MIXED LINEAGE KINASE INHIBITOR CEP- 1347 FAILS TO DELAY DISABILITY IN EARLY PARKINSON DISEASE

Abstract

We read the Parkinson Study Group’s article with interest.1 The disappointing result in PRECEPT that used mixed-lineage kinase (MLK) inhibitor CEP-1347 for treatment of Parkinson disease (PD) may be because 1) the hypothesis that MLK inhibitors retard disease progression is incorrect; 2) the inhibitor does not reach therapeutic levels in the CNS; or 3) MLK inhibitors require an additional signal to maintain dopaminergic neuronal survival. Based on our research into the molecular mechanism of MLK inhibitors, we propose the third possibility as why MLK inhibitors did not maintain neuronal survival. Small-molecule MLK inhibitors such as CEP-1347 and CEP-11004 inhibit activation of the c-Jun NH2-terminal kinase (JNK) and neuronal cell death pathway in many cell culture and animal models. However, in three well-defined cell culture models of trophic factor-withdrawal neuronal cell death, neurons maintained by MLK inhibitors require additional activation of the phosphatidylinositol 3-kinase (PI3-kinase) pathway for survival.2,3 In sympathetic neurons deprived of nerve growth factor, MLK inhibitors induce TrkA receptor overexpression.3 Increases in TrkA expression cause ligand-independent activation of the receptor and, consequently, the PI3-kinase-Akt-GSK (glycogen synthase kinase)-3 pathway. Inhibition of PI3-kinase negates the long-term cell survival and trophic effects of MLK inhibitors. In contrast, MLK inhibitors only maintain short-term survival in trophic-deprived cerebellar granule neurons (CGNs) that express TrkB, another Trk-receptor family member. While MLK inhibitors increase TrkB expression, this does …