Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts:   Target Concepts:
Query: EC:3.1.3.16 (calcineurin)
 17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

A topographical and cellular immunohistochemical analysis was performed on the striatonigral system of rats with unilateral, reversible middle cerebral artery (MCA) occlusion. Antibodies to calcineurin (CaN), parvalbumin (PV), choline acetyltransferase (ChAT) and glial fibrillary acidic protein (GFAP) were used in this study. Sixty days after the operation, the ipsilateral striatum showed a characteristic cell type-specific injury in the dorsolateral part of the nucleus (i.e., non-limbic striatum): a marked reduction in the number of medium-sized spinous neurons expressing CaN immunoreactivity and a selective sparing of PV- and ChAT-positive interneurons. There was also a marked depletion of striatonigral afferents visualized by CaN immunostaining in the lateral portion of the substantia nigra pars reticulata, which is considered to be implicated with motor function. In addition, it was noted that such striatonigral involvement was accompanied by marked gliosis showing strong GFAP immunolabeling. The present data suggest that rats with reversible MCA occlusion can be a useful animal model for studying cell type-specific ischemic injury and subdivisional involvement of the striatonigral pathway as a part of the cortico-subcortical loop subserving motor function.
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PMID:Striatonigral involvement following transient focal cerebral ischemia in the rats: an immunohistochemical study on a reversible ischemia model. 838 49

The cellular mechanisms underlying the neuroprotective action of the immunosuppressant FK506 in experimental stroke remain uncertain, although in vitro studies have implicated an antiexcitotoxic action involving nitric oxide and calcineurin. The present in vivo study demonstrates that intraperitoneal pretreatment with 1 and 10 mg/kg FK506, doses that reduced the volume of ischemic cortical damage by 56-58%, did not decrease excitotoxic damage induced by quinolinate, NMDA, and AMPA. Similarly, intravenous FK506 did not reduce the volume of striatal quinolinate lesions at a dose (1 mg/kg) that decreased ischemic cortical damage by 63%. The temporal window for FK506 neuroprotection was defined in studies demonstrating efficacy using intravenous administration at 120 min, but not 180 min, after middle cerebral artery occlusion. The noncompetitive NMDA receptor antagonist MK801 reduced both ischemic and excitotoxic damage. Histopathological data concerning striatal quinolinate lesions were replicated in neurochemical experiments. MK801, but not FK506, attenuated the loss of glutamate decarboxylase and choline acetyltransferase activity induced by intrastriatal injection of quinolinate. The contrasting efficacy of FK506 in ischemic and excitotoxic lesion models cannot be explained by drug pharmacokinetics, because brain FK506 content rose rapidly using both treatment protocols and was sustained at a neuroprotective level for 3 d. Although these data indicate that an antiexcitotoxic mechanism is unlikely to mediate the neuroprotective action of FK506 in focal cerebral ischemia, the finding that intravenous cyclosporin A (20 mg/kg) reduced ischemic cortical damage is consistent with the proposed role of calcineurin.
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PMID:Neuroprotective actions of FK506 in experimental stroke: in vivo evidence against an antiexcitotoxic mechanism. 927 29

We aimed to clarify the topology and immunohistochemistry of CO2/H+-sensitive neurons in the ventral medullary surface (VMS), the central chemoreceptor area in rats. Inhalation of 3 and 7% CO2 in air significantly decreased pH in arterial blood and increased paCO2, which caused hyperpneic and tachypneic responses. Following inhalation of 3 and 7% CO2 in air for 5 min, the density of c-Fos-immunoreactive (IR) neurons increased stepwise not only in the 3rd-5th divisions of the VMS (between the caudal end of the nucleus corporis trapezoidei and the caudal end of the area postrema), but also in the rostroventromedial medulla (RVMM). Following inhalation of 7% CO2 in air for 5 min, glutamate-, glutamic acid decarboxylase (GAD)-, calcineurin- and cAMP-IR neurons were found not only in the VMS, but also in the RVMM. The topology of these neurons was similar to that of the c-Fos-IR neurons. No immunoreactivity was found for serotonin, substance P, somatostatin, cholecystokinin-octapeptide, methionine-enkephalin, choline acetyltransferase, tyrosine hydroxylase, phenylethanolamine N-methyltransferase, NO-synthase, S-100, calbindin-D, calmodulin, or parvalbumin. The densities of c-Fos-, glutamate-, GAD-, calcineurin- and cAMP-IR neurons were almost zero in the 1st division of the VMS, but became higher along the 2nd-4th divisions of the VMS. Regression lines of the density against the 1st-4th divisions of the VMS were significantly linear. These results indicate that H+-sensitive neurons are common in the 4th-5th divisions of the VMS, and that they are glutamatergic, GABAergic, and containing calcineurin and cAMP.
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PMID:Topology and immunohistochemistry of proton-sensitive neurons in the ventral medullary surface of rats. 947 76

Cyclosporine-A (CsA) is the primary anti-rejection drug used for organ and neural transplantation therapy. In addition to its immunosuppressive action, CsA has been recently shown to exert neuroprotective and neurotrophic effects in the central nervous system when able to cross the blood-brain barrier. Postulated mechanisms for these CsA-induced beneficial effects include the drug's powerful inhibition of the calcium-dependent phosphatase calcineurin (CN) and blockade of the assembly of the mitochondrial permeability transition pore. We report here, for the first time, that adult Wistar rats treated with CsA (10 mg/kg per day, i.p. for 9 days) displayed significantly reduced septal CN expression in combination with enhanced levels of septal choline acetyltransferase (ChAT) immunoreactivity as compared to controls. The observed enhancement of septal ChAT immunoreactivity suggests potential therapeutic utility of CsA for brain disorders characterized by alterations of the cholinergic system.
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PMID:Cyclosporine-A enhances choline acetyltransferase immunoreactivity in the septal region of adult rats. 1067 24

We have characterized a region of the mouse vesicular acetylcholine transporter(VAChT)/choline acetyltransferase (ChAT) gene locus that serves as a cholinergic-specific promoter for the expression of both VAChT and ChAT genes, as well as a reporter gene (LacZ) in vivo. We have used this promoter to direct the expression of an inhibitor peptide, derived from the calcineurin (CalN) autoregulatory domain, to directly neutralize the function of CalN to define the role of this Ca2+/Calmodulin regulated phosphatase in neurite outgrowth. Targeted inhibition of CalN promotes neurite outgrowth in PC12 cells in the presence of NGF, as early as 24 h after transfection. Inhibition of CalN-mediated enhancement of neurite outgrowth in PC12 cells reaches a maximum effect within the first 4 to 6 days after transfection, and does not cause adverse effects when highly expressed for up to 12 days. Cyclosporin A, a nontargeted CalN inhibitor, increases the number of neurites in mock transfected cells by 1.5 fold, while in transfected PC12 cells, the expression of the CalN inhibitor peptide increases the neurite number by 1.8 fold. These data demonstrate that CalN is an important regulator of the neurotrophic response in cholinergic cells and may prove valuable in developing treatment strategies to promote recovery from neurological injury.
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PMID:Targeted neutralization of calcineurin, by expression of an inhibitor peptide under the control of a cholinergic specific promoter in PC12 cells, promotes neurite outgrowth in the presence of NGF. 1088 41

Abnormal hyperphosphorylation of tau and cholinergic deficit occur in the early stage of Alzheimer's disease (AD) and relate to the dementia symptom. Hyperphosphorylation of tau, neurofilament (NF) and other proteins in AD brain appears to be caused by a down-regulation of protein phosphatase 2A (PP2A), but the mechanism leading to cholinergic deficit is still unknown. In this study, we selectively inhibited PP2A by injection of okadaic acid (OA) into the Meynert nucleus basalis of rats. We found that injection of OA induced hyperphosphorylation of tau and NF and decreased acetylcholine (ACh) level in the nucleus basalis of Meynert. These alterations were accompanied by spatial memory deficit in OA-injected rats. We also demonstrated that the OA-induced ACh reduction may be due to a failure of intraneuronal transport of choline acetyltransferase (ChAT) from cell body to the neuronal terminals rather than an alteration of activity of ChAT or acetylcholinesterase. This study suggests that a down-regulation of PP2A may underlie both abnormal hyperphosphorylation of cytoskeletal proteins leading to neurofibrillary degeneration and cholinergic deficiency in AD.
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PMID:Injection of okadaic acid into the meynert nucleus basalis of rat brain induces decreased acetylcholine level and spatial memory deficit. 1520 45

Alzheimer's disease (AD), the most prevalent form of dementia, is characterized by several major morphological hallmarks such as senile plaques, neurofibrillary tangles and a loss of cholinergic basal forebrain neurons. Apart from cholinergic markers like choline acetyltransferase and acetylcholinesterase, there have been reports on changes in muscarinic acetylcholine receptors (mAChR) as well as on influences of zinc metabolism in the disease. As recent studies gave hints about a possible link between mAChRs and zinc uptake, the human neuroblastoma cell line SK-SH-SY5Y was used to evaluate the role of M1-mAChR on zinc uptake. Zinc levels were semi-quantitatively detected by using the zinc-specific fluorophor Zn-AF2-DA. In the presence of 1 microM extracellular zinc, M1-mAChR stimulation with talsaclidine increased intracellular zinc levels as did stimulation of PKC by phorbol esters. Furthermore, the effect of extracellular zinc on the expression of the zinc finger protein PNUTS (protein phosphatase 1 nuclear targeting subunit 10) was investigated and revealed an upregulation of PNUTS expression in the presence of 1 microM extracellular zinc by 294% when compared to incubation in zinc free medium. In summary, this report demonstrates that intracellular zinc uptake in SK-SH-SY5Y cells is controlled by M1-mAChR mediated signalling pathways and that zinc may act as a cofactor for transcriptional regulation of zinc finger genes such as PNUTS.
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PMID:Zinc uptake is mediated by M1 muscarinic acetylcholine receptors in differentiated SK-SH-SY5Y cells. 1640 70

Using antibodies to calcineurin (CaN) and choline acetyltransferase (ChAT), we performed topographical and cellular immunohistochemical analysis on the posterior putamen of autopsied patients with multiple system atrophy with predominant parkinsonism (MSA-P). We document that in these patients, medium spiny neurons positive for CaN were severely depleted in the dorsolateral portion of the posterior putamen where ChAT-positive neurons are normally distributed. Our findings indicate that in patients with MSA-P, striatal neurons manifest a cell type-specific vulnerability to neurodegeneration.
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PMID:Cell type-specific neuronal loss in the putamen of patients with multiple system atrophy. 1726 45