Figure 5. Pharmacological evidence indicates that selamectin’s proneurogenic activity is mediated by GABAA receptors.
(A) Selamectin and avermectin belong to a chemical family of macrocyclic lactones and have the same structural backbone. (B) Avermectin has less potent proneurogenic activity than selamectin. Only 250 nM avermectin shows a significant effect, which was much less potent compared to that of 250 nM selamectin (t-test, n = 4, p=0.034 for Avermetin vs p=0.002 for selamectin). (C) Taurine, the most abundant endogenous ligand for glycine receptors during neocortical development has no proneurogenic activity in mESC cultures. (D) Muscimol, a GABAA receptor agonist, has a significant proneurogenic activity (t-test, n = 4, p<0.001). (E) Chlordiazepoxide (CDZ), a positive allosteric modulator of GABAA receptor, also has a significant proneurogenic activity (t-test, p<0.05), but there was no obvious additive effect when cells were treated with both selamectin and CDZ (t-test, p=0.480). (F) The GABAA receptor antagonist bicucullin and non-competitive blockers picrotoxin and pentylenetetrazol alone had no effect on neuronal production (white columns, control group were normalized to fold change = 1, displayed as the red dot line). However, when tested together with selamectin, the effect of selamectin was blocked (gray columns). In contrast, the glycine receptor inhibitor strychnine does not block the effect of selamectin. Final concentration: Bicuculline (Bicu) = 100 μM; Picrotoxin (PTX) = 500 μM; Pentylenetetrazol (PTZ) = 5 mM; Strychnine (STY) = 100 μM; Selamectin (Sela) = 0.3 μM; Muscimol (Musci) = 10 μM (t-test, n = 4).