4. Discussion and conclusions
To date no cell or animal model of ALS accurately predicts effi- cacy of neuroprotective treatments for the most commonly occurring, sporadic form of the illness (sALS). Because of the survivalpromoting, pleiotropic actions of neurotrophins on neurons [24], and the demonstrated efficacy of neurotrophins or neurotrophin receptors in preventing motor neuron death following axotomy [25–27], we are pursuing the pre-clinical development of microneurotrophins for ALS. As part of this development effort, we characterized the in vitro permeability of the MNT’s to artificial membrane and their interactions with ABC transporters that can remove drugs by reversepumping across the BBB. We observed that MNT’s had excellent potential BBB permeability and were not major substrates for ABC drug transporters. We then examined the metabolism of a lead MNT, BNN27, by mouse and human liver cells. We observed rapid metabolism by mouse and slower metabolism by human liver cells. In both systems BNN27 metabolites could be detected and are likely ring single hydroxylation metabolites produced by the cytochrome P450 system. However, because we did not characterize any of the metabolites structurally, we can only speculate as to their chemical identity.
