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. (26th February 2019)

• Record Type: Journal Article
• Authors: Tian, Jide; Dang, Hoa; Karashchuk, Nataliya; Xu, Irvin; Kaufman, Daniel L.
• Other Names: Calafiore Riccardo Academic Editor.
• Is Part Of: Journal of diabetes research. Volume 2019(2019)
• Publication Date: 2019-02-26
• Subjects: Diabetes -- Periodicals; Diabetes -- Pathophysiology -- Periodicals; Diabetes -- Prevention -- Periodicals; Diabetes -- Etiology -- Periodicals; Diabetes -- Epidemiology -- Periodicals; Diabetes -- Pathogenesis -- Periodicals; 616.462005
• DOI: 10.1155/2019/5783545
• Languages: English
• ISSNs: 2314-6745

Abstract

Abstract : 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.