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 GABAA-R PAM promotes human β-cell replication, and to a greater extent when combined with exogenous GABA treatment. Hyperglycemic NOD/scid mice were transplanted with human islets under the kidney capsule. All islet recipients became normoglycemic within two days after transplantation. They were then randomized to receive vehicle or alprazolam (0.25 or 0.75 mg/kg/day IP) and/or GABA through their drinking water (6 mg/ml). All mice received BrdU through their drinking water as described in Materials and Methods. After ten days of drug treatment, the replication of human β-cells in the islet grafts was characterized by immunofluorescent staining of Ki67/insulin and BrdU/insulin as described in Materials and Methods. The data are representative images (magnification ×400) or expressed as the mean percentages of Ki67+insulin+ or BrdU+insulin+ islet of each group (-6) of mice from at least three separate experiments. (a) Representative image of islet cells (magnification ×400) costained with anti-insulin (green) and anti-Ki67 (red) (arrows). Scale bar = 25 μm. (b) Representative image of islet cells costained with anti-insulin (green) and anti-BrdU (red) (arrows). (c) The percentages of Ki67+insulin+ cells in the islet grafts. (d) The percentages of BrdU+insulin+ cells in the grafts. ,, and vs. the control with vehicle injection and plain water. and vs. the GABA-treated mice. vs. the alprazolam alone (0.25 mg/kg/day). vs. the alprazolam alone (0.75 mg/kg/day).
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