Use of potassium channel inhibitor for treating depression

Abstract

The present disclosure provides a method for treating depression using a therapeutically effective amount of a pharmaceutical agent. The pharmaceutical agent can inhibit an activity of an astroglial potassium channel, and especially inhibit the functionality of Kir4.1, in astrocytes in the lateral habenula of a subject so that the abnormal burst firings of neurons in the lateral habenula of the subject can be suppressed. The pharmaceutical agent can include a vector expressing a target nucleotide sequence in the astrocytes in the lateral habenula, whose expression is configured to suppress Kir4.1 expression by RNA interference, or to block Kir4.1 functionality by a dominant negative effect of a mutant Kir4.1 protein. The pharmaceutical agent can alternatively comprise a small molecule compound, or an active macromolecule such as an anti-Kir4.1 antibody, that can directly inhibit the astroglial potassium channel activity.

1 . A method for treating depression in a subject, wherein the depression is characterized by abnormal burst firings of neurons in a lateral habenula (LHb) of the subject, the method comprising:
 administering to the subject a therapeutically effective amount of a pharmaceutical agent capable of interfering with a function or inhibiting an activity of Kir4.1 in the LHb of the subject such that the abnormal burst firing of the neurons in the LHb of the subject is suppressed, wherein the Kir4.1 has at least 95% sequence identity to SEQ ID NO. 18.   
     
     
         2 . The method of  claim 1 , wherein the pharmaceutical agent comprises a recombinant vector configured to express in astrocytes in the LHb of the subject polypeptide molecules capable of inhibiting the function or the activity of the Kir4.1. 
     
     
         3 . The method of  claim 2 , wherein the polypeptide molecules comprise a mutant Kir4.1 protein capable of interfering with the function of the Kir4.1 in a dominant negative manner, wherein the mutant Kir4.1 protein comprises a sequence alteration at a channel core region of the Kir4.1. 
     
     
         4 . The method of  claim 3 , wherein the sequence alteration is at a GYG segment corresponding to positions 130-132 of the Kir4.1 as set forth in any one of SEQ ID NOS. 8, 16 or 18. 
     
     
         5 . The method of  claim 4 , wherein the sequence alteration comprises a GYG-to-AAA point mutation. 
     
     
         6 . The method of  claim 2 , wherein the polypeptide molecules comprise an anti-Kir4.1 antibody. 
     
     
         7 . The method of  claim 2 , wherein the recombinant vector is a recombinant viral vector capable of preferentially or specifically targeting the astrocytes of the subject. 
     
     
         8 . The method of  claim 7 , wherein the recombinant vector is based on an adeno-associated virus (AAV) of 2/5 serotype (AAV2/5). 
     
     
         9 . The method of  claim 7 , wherein the administering to the subject a therapeutically effective amount of a pharmaceutical agent comprises:
 obtaining virus particles carrying the recombinant viral vector; and   administering the virus particles to the subject.   
     
     
         10 . The method of  claim 9 , wherein the administering the virus particles to the subject is through an injection or an inhalation. 
     
     
         11 . The method of  claim 1 , wherein the pharmaceutical agent comprises a small molecule agent capable of inhibiting the activity of the Kir4.1 in the LHb of the subject. 
     
     
         12 . The method of  claim 11 , wherein the small molecule agent comprises a selective serotonin reuptake inhibitor (S SRI) capable of inhibiting the activity of the Kir4.1 in the LHb of the subject. 
     
     
         13 . The method of  claim 12 , wherein the SSRI is selected from a group consisting of buspirone, mianserin, fluoxetine, sertraline, and fluvoxamine. 
     
     
         14 . The method of  claim 11 , wherein the small molecule agent comprises a tricyclic antidepressant (TCA) capable of inhibiting the activity of the Kir4.1 in the LHb of the subject. 
     
     
         15 . The method of  claim 14 , wherein the TCA is selected from a group consisting of nortriptyline, amitriptyline, desipramine, and imipramine. 
     
     
         16 . The method of  claim 11 , wherein the small molecule agent comprises a selective Kir4.1 inhibitor. 
     
     
         17 . The method of  claim 16 , wherein the selective Kir4.1 inhibitor comprises VU0134992. 
     
     
         18 . The method of  claim 1 , wherein the pharmaceutical agent comprises a recombinant vector configured to express in astrocytes in the LHb of the subject express a short hairpin RNA (shRNA) molecule, wherein the shRNA molecule comprises two complementary sequences, and one of the two complementary sequences has a nucleotide sequence that is substantially identical to a sequence as set forth in any one of SEQ ID NOS. 1-4 and 6. 
     
     
         19 . The method of  claim 1 , wherein the administering to the subject a therapeutically effective amount of a pharmaceutical agent comprises:
 administering the pharmaceutical agent to the subject in a systemic manner.   
     
     
         20 . The method of  claim 1 , wherein the administering to the subject a therapeutically effective amount of a pharmaceutical agent comprises:
 administering the pharmaceutical agent locally to the LHb of the subject.