Gene/Protein Disease Symptom Drug Enzyme Compound
Pivot Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound   Target Concepts: Gene/Protein Disease Symptom Drug Enzyme Compound

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Query: EC:3.1.3.16 (calcineurin)
17,112 document(s) hit in 31,850,051 MEDLINE articles (0.00 seconds)

L-Deprenyl, an irreversible MAO-B (monoamine oxidase B, EC 1.4.3.4) inhibitor, is used for the treatment of Parkinson's disease and to delay the progression of Alzheimer's disease. L-Deprenyl also exhibits protective effects against neuronal apoptosis which are independent of its ability to inhibit MAO-B. The purpose of this study was to compare the antiapoptotic efficacy of L-deprenyl against different types of apoptotic inducers in three neuronal cell culture models. The level of apoptosis was quantified by measuring the activation of caspase-3 enzyme, which is the main apoptotic executioner in neuronal cells. MTT [3-(4,5-dimethylthiazol-2-yl)-2, 5-diphenyltetrazolium bromide] and LDH (lactate dehydrogenase, EC 1. 1.1.27) assays were used to demonstrate the cytotoxic response of apoptotic treatments. Our results showed that okadaic acid, an inhibitor of protein phosphatase 1 and 2A, induced a prominent increase in caspase-3 activity both in cultured hippocampal and cerebellar granule neurons as well as in Neuro-2a neuroblastoma cells. Interestingly, L-deprenyl offered a significant protection against the apoptotic response induced by okadaic acid in all three neuronal models. The best protection appeared at the concentration level of 10(-9) M. L-Deprenyl also provided a protection against apoptosis after AraC (cytosine beta-D-arabinoside) treatment in hippocampal neurons and Neuro-2a cells and after etoposide treatment in Neuro-2a cells. However, L-deprenyl did not offer any protection against apoptosis caused by serum withdrawal or potassium deprivation. Okadaic acid treatment in vivo is known to induce an Alzheimer's type of hyperphosphorylation of tau protein, formation of beta-amyloid plaques, and a severe memory impairment. Our results show that the okadaic acid model provides a promising tool to study the molecular basis of Alzheimer's disease and to screen the neuroprotective capacity of L-deprenyl derivatives.
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PMID:Protective effect of L-deprenyl against apoptosis induced by okadaic acid in cultured neuronal cells. 1079 57

The current study examined effects of chronic estradiol replacement on cognition and biomarkers of aging. Young, middle-aged, and aged rats were ovariectomized and implanted with blank capsules, or capsules containing high or low doses of estradiol benzoate (EB). Three weeks later, animals were tested on inhibitory avoidance and cue and spatial discrimination on the Morris water maze. High plasma estradiol levels were associated with slower swim speed and impaired retention of inhibitory avoidance. No effect of EB treatment was observed for acquisition of the spatial discrimination task, however, a dose by age interaction was observed for retention of spatial discrimination such that higher retention scores were observed for young, middle-aged and aged animals under blank, low and high dose conditions, respectively. EB treatment reversed several hippocampal markers of age-related memory impairment, blocking induction of long-term depression and decreasing cytosolic calcineurin activity. Results indicate that the level of chronic hormone replacement interacts with age to influence hippocampal function.
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PMID:Interaction of age and chronic estradiol replacement on memory and markers of brain aging. 1292 66

We have found recently that melatonin protects SH-SY5Y neuroblastoma cells from calyculin A-induced neurofilament impairment and neurotoxicity. In the present study, we further investigated the in vivo effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rats and the potential underlying mechanisms by using haloperidol, a specific inhibitor of 5-hydroxyindole-O-methyltransferase, and a key enzyme in melatonin biosynthesis. We have found that injection of haloperidol into the lateral ventricle and into peritoneal cavity compromises spatial memory retention of rats and induces hyperphosphorylation of microtubule-associated protein tau at tau-1 (Ser199/Ser202) and PHF-1 (Ser396/Ser404) epitopes. At mean time, the activity of protein phosphatase-2A (PP-2A), a deficit phosphatase in the Alzheimer's disease brain and superoxide dismutase decreases with an elevated level of malondialdehyde. Supplementation with melatonin by prior injection for 1 wk and reinforcement during the haloperidol administration significantly improves memory retention deficits, arrests tau hyperphosphorylation and oxidative stress, and restores PP-2A activity. These results strongly support the involvement of decreased melatonin in Alzheimer-like spatial memory impairment and tau hyperphosphorylation, and PP-2A may play a role in mediating aberrant melatonin-induced lesions.
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PMID:Effect of inhibiting melatonin biosynthesis on spatial memory retention and tau phosphorylation in rat. 1529 64

The abnormal hyperphosphorylation of tau protein is one of the hallmarks of Alzheimer disease and other tauopathies; as yet the exact role of various tau kinases in this pathology is not fully understood. Here, we show that injection of isoproterenol, an activator of cAMP-dependent kinase (PKA), into rat hippocampus bilaterally results in the activation of PKA, calcium/calmodulin-dependent kinase II and cyclin-dependent kinase-5, inhibition of protein phosphatase-2A, hyperphosphorylation of tau at several Alzheimer-like epitopes and a disturbance of spatial memory retention 48 h after the drug injection. These findings suggest the involvement of PKA and PKA-mediated signaling pathway in the Alzheimer-like tau hyperphosphorylation and memory impairment.
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PMID:Bilateral injection of isoproterenol into hippocampus induces Alzheimer-like hyperphosphorylation of tau and spatial memory deficit in rat. 1562 Jul 22

Hypothyroidism impairs synaptic plasticity as well as learning and memory. Clinical reports are conflicting about the ability of thyroid hormone replacement therapy to fully restore the hypothyroidism-induced learning and memory impairment. Recently, we have shown that hypothyroidism impairs LTP and cognition in adult rats. We have studied the effect of thyroxin replacement therapy on hypothyroidism-induced LTP impairment using electrophysiological and molecular approaches. Recording from CA1 region of the hippocampus in anesthetized adult rat indicated that 6 weeks of thyroxin replacement therapy (20 microg/kg/day) fully restored LTP impaired by hypothyroidism. Western blotting showed reduction in phosphorylated (P)-CAMKII, total-CaMKII, neurogranin, and calmodulin basal levels in the CA1 region of the hippocampus of hypothyroid rats. The levels of these molecules were normalized by thyroxin replacement therapy. The hypothyroid-induced elevation of basal calcineurin levels and activity was also normalized by thyroxin treatment. However, thyroxin replacement therapy did not restore hypothyroidism-induced reduction in PKCgamma basal protein levels. Additionally, real-time PCR, showed a reduction in basal neurogranin mRNA level that was normalized by thyroxin replacement therapy. In the sham (control) rats, induction of LTP by high-frequency stimulation increases P-CaMKII, and total CaMKII levels as well as CaMKII phosphotransferase activity. However, in hypothyroid rats, the same stimulation protocol induced an increase only in total-CaMKII. Thyroxin treatment normalized the levels and activity of these molecules. The results demonstrated that thyroxin therapy normalized the electrophysiological and molecular effects of hypothyroidism on the CA1 region and emphasized the critical role P-CaMKII plays in hypothyroidism-induced LTP impairment.
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PMID:Levothyroxin restores hypothyroidism-induced impairment of LTP of hippocampal CA1: electrophysiological and molecular studies. 1600 82

We have recently shown that chronic nicotine treatment reverses hypothyroidism-induced learning and memory impairment. Chronic nicotine treatment also reverses the hypothyroidism-induced impairment of long-term potentiation (LTP). Analysis of LTP associated key signaling molecules revealed that chronic nicotine treatment prevented the hypothyroidism-induced reduction of the basal phosphotransferase activity of CaMKII and protein levels of P-CaMKII. In addition, the failure of high frequency stimulation to increase the levels of P-CaMKII in hypothyroid rats was reversed by nicotine treatment, suggesting that the neuroprotective effect of nicotine during hypothyroidism involved activation of CaMKII. Furthermore, chronic nicotine treatment reverses the hypothyroidism-induced elevated phosphatase activity and protein levels of calcineurin, a phosphatase that regulates CaMKII activation. We conclude that the neuroprotective effects of nicotine in adult-onset hypothyroidism may result from restoration of CaMKII and calcineurin activity.
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PMID:Molecular studies on the protective effect of nicotine in adult-onset hypothyroidism-induced impairment of long-term potentiation. 1689 21

The activity of protein phosphatase (PP)-2A and PP-1 decreased in the brains of Alzheimer's disease and inhibition of the phosphatases led to spatial memory deficit in rats. However, the molecular basis underlying memory impairment of the phosphatase inhibition is elusive. In the present study, we observed a selective inhibition of PP-2A and PP-1 with Calyculin A (CA) not only caused hyperphosphorylation of cytoskeletal proteins, but also impaired the transport of pEGFP-labeled neurofilament-M subunit in the axon-like processes of neuroblastoma N2a cells and resulted in accumulation of neurofilament in the cell bodies. To analyze the morphological alteration of the cells during inhibition of the phosphatases, we established a cell model showing steady outgrowth of axon-like cell processes and employed a stereological system to analyze the retraction of the processes. We found CA treatment inhibited outgrowth of the cell processes and prolonged treatment with CA caused retraction of the processes and meanwhile, the early neurodegenerative varicosities were also obvious in the CA-treated cells. We conclude suppression of PP-2A and PP-1 by CA not only damages intracellular transport but also leads to cell degeneration, which may serve as the functional and structural elements for the memory deficits induced by suppression of the phosphatases.
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PMID:Inhibition of protein phosphatases induces transport deficits and axonopathy. 1747 9

Aging is often associated with decline of memory function. Aged animals, like humans, can naturally develop memory impairments and thus represent a useful model to investigate genes involved in long-term memory formation that are differentially expressed between aged memory-impaired (AI) and aged memory-unimpaired (AU) animals following stimulation in a spatial memory task. We found that alterations in hippocampal gene expression of transthyretin (TTR), calcineurin, and NAD(P)H dehydrogenase quinone 2 (NQO2) were associated with memory deficits in aged animals. Decreased TTR gene expression could be attributed at least partially to diminish activity of C/EBP immediate-early gene cascade initiated by CREB since protein levels of C/EBP, a transcription factor regulating both TTR and NQO2 expression, was decreased in AI animals. Memory deficits were also found during aging in mice lacking TTR, a retinol transporter known to prevent amyloid-beta aggregation and plaque formation as seen in Alzheimer's disease. Treatment with retinoic acid reversed cognitive deficits in these knock-out mice as well as in aged rats. Our study provides genetic, behavioural and molecular evidence that TTR is involved in the maintenance of normal cognitive processes during aging by acting on the retinoid signalling pathway.
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PMID:Transthyretin: a key gene involved in the maintenance of memory capacities during aging. 1751 93

Alzheimer's disease (AD), the most common neurodegenerative disease in the elderly population, is characterized by the hippocampal deposition of fibrils formed by amyloid beta-protein (A beta), a 40- to 42-amino-acid peptide. The folding of A beta into neurotoxic oligomeric, protofibrillar, and fibrillar assemblies is believed to mediate the key pathologic event in AD. The hippocampus is especially susceptible in AD and early degenerative symptoms include significant deficits in the performance of hippocampal-dependent cognitive abilities such as spatial learning and memory. Transgenic mouse models of AD that express C-terminal segments or mutant variants of amyloid precursor protein, the protein from which A beta is derived, exhibit age-dependent spatial memory impairment and attenuated long-term potentiation (LTP) in the hippocampal CA1 and dentate gyrus (DG) regions. Recent experimental evidence suggests that A beta disturbs N-methyl-D-aspartic acid (NMDA) receptor-dependent LTP induction in the CA1 and DG both in vivo and in vitro. Furthermore, these studies suggest that A beta specifically interferes with several major signaling pathways downstream of the NMDA receptor, including the Ca(2+)-dependent protein phosphatase calcineurin, Ca(2+)/calmodulin-dependent protein kinase II (CaMKII), protein phosphatase 1, and cAMP response element-binding protein (CREB). The influence of A beta on each of these downstream effectors of NMDA is reviewed in this article. Additionally, other mechanisms of LTP modulation, such as A beta attenuation of alpha-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid receptor currents, are briefly discussed.
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PMID:NMDA receptor-dependent signaling pathways that underlie amyloid beta-protein disruption of LTP in the hippocampus. 1917 Jan 66

To explore the role of protein kinase A (PKA) in regulating tau phosphorylation and spatial memory, we injected forskolin, an activator of PKA, at different concentrations into the rat brains. We found that forskolin at concentrations up to 80 microM enhanced tau phosphorylation and was associated with prominent spatial memory impairment. Higher concentrations of forskolin, up to 200 microM, were associated with reduced phosphorylation levels of tau and no memory deficits. Forskolin elevated cAMP and activated PKA in a dose-dependent manner. When infused at 200 microM, forskolin also resulted in the activation and overexpression of protein phosphatase-2A (PP-2A) and attenuated the okadaic acid-induced PP-2A inhibition. These data suggest that the upregulation of PKA by forskolin to a certain level may activate PP-2A but that the latter can ameliorate the PKA-induced tau phosphorylation and memory impairment in the rats.
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PMID:Biphasic effects of forskolin on tau phosphorylation and spatial memory in rats. 1943 99


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