Protein synthesis required for long-term memory is induced by PKC activation on days preceding associative learning

a protein synthesis and associative learning technology, applied in the direction of biocide, heterocyclic compound active ingredients, drug compositions, etc., can solve the problems of long-term antagonism and complicated approach, and achieve the effect of reducing myalgia, reducing myalgia produced, and preferentially inhibiting

Inactive Publication Date: 2007-03-08
BLANCHETTE ROCKEFELLER NEUROSCI INST
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0026] In one embodiment, the pharmaceutical composition further comprises a PKC inhibitor. In another embodiment, the PKC inhibitor is a compound that inhibits PKC in peripheral tissues. As used herein, “peripheral tissues” means tissues other than brain. In another embodiment, the PKC inhibitor is a compound that preferentially inhibits PKC in peripheral tissues. In another embodiment, the PKC inhibit is a compound that reduces myalgia associated with the administration of a PKC activator to subjects in need thereof. In another embodiment, the PKC inhibitor is a compound that reduces myalgia produced in a subject treated with a PKC activator. In another embodiment, the PKC inhibitor is a compound that increases the tolerable dose of a PKC activator. Specifically, PKC inhibitors include, for example, but are not limited to vitamin E, vitamin E analogs, and salts thereof; calphostin C; thiazolidinediones; ruboxistaurin, and combinations thereof. As used herein, “vitamin E” means α-tocopherol (5,7,8-trimethyltocol); β-tocopherol (5,8-dimethyltocol; 6-tocopherol (8-methyltocal); and γ-tocopherol (7,8-dimethyltocol), salts and analogs thereof.

Problems solved by technology

This approach is complicated by the fact that the catalytic domain is not the domain primarily responsible for the isotype specificity of PKC.
Alternatively, by inducing down-regulation of PKC after acute activation, PKC activators may cause long term antagonism.

Method used

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  • Protein synthesis required for long-term memory is induced by PKC activation on days preceding associative learning
  • Protein synthesis required for long-term memory is induced by PKC activation on days preceding associative learning
  • Protein synthesis required for long-term memory is induced by PKC activation on days preceding associative learning

Examples

Experimental program
Comparison scheme
Effect test

example 1

Behavioral Pharmacology

[0076] Bryostatin exposure—Specimens of Hermissenda Crassicornis were maintained in artificial sea water (ASW) at 15° for three days in perforated 50-ml conical centrifuge tubes before starting experiments. Bryostatin, purified from the marine bryozoan Bugula neritina, was dissolved in EtOH and diluted to its final concentration in ASW. Animals were incubated with bryostatin in ASW for 4 hr, then rinsed with normal ASW. For selected experiments lactacysteine (10 μM) or anisomycin was added to the ASW.

[0077] Bryostatin effects on Hermissenda behavior and biochemistry were produced by adding the drug to the bathing medium within an 8 cm long, 1 cm diameter test tube housing each individual animal.

example 2

Immunostaining Methods

[0078] Following experimental treatments and testing, animals were rapidly decapitated, the central nervous systems (CNS) removed and then fixed in 4% para-formaldehyde in 20 mM Tris-buffered (pH 8) natural seawater (NSW; 0.2 μm micropore-filtered). The CNSs were then embedded in polyester wax (20), sectioned (6 μm) and immunostained using a biotinylated secondary antibody coupled to avidin-bound microperoxidase (ABC method, Vector), Aminoethylcarbazole (AEC) was used as the chromogen. The primary polyclonal antibody (designated 25U2) was raised in rabbits from the full length calexcitin protein extracted from squid optic lobes. Gray-scale intensity measures were done from digital photomicrographs on circumscribed cytoplasmic areas of the B-photoreceptors minus the same background area (non-staining neuropile).

example 3

Protein Kinase C Assay

[0079] Cells were homogenized by sonication (5 sec, 25 W) in 100 μl of 10 mM Tris-HCl pH 7.4 buffer containing 1 mM EGTA, 1 mM PMSF, and 50 mM NaF. Homogenate was transferred to a polyallomer centrifuge tube and was centrifuged at 100,000×g for 10 min at 4°. The supernatant was removed and immediately frozen on dry ice. The particulate fraction was resuspended by sonication in 100 μl of the same buffer and stored at −80°. To measure PKC, 10 μl of cytosol or particulate fraction was incubated for 15 min at 37° in the presence of 10 μM histones, 4.89 mM CaCl2, 1.2 μg / μl phosphatidyl-L-serine, 0.18 μg / μl 1.2-dioctanoyl-sn-glycerol, 10 mM MgCl2, 20 mM HEPES (pH 7.4), 0-8 mM EDTA, 4 mM EGTA, 4% glycerol, 8 μg / ml aprotinin, 8 μg / ml leupeptin, and 2 mM benzamidine. 0.5 μCi [γ32P]ATP was added and 32P-phosphoprotein formation was measured by adsorption onto phosphocellulose as described previously (25). This assay was used with slight adjustments for either Hermissend...

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Abstract

The present invention provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to stimulate the synthesis of proteins sufficient to consolidate long-term memory. The present invention also provides methods of contacting a protein kinase C (PKC) activator with a PKC activator in a manner sufficient to downregulate PKC.

Description

PRIORITY OF INVENTION [0001] This application claims priority to U.S. Provisional Application No. 60 / 703,501 filed Jul. 29, 2005 and U.S. Provisional Application No. 60 / 728,753 filed on Oct. 21, 2005.FIELD OF THE INVENTION [0002] The present invention relates to methods of upregulating and downregulating protein kinase C that are useful for enhancing memory and the treatment of cell proliferative disorders. BACKGROUND OF THE INVENTION [0003] Various disorders and diseases exist which affect cognition. Cognition can be generally described as including at least three different components: attention, learning, and memory. Each of these components and their respective levels affect the overall level of a subject's cognitive ability. For instance, while Alzheimer's Disease patients suffer from a loss of overall cognition and thus deterioration of each of these characteristics, it is the loss of memory that is most often associated with the disease. In other diseases patients suffer from ...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/407A61K31/365
CPCA61K31/365A61K31/366A61K31/437A61K31/407A61K31/40A61K31/4015A61P25/00A61P25/28A61P29/00A61P43/00
Inventor ALKON, DANIEL L.
Owner BLANCHETTE ROCKEFELLER NEUROSCI INST
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