A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells
A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive...
Saved in:
| Main Authors: | , , , , |
|---|---|
| Format: | Article |
| Language: | English |
| Published: |
Wiley
2019-01-01
|
| Series: | Journal of Diabetes Research |
| Online Access: | http://dx.doi.org/10.1155/2019/5783545 |
| Tags: |
Add Tag
No Tags, Be the first to tag this record!
|
| _version_ | 1849684522011983872 |
|---|---|
| author | Jide Tian Hoa Dang Nataliya Karashchuk Irvin Xu Daniel L. Kaufman |
| author_facet | Jide Tian Hoa Dang Nataliya Karashchuk Irvin Xu Daniel L. Kaufman |
| author_sort | Jide Tian |
| collection | DOAJ |
| description | A major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process. |
| format | Article |
| id | doaj-art-c11aff7dfd58428cacad6fe2714dd2d0 |
| institution | DOAJ |
| issn | 2314-6745 2314-6753 |
| language | English |
| publishDate | 2019-01-01 |
| publisher | Wiley |
| record_format | Article |
| series | Journal of Diabetes Research |
| spelling | doaj-art-c11aff7dfd58428cacad6fe2714dd2d02025-08-20T03:23:26ZengWileyJournal of Diabetes Research2314-67452314-67532019-01-01201910.1155/2019/57835455783545A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T CellsJide Tian0Hoa Dang1Nataliya Karashchuk2Irvin Xu3Daniel L. Kaufman4Department of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USADepartment of Molecular and Medical Pharmacology, University of California, Los Angeles, CA, USAA major goal of T1D research is to develop new approaches to increase β-cell mass and control autoreactive T cell responses. GABAA-receptors (GABAA-Rs) are promising drug targets in both those regards due to their abilities to promote β-cell replication and survival, as well as inhibit autoreactive T cell responses. We previously showed that positive allosteric modulators (PAMs) of GABAA-Rs could promote rat β-cell line INS-1 and human islet cell replication in vitro. Here, we assessed whether treatment with alprazolam, a widely prescribed GABAA-R PAM, could promote β-cell survival and replication in human islets after implantation into NOD/scid mice. We observed that alprazolam treatment significantly reduced human islet cell apoptosis following transplantation and increased β-cell replication in the xenografts. Evidently, the GABAA-R PAM works in conjunction with GABA secreted from β-cells to increase β-cell survival and replication. Treatment with both the PAM and GABA further enhanced human β-cell replication. Alprazolam also augmented the ability of suboptimal doses of GABA to inhibit antigen-specific T cell responses in vitro. Thus, combined GABAA-R agonist and PAM treatment may help control inflammatory immune responses using reduced drug dosages. Together, these findings suggest that GABAA-R PAMs represent a promising drug class for safely modulating islet cells toward beneficial outcomes to help prevent or reverse T1D and, together with a GABAA-R agonist, may have broader applications for ameliorating other disorders in which inflammation contributes to the disease process.http://dx.doi.org/10.1155/2019/5783545 |
| spellingShingle | Jide Tian Hoa Dang Nataliya Karashchuk Irvin Xu Daniel L. Kaufman A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells Journal of Diabetes Research |
| title | A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells |
| title_full | A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells |
| title_fullStr | A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells |
| title_full_unstemmed | A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells |
| title_short | A Clinically Applicable Positive Allosteric Modulator of GABA Receptors Promotes Human β-Cell Replication and Survival as well as GABA’s Ability to Inhibit Inflammatory T Cells |
| title_sort | clinically applicable positive allosteric modulator of gaba receptors promotes human β cell replication and survival as well as gaba s ability to inhibit inflammatory t cells |
| url | http://dx.doi.org/10.1155/2019/5783545 |
| work_keys_str_mv | AT jidetian aclinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT hoadang aclinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT nataliyakarashchuk aclinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT irvinxu aclinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT daniellkaufman aclinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT jidetian clinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT hoadang clinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT nataliyakarashchuk clinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT irvinxu clinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells AT daniellkaufman clinicallyapplicablepositiveallostericmodulatorofgabareceptorspromoteshumanbcellreplicationandsurvivalaswellasgabasabilitytoinhibitinflammatorytcells |