E2511, a novel small compound TrkA biased positive allosteric modulator, reinnervates cholinergic neuron and activates cholinergic functions in non‐clinical studies

Background Cholinergic innervation is particularly vulnerable in many neurodegenerative diseases associated with cognitive dysfunction, and loss of cholinergic neurons Alzheimer’s disease (AD) pathogenic event observed from early stage correlated impairment. Nerve growth factor (NGF) plays a major role the maintenance function neurons, decrease trophic signalling by NGF-Tropomyosin receptor kinase A (TrkA) contributes to neurodegeneration decline during course AD. The activation NGF-induced signal could be promising therapy for including AD, reinnervating maintaining functional status. E2511 was identified as novel small compound TrkA biased positive allosteric modulator that can enhance specific NGF without induction NGF-like adverse effect via direct binding primary neuron culture animal model. We present evidence induced restoration model rats. Method on assessed biochemical studies such western blotting immunohistochemistry human Tau P301S transgenic mice (Tau tg mice) following once-daily oral administrations 3 months. downstream effects acetylcholine (ACh) were evaluated cerebrospinal fluid (CSF) collected cisterna magna normal SD rats treated 14 days, using an original LCMS method. Result Chronic administration demonstrated reinnervative presynapses well correlation improvement number mice. In rats, CSF ACh increased dose-dependent manner at exposures reinnervation, changes also correlating increases choline acetyltransferase mRNA level. These results suggest may useful marker establish effective dose humans. Conclusion functionally reinnervates neuronal network dose-related used pharmacodynamic showing clinical studies.