Modulation of sodium channels by nicotinamide adenine dinucleotide

a technology of nicotinamide adenine dinucleotide and sodium channel, which is applied in the direction of biocide, cardiovascular disorder, drug composition, etc., can solve the problems of sudden death, cardiac arrest, etc., and achieve the effect of increasing current necessary, reducing arrhythmic risk, and reducing arrhythmic risk

Inactive Publication Date: 2011-11-24
U S DEPT OF VETERANS AFFAIRS TECH TRANSFER PROGRAM OFFICE OF RES & DEV +1
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  • Summary
  • Abstract
  • Description
  • Claims
  • Application Information

AI Technical Summary

Benefits of technology

[0010]It is well know that a reduction in the voltage-gated sodium current is arrhythmogenic. Such reductions are observed in such conditions as heart failure that is associated with arrhythmic risk. For example, very low sodium current is observed in systolic heart failure. The present inventors have discovered that NAD+ increases sodium channel current and sodium channel levels, while NADH reduces sodium channel current and sodium channel levels.
[0011]Accordingly, an object of the present invention provides NAD+ and NADH for modulating sodium channel current, thereby reducing arrhythmic risk, including heart failure and ventricular fibrillation.
[0012]Another object of the present invention is to reduce arrhythmic risk by increasing the current necessary for proper heart function. Arrhythmic risk as used herein includes heart failure and ventricular fibrillation. This is accomplished by the use of NAD+, as a dietary supplement or a drug, to mitigate arrhythmic risk. The NAD+ can be administered using various routes of drug administration known in the art, preferably intravenously administration.

Problems solved by technology

Some arrhythmias are life-threatening and can cause cardiac arrest and sudden death.

Method used

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  • Modulation of sodium channels by nicotinamide adenine dinucleotide
  • Modulation of sodium channels by nicotinamide adenine dinucleotide
  • Modulation of sodium channels by nicotinamide adenine dinucleotide

Examples

Experimental program
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Effect test

example 1

Methods

Cell Culture and Cell Viability Assays

[0047]Human embryonic kidney (HEK) cell line was used for all experiments. A HEK cell line stably expressing a SCN5A-IRES-GFP construct as described in our previous study (Arnold et al., Hearth Rhythm 4:46-53 (2007)) was maintained by antibiotic selection using 0.2 mg / mL Geneticin (G-8168, Sigma-Aldrich). Cells were cultured in Dulbecco's modified Eagle's medium (DMEM; ATCC, Manassas, Va.) with 10% fetal calf serum (ATCC) at 37° C. in 60 mm×15 mm cell culture dishes (Corning Incorporated, Corning, N.Y.) until 70-80% confluence. After reaching confluence, cells were exposed to NADH (Sigma, St. Louis, Mo.) or NAD+ (Sigma) in culture medium for a total of 12-14 h in triplicate. Experiments were repeated three times. After dissociation with 0.125% trypsin-EDTA, 40 μL of 0.4% Trypan-blue (Sigma, St. Louis, Mo.) was added to each well, and a Trypan-blue exclusion viability assay was performed.

Measuring Cellular NADH Levels

[0048]Chelex was obtai...

example 2

Methods

Cell Viability Assay

[0070]As previously described, we maintained a human embryonic kidney (HEK) cell line that stably expresses the human cardiac Na+ channel (SCN5A) with antibiotic selection using 0.2 mg / mL geneticin (G-8168, Sigma-Aldrich, St. Louis, Mo.) (23). Expression of SCN5A was linked to green fluorescent protein (GFP) expression by an internal ribosomal entry site (SCN5A-IRES-GFP). Cells were cultured in Dulbecco's modified Eagle's medium (DMEM; ATCC, Manassas, Va.) with 10% fetal calf serum (ATCC) at 37° C. in 60 mm×15 mm cell culture dishes (Corning Incorporated, Corning, N.Y.) until 70-80% confluency. Then, cells were exposed to NADH or NAD+ (both from Sigma-Aldrich) in culture medium for a total of 24 h. After dissociation with 0.125% trypsin-ethylenediaminetetraacetic acid (EDTA), 40 μL of 0.4% Trypan-blue (Sigma) was added to each well of a 6-well plate, and a Trypan-blue exclusion viability assay was performed. SCN5A cells were tolerant of a wide range of NAD...

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Abstract

The present invention relates to the use of oxidized nicotinamide adenine dinucleotide (NAD+) or of its reduced form, NADH, as sodium channel modulators. The present invention also relates to the use of compositions containing NAD+ or NADH to treat conditions associated with sodium channel current, such as arrhythmia. NAD+ is found to increase sodium channel current, while NADH is found to decrease sodium channel current. Thus, conditions that are associated with decreased sodium channel current can be treated with NAD+, while conditions that is associated with increased sodium channel current can be treated with NADH.

Description

CROSS-REFERENCE TO RELATED APPLICATIONS[0001]This is a divisional application of U.S. application Ser. No. 12 / 289,005, filed Oct. 17, 2008, which claims the priority benefit of U.S. Provisional Patent Application Ser. No. 60 / 960,883, filed Oct. 18, 2007, both of which are hereby incorporated herein in their entirety by reference.STATEMENT REGARDING FEDERALLY SPONSORED RESEARCH OR DEVELOPMENT[0002]The subject invention was made with government support under Grant Nos. R01 HL077398 and R01 HL073753, awarded by the National Institute of Health. The government has certain rights in this invention.FIELD OF THE INVENTION[0003]The present invention relates to the use of oxidized nicotinamide adenine dinucleotide (NAD+) or of its reduced form, NADH, as sodium channel modulators. The present invention also relates to the use of NAD+ or NADH to treat conditions associated with sodium channel current, such as arrhythmia.BACKGROUND OF THE INVENTION[0004]Voltage-gated sodium channels are pore-fo...

Claims

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Application Information

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Patent Type & Authority Applications(United States)
IPC IPC(8): A61K31/7084A61P9/06C12N5/00
CPCA61K31/7084A61P9/06
Inventor DUDLEY, JR., SAMUEL C.
Owner U S DEPT OF VETERANS AFFAIRS TECH TRANSFER PROGRAM OFFICE OF RES & DEV
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