S-nitrosoglutathione (GSNO) and GSNO reductase inhibitors for use in therapy
Inventors
Singh, Inderjit • SINGH, Avtar K.
Assignees
MUSC Foundation for Research and Development • US Department of Veterans Affairs
Publication Number
US-10925858-B2
Publication Date
2021-02-23
Expiration Date
2038-05-08
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Abstract
The present disclosure provides methods for the treatment of neurological deficits by the administration of GSNO or GSNO reductase inhibitor. Further provided herein are methods of treating autoimmune diseases by administering GSNO or GSNO reductase inhibitor.
Core Innovation
The invention provides methods for treating neurological deficits and autoimmune diseases by administering S-nitrosoglutathione (GSNO) and/or GSNO reductase inhibitors to a subject. The methods involve administering an effective amount of GSNO and/or one or more inhibitors of GSNO reductase such as N6022, which may restore blood brain barrier (BBB) integrity, decrease neurological inflammation and brain edema, improve the ultrastructure of microvessels, and enhance cognition.
The background identifies the problem that diseases such as diabetes induce hyperglycemia which leads to increased permeability and dysfunction of the blood brain barrier (BBB). This BBB disruption is characterized by loss of tight junction proteins such as ZO-1 and occludin, increased expression of cell adhesion molecules like ICAM-1 and VCAM-1, and aberrant microvessel ultrastructure. These changes result in neurological deficits including cognitive impairment in diabetic subjects.
The invention addresses the unmet need to protect and restore BBB integrity and prevent neurological complications, by using GSNO and GSNO reductase inhibitors. GSNO acts as a reservoir of nitric oxide (NO) and has been found to regulate BBB permeability, reduce endothelial cell activation, prevent loss of tight junction proteins, and lower matrix metalloproteinase activity, thereby improving cognitive functions. The methods also relate to treatment of autoimmune diseases such as multiple sclerosis and rheumatoid arthritis by modulating immune responses via GSNO-mediated mechanisms and inhibition of GSNO reductase.
Claims Coverage
The patent includes two independent claims related to methods of treating neurological deficits and autoimmune diseases by administering GSNO reductase inhibitors.
Treatment of neurological deficits by GSNO reductase inhibitor administration
A method of treating neurological deficits in a subject comprising administering an effective amount of a GSNO reductase inhibitor to the subject.
Treatment of autoimmune diseases by GSNO reductase inhibitor administration combined with a second therapy
A method of treating an autoimmune disease in a subject comprising administering an effective amount of a GSNO reductase inhibitor and at least a second therapy to the subject.
The claims cover methods of using GSNO reductase inhibitors, such as N6022, to treat neurological deficits by restoring BBB integrity and decreasing inflammation, as well as methods to treat autoimmune diseases, optionally combined with established therapies. The inventive features focus on administration of GSNO reductase inhibitors, mechanisms involving modulation of tight junction proteins and cell adhesion molecules, and selective immune modulation.
Stated Advantages
GSNO administration protects and restores blood brain barrier integrity by preserving tight junction protein expression and downregulating cell adhesion molecules.
GSNO reductase inhibitors selectively modulate pro- and anti-inflammatory subsets of CD4+ T cells without causing lymphopenia.
The methods improve cognitive function, decrease neurological inflammation and brain edema, and improve microvessel ultrastructure.
GSNO and GSNO reductase inhibitors offer potential therapeutic benefit in treating neurological deficits including diabetes-associated cognitive decline and autoimmune diseases such as multiple sclerosis and rheumatoid arthritis.
Documented Applications
Treatment of neurological deficits associated with diabetes, including hyperglycemia-induced BBB disruption and cognitive impairment.
Treatment of autoimmune diseases including multiple sclerosis, rheumatoid arthritis, systemic lupus erythematosus, type 1 diabetes mellitus, and Crohn's disease.
Use in treating neurological disorders involving blood brain barrier disruption such as stroke, traumatic brain injury, and spinal cord injury.
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