While direct evidence linking MC4R activation to changes in GFAP or AQP4 in epilepsy models is scarce, melanocortin signaling, including MC4R activation, exerts anti-inflammatory and astrocytic modulation in CNS disease (Caruso et al., 2007; Chen et al., 2021) opening an important question about the effect of MC4R activation on astrocytic protein expression normalization. This evidence concerns the gene AQP4 and epilepsy.