The mPTP was first implicated in ALS pathogenesis using pharmacological approaches. Cyclopsorine A treatment of G93Ahigh mice, delivered intracerebroventricularly or systemically to mice on a multiple drug resistance type 1a/b background, improved outcome modestly [481,482,483]. These studies were confounded by the immunosuppressant actions of cyclopsorine A through calcineurin inhibition. Pharmacological studies using CyPD inhibitors devoid of effects on calcineurin need to be done on ALS mice. Another study showed that treatment with cholest-4-en-3-one oxime (TRO19622), a drug that binds VDAC and the 18 kDa translocator protein (TSPO, or peripheral benzodiazepine receptor), improved motor performance, delayed disease onset, and extended survival of G93Ahigh mice [484]. However, another study using a different TSPO ligand (Ro-4864) did not show positive effects with G93Ahigh mice [485].