Wide spectrum modulation by KP-544 in models relevant for neuronal survival

Reduced neurotrophic signalling has been proposed as a part of the pathophysiology behind neuronal death and dysfunction. The small molecule KP-544 was developed with the intention to enhance nerve growth factor signalling. To characterize the actions of KP-544 pharmacologically, we used four diverse models with relevance for neuronal function and survival. We found that 300-1000 nM KP-544 enhanced the neurite outgrowth in PC12 cells in response to a suboptimal concentration of nerve growth factor. KP-544 also protected the cerebellar granule cells from excitotoxicity apoptosis induced by the mitochondrial toxin methyl-phenyl-pyridinium, and modulated inflammation by inhibiting interleukin-6 production in primary astrocytes. Chronic treatment of rats with KP-544 prevented the hyper-responsiveness to amphetamine of animals treated with methylazoxymethanol acetate, a recently described neurodevelopmental model of schizophrenia.