The Innovation

CureDiab addresses NAFLD with a novel first in class therapy. Positive allosteric modulators of the GABA-A receptor are able to counteract lipotoxic damage of hepatocytes. Therefore, activation of this pathway protects hepatocytes at an early stage and these molecules are exceptional candidates for combination therapy.

A protective Effect in Liver toxicity

Exposure to GABA has been proposed to exert a protective effect in liver toxicity both in vivo and in vitro1-3. We can confirm a protective function in hepatocyte injury with the compound HK4, acting as a positive allosteric modulator (PAM) of the GABAA receptor. The GABAA receptor is a pentameric Cl- channel, composed of different combinations of subunits: α(1–6), β(1–4), γ(1–3), δ, ε, θ, π and ρ(1–3). HK4 is a small molecule, devoid of blood brain barrier penetration and binding at an allosteric binding site. We proofed its selective modulator activity by patch clamping, calcium influx measurements and assays with the non-competitive GABAA channel blocker picrotoxin.

The promising antiapoptotic effect was demonstrated by reduced caspase 3/7 activity, cleaved caspase 7-protein expression and TUNEL assay in hepatocytes. The PAM reduces lipotoxic-induced apoptosis in hepatocytes by preventing inflammation, DNA damage and ER stress. Since cell death, including apoptosis, is a critical step in the progression of NAFL to NASH, HK4 or other PAMs of the GABAA receptor may arise as an innovative pharmacological tool to treat or prevent NAFLD as a first-in-class drug.
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Schematic overview of the potential of the activated GABAA receptor to counteract lipotoxicity – Created with

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TUNEL-staining of our lipotoxicity model and the protective impact of HK4: DNA fragmentation, a signal of apoptosis, was assessed by TUNEL-staining in HepG2 cells after 24h of lipotoxicity treatment. Representative images of TUNEL-positive stained cells (red), while nuclei were counterstained with Hoechst (blue). Palmitate (PA), Staurosporine (STP)




1. Norikura T, Kojima-Yuasa A, Opare Kennedy D, Matsui-Yuasa I. Protective effect of gamma-aminobutyric acid (GABA) against cytotoxicity of ethanol in isolated rat hepatocytes involves modulations in cellular polyamine levels. Amino Acids. 2007;32(3):419-423. https://doi:10.1007/s00726-006-0381-3.

2. Hata T, Rehman F, Hori T, Nguyen JH. GABA, γ-Aminobutyric Acid, Protects Against Severe Liver Injury. J Surg Res. 2019;236:172-183. https://doi:10.1016/j.jss.2018.11.047.

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4. Jacob, T.C.; Moss, S.J.; Jurd, R. GABA(A) receptor trafficking and its role in the dynamic modulation of neuronal inhibition. Nat. Rev. Neurosci. 2008, 9, 331–343, doi:10.1038/nrn2370