COMPOSITIONS AND METHODS FOR TREATING NEUROLOGICAL DISORDERS

• US 20100136004A1
• Filed: 11/23/2009
• Published: 06/03/2010
• Est. Priority Date: 05/23/2007
• Status: Abandoned Application

• Current Assignee: Georgia Health Sciences University Research Institute, Inc.
• Original Assignee: Medical College of Georgia (University System of Georgia)
• Inventors: XIONG, WEN-CHENG, LI, XIAOMING, WOO, RAN-SOOK, MEI, LIN
• Application Number:
  US12/624,035
• Publication Number:
  US 20100136004A1
• Time in Patent Office: Days
• US Class Current: 424/133.100
• CPC Class Codes: A61K 38/177 Receptors; Cell surface antigens; Cell surface determinants
• CPC Class Codes: A61K 38/1883 Neuregulins, e.g.. p185erbB2 ligands, glial growth factor, heregulin, ARIA, neu differentiation factor
• CPC Class Codes: A61K 38/45 Transferases (2)
• CPC Class Codes: A61K 39/3955 against proteinaceous materials, e.g. enzymes, hormones, lymphokines
• CPC Class Codes: A61P 25/00 Drugs for disorders of the nervous system
• CPC Class Codes: A61P 25/08 Antiepileptics; Anticonvulsants
• CPC Class Codes: A61P 25/18 Antipsychotics, i.e. neuroleptics; Drugs for mania or schizophrenia
• CPC Class Codes: A61P 25/22 Anxiolytics
• CPC Class Codes: A61P 25/24 Antidepressants

Abstract

Methods and compositions for modulating GABA release in a subject are provided. A preferred embodiment provides a composition containing an effective amount of an ErbB4 ligand to enhance or promote GABA release, i.e., GABAergic transmission. The ErbB4 ligand can be an agonist ligand or an antagonist ligand depending on the disorder to be treated. Methods for treating neurological disorders are also provided. Representative disorders that can be treated include, but are not limited to schizophrenia, epilepsy, depression and anxiety, insomnia, stroke, pain, bipolar, autism, or a combination thereof. By increasing GABA release a sedative effective can be induced in the subject. Methods for inducing a stimulatory effect in a subject are also provided. In these methods, an effective amount of an ErbB4 antagonist ligand is administered to the subject to reduce or inhibit GABA release in the subject.

Claims

1. A pharmaceutical composition comprising an ErbB4 ligand in an amount effective to increase or decrease GABAergic transmission in a subject.

2. The pharmaceutical composition of claim 1 wherein the ErbB4 ligand comprises NRG1, a variant thereof, or an ErbB4-binding fragment thereof.

3. The pharmaceutical composition of claim 2 wherein the ErbB4 ligand induces or promotes GABAergic transmission in the subject.

4. The pharmaceutical composition of claim 1 wherein the ErbB4 ligand comprises soluble ErbB4.

5. The pharmaceutical composition of claim 4 wherein the ErbB4 ligand promotes a stimulatory response in host by reducing or inhibiting GABAergic transmission.

6. The pharmaceutical composition of claim 1 wherein the ErbB4 ligand comprises a small molecule ligand.

7. The pharmaceutical composition of claim 1 further comprising a second therapeutic agent.

8. The pharmaceutical composition of claim 7 wherein the second therapeutic agent is selected from the group consisting of diazepam, methamphetamine, amphetamine and dextroamphetamine, gabapentin, potassium chloride, methylphenidate, clonazepam, modafinil, lamotrigine, aripiprazole, triamcinolone, valproate semisodium, divalproex sodium, phenyloin sodium, lithium, natalizumab, promethazine, reperidone, temazepam, topiramate, prednisone, triamcinolone, verapamil, or combinations thereof.

9. A method for treating a neurological disorder comprising administering to subject in need thereof an effective amount of a pharmaceutical composition comprising of an ErbB4 agonist ligand to inhibit or reduce the disorder.

10. The method of claim 9 wherein the neurological disorder is selected from the group consisting of schizophrenia, epilepsy, depression and anxiety, insomnia, stroke, pain, bipolar, autism, or a combination thereof.

11. The method of claim 9 wherein the ErbB4 ligand is an ErbB4 agonist in an amount effective to increase or promote GABAergic transmission relative to a control, wherein the increase in GABAergic transmission induces a sedative effect in the subject.

12. The method of claim 11 wherein the neurological disorder is epilepsy.

13. The method of claim 9 wherein the ErbB4 ligand is an ErbB4 antagonist ligand in an amount effective to reduce or inhibit GABAergic transmission relative to a control, wherein the decrease in GABAergic transmission induces a stimulatory effect in the subject.

14. The method of claim 12 wherein the ErbB4 agonist ligand comprises NRG1, a variant thereof, or an ErbB4-binding fragment thereof.

15. The method of claim 12 wherein the ErbB4 agonist ligand comprises an ErbB4 antibody or ErbB4-binding fragment thereof.

16. A method for inducing a sedative effect in a subject comprising administering to the subject an effective amount of an ErbB4 agonist ligand.

17. A method for inducing a stimulatory effect in a subject comprising administering to the subject an effective amount of an ErbB4 antagonist ligand.