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.