H₂SおよびATP補捉作用を有するrepagermanium (Ge-132) はマウスにおけるパクリタキセル誘発性末梢神経障害を抑制する

抄録

We have reported that the enhanced activity of Ca_v3.2 T-type Ca²⁺ channels caused by endogenous H₂S participates in the paclitaxel (PCT)-induced peripheral neuropathy (PIPN), and that neuron-derived ATP promotes the PCT-induced macrophage (Mφ) infiltration followed by extracellular release of HMGB1, a damage-associate molecular pattern protein, leading to PIPN development. On the other hand, we have found that repagermanium (i.e. Ge-132), once hydrolyzed into 3-(trihydroxygermyl)propanoic acid (THGP), can trap H₂S, in addition to ATP, and inhibit H₂S-induced enhancement of Ca_v3.2 activity and pain. Thus, we evaluated effects of THGP on PIPN in mice. In the mice treated with PCT repeatedly, daily i.p. administration of THGP at 100 mg/kg prevented PIPN development and Mφ accumulation in the sciatic nerves. In Mφ-like RAW264.7 cells, THGP at 10 mM inhibited the cell migration caused by ATP at 0.1 mM, but not extracellular HMGB1 release caused by ATP at 1 mM. Finally, a single i.p. administration of THGP at 100 mg/kg, as well as TTA-A2, a Ca_v3 inhibitor, at 1 mg/kg, reversed the established PIPN in mice. These data suggest that THGP prevents PIPN development by trapping ATP that promotes PCT-induced perineuronal Mφ accumulation and reverses PIPN most probably by trapping H₂S that enhances Ca_v3.2 activity.