Back to Search
Start Over
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
- Source :
- Journal of Diabetes Research, Journal of Diabetes Research, Vol 2019 (2019)
- Publication Year :
- 2019
- Publisher :
- Hindawi, 2019.
-
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.
- Subjects :
- Endocrinology, Diabetes and Metabolism
T-Lymphocytes
Medical Physiology
Apoptosis
Mice, SCID
Pharmacology
Inbred C57BL
lcsh:Diseases of the endocrine glands. Clinical endocrinology
GABA
Mice
Endocrinology
Mice, Inbred NOD
Insulin-Secreting Cells
Receptors
2.1 Biological and endogenous factors
Aetiology
gamma-Aminobutyric Acid
geography.geographical_feature_category
Cell cycle
Islet
medicine.anatomical_structure
Cell Division
Research Article
Agonist
Allosteric modulator
Article Subject
medicine.drug_class
Cell Survival
T cell
1.1 Normal biological development and functioning
SCID
Autoimmune Disease
Islets of Langerhans
Immune system
Receptors, GABA
Underpinning research
medicine
Animals
Humans
Cell Proliferation
Inflammation
geography
lcsh:RC648-665
Alprazolam
business.industry
Transplantation
Mice, Inbred C57BL
nervous system
Inbred NOD
Muramidase
business
Subjects
Details
- Language :
- English
- ISSN :
- 23146753 and 23146745
- Volume :
- 2019
- Database :
- OpenAIRE
- Journal :
- Journal of Diabetes Research
- Accession number :
- edsair.doi.dedup.....6efe5c3bac7ce619c9a835ba2a8bd1fd