Methods of modifying neuronal function by changing intracellular magnesium levels
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Publication Number
US-11278567-B2
Publication Date
2022-03-22
Expiration Date
Abstract
Methods for modifying neuronal functional activity and/or treating a neurological disorder by using agents that raise neuronal intracellular concentration of magnesium are disclosed. Also provided herein are methods of determining the amenability of an individual to treatment for a neurological disorder, by measuring changes in intracellular magnesium concentration.
Core Innovation
The disclosed approach increases intracellular magnesium in an individual by administering an intracellular magnesium concentration-elevating agent, including individuals having or suspected of having a neurological disorder. The method measures magnesium in blood cells from a first blood sample obtained before administering and evaluates a change in cognitive competency from before to after administering.
Increasing intracellular magnesium is described as increasing functional presynaptic terminal density and mitochondrial function and density, and altering presynaptic Ca2+ sensitivity protein abundance. The disclosure further links intracellular magnesium elevation to presynaptic Ca2+ handling and synaptic transmission properties, including reducing the probability of synaptic release to low-frequency background activity.
The description links intracellular Mg2+ elevation to mitochondrial function and ATP supply, and associates this with increased density of functional presynaptic terminals and increased abundance of Ca2+-sensitivity-related presynaptic proteins. It also states that higher intracellular Mg2+ suppresses terminal probability of transmitter release in an input-type dependent manner, and that RBC ionized Mg2+ is presented as a biomarker correlated with learning/memory and hippocampal synaptic density.
The disclosure further describes intracellular Mg2+ measurement and modeling using magnesium indicator fluorescence corrected for branch geometry, and correlates intracellular magnesium-related neuronal functional properties with mitochondrial energetics and ATP measurement concepts. It reports that presynaptic protein changes, including SYT1, Rab3a, RIM1, Munc13-1, ELKS, and Syntaxin1, and mitochondrial function and density relate to intracellular magnesium elevation and to responsiveness in clinical-trial-related content for MMFS-01 (L-TAMS/ClariMem) with cognitive endpoints and magnesium biomarker outcomes.
Claims Coverage
The independent claim set covers administering an intracellular magnesium concentration-elevating agent, determining a first level of magnesium in blood cells from a baseline blood sample, and evaluating a change in cognitive competency before and after administering. The claims include refinements that specify the neurological disorder scope, the magnesium form measured, and continued administration based on comparisons between first and second magnesium levels and cognitive-competency outcomes.
Administering intracellular magnesium concentration-elevating agent for a neurological disorder
Administering an intracellular magnesium concentration-elevating agent to an individual having or suspected of having a neurological disorder to increase the intracellular concentration of magnesium in the individual.
Baseline blood-cell magnesium determination
Determining a first level of magnesium in blood cells of a first blood sample obtained from the individual before the administering.
Evaluating change in cognitive competency
Evaluating a change in cognitive competency of the individual from before to after the administering.
Neurological disorder scope including cognitive impairment and magnesium deficiency-caused disorders
The neurological disorder includes cognitive impairment and/or a magnesium deficiency-caused neurological disorder.
Measuring total intracellular magnesium
The magnesium being measured is total intracellular magnesium.
Measuring ionized magnesium
The magnesium being measured is ionized magnesium.
Continuing administration based on magnesium-level comparison
Continuing administration of an intracellular magnesium concentration-elevating agent when a second magnesium level is greater than a first magnesium level.
Continuing administration based on cognitive outcome and magnesium-level comparison
Continuing administration when cognitive competency is not improved or is substantially the same after initial administration, and when a second magnesium level is greater than a first magnesium level.
Overall, the claims are directed to administering an intracellular magnesium concentration-elevating agent, baseline determination of magnesium in blood cells, and evaluating cognitive competency change, with refinements that specify neurological disorder scope, ionized versus total magnesium, and continued administration based on first and second magnesium levels and cognitive-change criteria.
Stated Advantages
Increased body magnesium status via RBC Mg2+.
Statistically significant improvements in cognitive composite score and certain cognitive tests over 12 weeks in elderly (50–70).
RBC Mg2+ change predicts cognitive improvement in responders.
RBC ionized Mg2+ is correlated with learning/memory and hippocampal synaptic density.
Documented Applications
Individuals having or suspected of having a neurological disorder.
Cognitive impairment.
Magnesium deficiency-caused neurological disorder.
Modifying neuronal function.
Determining treatment amenability using blood-cell Mg2+ changes.
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