A hydrolysate of poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132) suppresses Ca3.2-dependent pain by sequestering exogenous and endogenous sulfide.

Poly-trans-[(2-carboxyethyl)germasesquioxane] (Ge-132), an organogermanium, is hydrolyzed to 3-(trihydroxygermyl)propanoic acid (THGP) in aqueous solutions, and reduces inflammation, pain and cancer, whereas the underlying mechanisms remain unknown. Sulfides including HS, a gasotransmitter, generated from l-cysteine by some enzymes including cystathionine-γ-lyase (CSE), are pro-nociceptive, since they enhance Ca3.2 T-type Ca channel activity expressed in the primary afferents, most probably by canceling the channel inhibition by Zn linked via coordinate bonding to His of Ca3.2. Given that germanium is reactive to sulfur, we tested whether THGP would directly trap sulfide, and inhibit sulfide-induced enhancement of Ca3.2 activity and sulfide-dependent pain in mice. Using mass spectrometry and H NMR techniques, we demonstrated that THGP directly reacted with sulfides including NaS and NaSH, and formed a sulfur-containing reaction product, which decreased in the presence of ZnCl. In Ca3.2-transfected HEK293 cells, THGP inhibited the sulfide-induced enhancement of T-type Ca channel-dependent membrane currents. In mice, THGP, administered systemically or locally, inhibited the mechanical allodynia caused by intraplantar NaS. In the mice with cyclophosphamide-induced cystitis and cerulein-induced pancreatitis, which exhibited upregulation of CSE in the bladder and pancreas, respectively, systemic administration of THGP as well as a selective T-type Ca channel inhibitor suppressed the cystitis-related and pancreatitis-related visceral pain. These data suggest that THGP traps sulfide and inhibits sulfide-induced enhancement of Ca3.2 activity, leading to suppression of Ca3.2-dependent pain caused by sulfide applied exogenously and generated endogenously.