Methods of metabolic regulation of mitochondria for treating neural injury and neurological disorders
Inventors
Li, Wei • ZHAO, Tantai • Ou, Jingxing
Assignees
US Department of Health and Human Services
Publication Number
US-12011426-B2
Publication Date
2024-06-18
Expiration Date
2039-08-21
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Abstract
Methods are disclosed for treating and/or preventing a neurological condition, such as neural injury or neurological disorder, in a subject through metabolic regulation of mitochondria using compounds that are natural metabolites, metabolite analogs, or derivatives of natural metabolites to modulate biochemical pathways comprising succinate and/or succinate dehydrogenase, thereby reducing microglial cell and/or astrocyte activation. Compounds and related formulations are also provided to modulate the biochemical pathways comprising succinate and/or succinate dehydrogenase for reducing or inhibiting microglial cell and/or astrocyte activation.
Core Innovation
The invention provides methods for treating and preventing neurological conditions, specifically neural injuries or neurological disorders, through metabolic regulation of mitochondria by modulating biochemical pathways involving succinate and/or succinate dehydrogenase (SDH). It involves administering compounds that are natural metabolites, metabolite analogs, or derivatives that reduce the level of succinate or the activity of succinate dehydrogenase, thereby reducing microglial and astrocyte activation.
The problem addressed is that neurological disorders and neural injuries often involve an immune response that exacerbates neuronal damage, particularly through activation of microglial cells and astrocytes, which release cytokines that kill neurons. Current microglial inhibition interventions have limited beneficial effects, so there is a need for improved treatment methods. The inventors discovered that regulation of succinate dehydrogenase contributes to microglia inactivation during hibernation, suggesting that modulating succinate and SDH pathways can reduce immune activation and neuronal damage.
The inventors found that metabolic adaptation during hibernation, including lower succinate levels, suppresses local immune responses by reducing microglial and astrocyte activity, which protects neurons from death after injury. Mimicking this metabolic state pharmacologically using compounds that lower succinate or inhibit SDH improves neuronal survival and reduces inflammation. The methods include administering compounds that modulate any enzymes in the succinate biochemical pathway upstream or downstream of succinate dehydrogenase, directly inhibit SDH, or alter succinate levels to inhibit microglial and astrocyte activation, thus preventing neuronal damage in various neurological diseases and injuries.
Claims Coverage
The patent contains one independent claim that covers methods for inhibiting microglial activation and preventing astrocyte activation using compounds acting on succinate or succinate dehydrogenase pathways. This claim encompasses multiple inventive features related to biochemical modulation and compound types.
Inhibition of microglial activation using specific compounds
A method of inhibiting activation of microglial cells by contacting them with a compound that decreases succinate level or reduces succinate dehydrogenase activity, wherein the compound includes dimethyl malonate (DMM), oxaloacetic acid, or octyl itaconate.
Reduction or prevention of cytokine release from microglia
Inhibition of microglial activation includes reducing or preventing cytokine release from these cells when contacted with the compounds.
Prevention of astrocyte activation in mixed cell systems
A method of preventing astrocyte activation in systems with microglial cells and astrocytes by introducing the same class of compounds that reduce succinate levels or succinate dehydrogenase activity.
Modulation of biochemical pathways involving succinate
The compounds modulate biochemical pathways comprising succinate, including enzymes upstream or downstream of succinate dehydrogenase.
Direct action and inhibition of succinate dehydrogenase
The compounds act directly on succinate dehydrogenase and inhibit its enzymatic activity.
Use of biochemical pathway molecules, prodrugs or analogs
The compounds may be molecules from the succinate dehydrogenase biochemical pathway or their prodrugs, active metabolites, analogs, or derivatives.
The claims collectively cover pharmacological methods for inhibiting microglial and astrocyte activation in neurological conditions by administering compounds that reduce succinate levels or inhibit succinate dehydrogenase activity, including specific compounds such as dimethyl malonate, oxaloacetic acid, and octyl itaconate, and methods involving modulation of related biochemical pathways.
Stated Advantages
Reducing microglial and astrocyte activation to diminish neuroimmune responses prevents neuronal damage.
Mimicking hibernation-induced metabolic states pharmacologically leads to neural protection after injury.
Use of compounds targeting succinate and succinate dehydrogenase pathways provides a novel approach to treat or slow progression of neurological diseases.
Administration of succinate dehydrogenase inhibitors reduces mitochondrial reactive oxygen species and pro-inflammatory cytokine production.
Therapeutic methods may prevent development, inhibit progression, or reduce severity of neurological symptoms by reducing immune-mediated neuronal damage.
Documented Applications
Treatment and prevention of neurological conditions such as neural injury and neurological disorders involving immune responses.
Therapy for neurodegenerative diseases including Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, and multiple sclerosis.
Treatment of neurological conditions arising from trauma, infections, toxins, nutritional deficiencies, or neoplasms.
Use in modulating microglial and astrocyte activation in both in vivo and in vitro systems.
Method of enhancing neuron survival after axonal injury, exemplified by optic nerve crush models.
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