ibotenic acid-lesioned neostriatum of adult rats. STEP immunoreactivity was found in discrete patches within the grafts, which colocalized with areas designated as 'patch' zones when stained for the enzyme acetylcholinesterase and with antibodies against tyrosine hydroxylase and DARPP-32. As previously hypothesized, the pattern of STEP immuno-reactivity in embryonic striatal tissue grafts provides further indication that the patch zones are indeed comprised of striatal like cell populations. The novel protein STEP provides a sensitive and precise marker for this compartment within the grafts.
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PMID:The localization of an antibody to STEP in embryonic striatal tissue grafts. 769 21

Tissue storage prior to intracerebral transplantation would represent a major advantage when conducting clinical transplantation trials in that the procurement of the embryonic donor tissue and the timing of neurosurgery could be planned more efficiently. In the present study, the effects of storing rat embryonic striatal tissue at either +4 degrees C or below freezing temperature prior to grafting to the adult striatum, were assessed with regard to transplant survival, morphology and integration. Eleven days following a unilateral injection of ibotenic acid into the head of the caudate-putamen, a control group of rats received grafts of striatal primordium prepared immediately after dissection from rat embryos (embryonic day 16). A second group of rat embryonic striatal tissue was stored at 4 degrees C (hibernation) for 5 days and then transplanted. A third group of the striatal donor tissue was cryopreserved in liquid nitrogen for 5 days before implantation surgery. Six to seven weeks following transplantation surgery, the grafts were analysed in brain sections processed for acetylcholinesterase histochemistry, DARPP-32 (dopamine and cyclic AMP regulated phosphoprotein with a molecular weight of 32 kDa) and tyrosine hydroxylase (TH) immunocytochemistry. The mean total graft volume and the relative size of the AChE-positive regions were not significantly different between the three groups. Striatal-specific graft regions, positively stained for AChE and DARPP-32, generally exhibited TH immunoreactivity, suggesting that they had received dopaminergic afferents from the host brain. We conclude that embryonic rat striatal tissue can be cryopreserved or hibernated over 5 days without significant impairment in the yield of striatal neurons following intrastriatal implantation and without markedly affecting transplant morphology.
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PMID:Effects of hibernation or cryopreservation on the survival and integration of striatal grafts placed in the ibotenate-lesioned rat caudate-putamen. 871 78

The effects of the stage of donor embryos on the survival of grafts from different neuronal cell types have been well documented. Indeed, this parameter has been shown to be highly important in the survival and function of transplants of various tissues of the CNS. However this question has not been addressed in grafts of embryonic striatal tissue transplanted into animal models of Huntington's disease. In this study, rats which had received a unilateral ibotenic acid lesion in the dorsal striatum received grafts from a standard dissection of embryonic striatal primordium taken from donors of embryonic stage either E14, E16, E17 or E19 days. Three months after transplantation six rats from each group were killed for analysis of graft survival and morphology. The remaining animals in each group were killed between 10 and 14 months after grafting. Graft morphology was detected using a range of markers including: acetylcholinesterase and Cresyl Violet, the 32,000 mol. wt dopamine- and cyclic AMP-regulated phosphoprotein (DARPP-32), tyrosine hydroxylase and striatally-enriched phosphatase. All the grafts from different donor stages survived well at both time-points and Cresyl Violet staining indicated neuronal cell types spread throughout the grafts. The transplants were seen to have a characteristic "patchy" appearance with areas of dense AChE activity and DARPP-32 immunopositivity interspersed with areas of much lighter expression. These areas also co-localized consistently with striatally-enriched phosphatase and tyrosine hydroxylase expression, indicating that they comprised the striatal-like compartment of the graft (the so called P zones, containing cells of the mature striatum), and receiving specific afferent input from the host dopaminergic system. There was no significant difference in total graft volume, when comparing individual groups at both time-points from grafting. However, when comparing the volume of the P zones, the striatal primordium from the youngest donor stages (E14 and E16) produced grafts with a significantly higher proportion of striatal-like tissue. Therefore, in order to increase the proportion of striatal tissue within these grafts, tissue from younger embryonic donors should be used. This has important implications in the application of this model towards clinical trials in Huntington's disease.
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PMID:The effects of donor stage on the survival and function of embryonic striatal grafts in the adult rat brain. I. Morphological characteristics. 921 34

Intrastriatal grafts of tissue obtained from the striatal or neocortical primordia of rat fetuses have been studied with respect to their intrinsic organization and connectivity using antibodies to DARPP-32 in combination with acetylcholinesterase (AChE) histochemistry, tyrosine hydroxylase (TH) immunocytochemistry, and anterograde and retrograde axonal tracing techniques. The striatal grafts were characterized by distinct patches of DARPP-32-immunoreactive neurons, which were identical to the densely AChE-positive patches stained in adjacent sections from the same specimens. The non-patch areas possessed only few DARPP-32-positive neurons and contained only sparse AChE-positive fibres. The cortical grafts, by contrast, contained no neurons with clear-cut DARPP-32-positivity and they exhibited a sparse, evenly distributed AChE fibre network, similar to that seen in the non-patch areas of the striatal grafts. The host dopaminergic afferents, as revealed by TH immunostaining, had grown selectively into the DARPP-32-positive patches in the striatal grafts, where they formed a dense terminal network around the DARPP-32-positive cell bodies. The non-patch areas, as well as the cortical grafts, received only sparse TH innervation. By contrast, the host cortical afferents, labelled by Phaseolus vulgaris leucoagglutinin from the host frontal cortex, were seen to extend into both the patch and non-patch areas of the striatal grafts. Transplant neurons projecting into the host brain were labelled by Fluoro-Gold injections into the ipsilateral host globus pallidus. These injections labelled large numbers of medium-sized neurons within the striatal grafts and the vast majority of them (over 85%) were confined to the DARPP-32-positive patches. Similar Fluoro-Gold injections labelled only few graft neurons in the cortical grafts. The results indicate that the striatal grafts are composed of a mixture of striatal and non-striatal tissue, and that the striatal graft compartment selectively establishes afferent and efferent connections with the host nigro-pallidal system. These graft connections demonstrate a remarkable specificity in the formation of graft - host connectivity. The results, moreover, suggest that developmental properties of the grafted striatal primordium are retained and expressed in the implanted cell suspension, and that the neuronal systems of the lesioned adult host brain, at least to some extent, remain responsive to growth regulating mechanisms normally operating during ontogenetic development.
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PMID:Intrinsic Organization and Connectivity of Intrastriatal Striatal Transplants in Rats as Revealed by DARPP-32 Immunohistochemistry: Specificity of Connections with the Lesioned Host Brain. 1210 27

Organophosphorus (OP) compounds cause toxic symptoms, including convulsions, coma, and death, as the result of irreversible inhibition of acetylcholinesterase (AChE). The development of effective treatments to block these effects and attenuate long-term cognitive and motor disabilities that result from OP intoxication is hampered by a limited understanding of the CNS pathways responsible for these actions. We employed a candidate method (called CNSProfile) to identify changes in the phosphorylation state of key neuronal phosphoproteins evoked by the OP compound, diisopropyl fluorophosphate (DFP). Focused microwave fixation was used to preserve the phosphorylation state of phosphoproteins in brains of DFP-treated mice; hippocampus and striatum were analyzed by immunoblotting with a panel of phospho-specific antibodies. DFP exposure elicited comparable effects on phosphorylation of brain phosphoproteins in both C57BL/6 and FVB mice. DFP treatment significantly altered phosphorylation at regulatory residues on glutamate receptors, including Serine897 (S897) of the NR1 NMDA receptor. NR1 phosphorylation was bi-directionally regulated after DFP in striatum versus hippocampus. NR1 phosphorylation was reduced in striatum, but elevated in hippocampus, compared with controls. DARPP-32 phosphorylation in striatum was selectively increased at the Cdk5 kinase substrate, Threonine75 (T75). Phencynonate hydrochloride, a muscarinic cholinergic antagonist, prevented seizure-like behaviors and the observed changes in phosphorylation induced by DFP. The data reveal region-specific effects of nerve agent exposure on intracellular signaling pathways that correlate with seizure-like behavior and which are reversed by the muscarinic receptor blockade. This approach identifies specific targets for nerve agents, including substrates for Cdk5 kinase, which may be the basis for new anti-convulsant therapies.
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PMID:Nerve agent exposure elicits site-specific changes in protein phosphorylation in mouse brain. 2042 8