Methods related to the treatment of neurodegenerative and inflammatory conditions
Inventors
Hong, Jau-Shyong • Qin, Liya • Li, Guorong • Block, Michelle • Zhang, Wei • Chen, Po-See • Peng, Giia-Shuen
Assignees
US Department of Health and Human Services
Publication Number
US-8088787-B2
Publication Date
2012-01-03
Expiration Date
2025-05-12
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Abstract
The invention includes methods of neuroprotection, inducing release of neurotrophic factors, inhibiting the over-activation of innate immune cells, attenuating the toxin-induced death and/or damage of tissues, reducing inflammation, treating an inflammation-related condition, and inhibiting NADPH oxidase, that includes contacting or administering an effective amount of at least one compound of the invention that include: valproic acid, sodium butyrate, and salts thereof; opioid peptides; a peptide comprising the tripeptide GGF; and morphinans, such as naloxone, naltrexone, 3-hydroxy-morphinan and dextromethorphan.
Core Innovation
The invention includes methods of neuroprotection, inducing release of neurotrophic factors, inhibiting the over-activation of innate immune cells, attenuating the toxin-induced death and/or damage of tissues, reducing inflammation, treating inflammation-related conditions, and inhibiting NADPH oxidase by administering effective amounts of specific compounds including valproic acid, sodium butyrate and their salts; opioid peptides; a peptide comprising the tripeptide GGF; and morphinans such as naloxone, naltrexone, 3-hydroxy-morphinan, and dextromethorphan.
The invention addresses the problem of inflammation-mediated neurodegeneration in diseases such as Parkinson's disease, Alzheimer's disease, and cerebral ischemia. Inflammation, characterized by activation of microglia and astroglia, leads to secretion of cytokines and free radicals causing neuronal death. Existing gaps include the need for greater understanding and treatments activating neuronal-survival pathways and enhancing brain cell resilience and plasticity.
The invention provides methods for activating neuronal-survival signaling pathways, inducing release of neurotrophic factors from astroglial cells, inhibiting over-activation of innate immune cells including microglia, reducing inflammation, and attenuating toxin-induced death/damage of dopaminergic neurons and other tissues. The compounds used act by inhibiting NADPH oxidase activity, particularly affecting its gp91 subunit, which contributes to pro-inflammatory agent release and innate immune cell activation.
Claims Coverage
The patent contains one independent claim focusing on a therapeutic method using naloxone for treating endotoxic shock with specified dosages.
Treatment of endotoxic shock with specific naloxone dosage
A method of treating a mammal for endotoxic shock by administering to the mammal an effective amount of naloxone, wherein the effective amount is from 10 pg/kg to 1 μg/kg.
The claims cover a method of treating endotoxic shock by administration of naloxone in an effective dosage range. The inventive feature is the specified dose range of naloxone for therapeutic efficacy in endotoxic shock treatment.
Stated Advantages
Dextromethorphan significantly increases survival rate in mice undergoing endotoxic shock.
The compounds protect dopaminergic neurons from inflammatory and toxin-induced neurodegeneration.
Valproic acid and similar compounds exhibit both neuroprotective and neurotrophic effects by inhibiting microglial activation and inducing neurotrophic factor release.
Methods enable dose-dependent attenuation of inflammatory markers such as TNFα, PGE2, nitric oxide, and superoxide.
Ultra low concentrations of compounds exhibit equipotent neuroprotective effects matching much higher concentrations.
Documented Applications
Treatment and prevention of neurodegenerative disorders including Parkinson's disease, Alzheimer's disease, and ALS.
Treatment of inflammation-related conditions such as arthritis, diabetes, atherosclerosis, multiple sclerosis, sepsis, septic shock, endotoxemia, multiple organ failure, and liver damage.
Methods for inhibiting toxin-induced death and/or damage of dopaminergic neurons and other cells including liver, lung, and kidney cells.
Use in managing brain inflammation characterized by activation of microglia and astroglia.
Use in treating endotoxic shock in mammals, including humans, by administration of naloxone in effective amounts.
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