Luteolin and diosmin/diosmetin as novel STAT3 inhibitors for treating autism

• US 8,778,894 B2
• Filed: 10/04/2013
• Issued: 07/15/2014
• Est. Priority Date: 10/30/2008
• Status: Expired due to Fees

• Current Assignee: US Department of Veterans Affairs (Government of the United States of America), University of South Florida (State University System of Florida)
• Original Assignee: University of South Florida (State University System of Florida)
• Inventors: Tan, Jun, Luo, Deyan, Shytle, Roland Douglas
• Primary Examiner(s): Bland, Layla
• Application Number:
  US14/046,381
• Publication Number:
  US 20140038913A1
• Time in Patent Office: 284 Days
• Field of Search: None
• US Class Current: 514/27
• CPC Class Codes: A61K 2300/00 Mixtures or combinations of active ingredients, wherein at least one active ingredient is fully defined in groups A61K31/00 - A61K41/00
• CPC Class Codes: A61K 31/352 condensed with carbocyclic rings, e.g. methantheline cannabinoids A61K31/658
• CPC Class Codes: A61K 31/353 3,4-Dihydrobenzopyrans, e.g. chroman, catechin
• CPC Class Codes: A61K 31/7048 having oxygen as a ring hetero atom, e.g. leucoglucosan, hesperidin, erythromycin, nystatin , digitoxin or digoxin
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/28 for treating neurodegenerative disorders of the central nervous system, e.g. nootropic agents, cognition enhancers, drugs for treating Alzheimer's disease or other forms of dementia
• CPC Class Codes: A61P 3/10 for hyperglycaemia, e.g. antidiabetics

Abstract

The present invention includes methods for the treatment of autoimmune disorders such as autism, schizophrenia, and type 1 diabetes. Flavonoids, luteolin, diosmin, and diosmin'"'"'s aglycone form, diosmetin, were found to inhibit activation/phosphorylation of STAT3 induced by IL-6 in cultured neuronal cells. Furthermore, mice treated with diosmin showed a significant reduction of autistic phenotype induced by IL-6 through inhibition of STAT3 activation.

Claims

1. A method of reducing the risk of developing autism in a patient due to exposure of the patient in utero to elevated levels of IL-6 from the patient'"'"'s mother-comprising:

inhibiting activation of STAT3 in both the patient and the patient'"'"'s mother by administering a therapeutically effective amount of a flavonoid selected from the group consisting of luteolin, diosmin, and diosmetin to the patient'"'"'s mother during pregnancy;

wherein STAT3 in the patient and the patient'"'"'s mother is activated by elevated levels of IL-6 from the patient'"'"'s mother.

2. The method of claim 1, wherein the flavonoid is administered orally.

3. The method of claim 1, wherein the flavonoid is administered at a dosage of between about 0.81 mg/kg/day and about 2.5 mg/kg/day.

4. The method of claim 1, wherein the patient'"'"'s mother suffered from an infection which resulted in maternal immune activation of IL-6 while pregnant.

5. The method of claim 3, wherein the flavonoid is diosmin.

6. A method of treating autism in a patient in utero comprising:

obtaining levels of IL-6 in a mother of the patient;

comparing the levels of IL-6 from the mother to a control level wherein an elevated level of IL-6 from the mother as compared to the control level is indicative of STAT3 activation; and

inhibiting the activation of STAT3 by administering a therapeutically effective amount of a flavonoid selected from the group consisting of luteolin, diosmin, and diosmetin to the mother;

wherein inhibiting STAT3 activation in the mother also inhibits STAT3 activation in the patient.

7. The method of claim 6, wherein the flavonoid is administered orally.

8. The method of claim 6, wherein the flavonoid is administered at a dosage of between about 0.81 mg/kg/day and about 2.5 mg/kg/day.

9. The method of claim 6, wherein TNF-α

and IL-1β

levels are increased in the patient as compared to a control level.

10. The method of claim 9, wherein the flavonoid is diosmin.

11. A method of reducing the risk of developing schizophrenia in a patient due to exposure of the patient in utero to elevated levels of IL-6 from the patient'"'"'s mother comprising:

inhibiting activation of STAT3 in both the patient and the patient'"'"'s mother by administering a therapeutically effective amount of a flavonoid selected from the group consisting of luteolin, diosmin, and diosmetin to the patient'"'"'s mother during pregnancy;

wherein STAT3 in the patient and the patient'"'"'s mother is activated by elevated levels of IL-6 from the patient'"'"'s mother.

12. The method of claim 11, wherein the flavonoid is administered orally.

13. The method of claim 11, wherein the flavonoid is administered at a dosage of between about 0.81 mg/kg/day and about 2.5 mg/kg/day.

14. The method of claim 11, wherein the mother suffered from an infection which resulted in maternal immune activation of IL-6 while pregnant.

15. The method of claim 13, wherein the flavonoid is diosmin.