rhyncophylline and Neurodegenerative-Diseases

The EphA4 receptor has been proposed to be a key actor in neurodegenerative diseases. In the last years, several research groups focused their efforts on the discovery of small molecules capable of blocking EphA4 activity by binding its extracellular domain. However, none of the compounds so far identified possess adequate chemical and/or pharmacological profiles to assess the "druggability" of EphA4 in animal models. New efforts are required to deliver a new generation of suitable pharmacological tools.

Topics: Animals; Humans; Indole Alkaloids; Models, Molecular; Neurodegenerative Diseases; Oxindoles; Pyrroles; Receptor, EphA4; Salicylates; Signal Transduction

Alzheimer's disease (AD), the most common neurodegenerative disease, has limited treatment options. As such, extensive studies have been conducted to identify novel therapeutic approaches. We previously reported that rhynchophylline (Rhy), a small molecule EphA4 inhibitor, rescues impaired hippocampal synaptic plasticity and cognitive dysfunctions in APP/PS1 mice, an AD transgenic mouse model. To assess whether Rhy can be developed as an alternative treatment for AD, it is important to examine its pharmacokinetics and effects on other disease-associated pathologies. Here, we show that Rhy ameliorates amyloid plaque burden and reduces inflammation in APP/PS1 mice. Transcriptome analysis revealed that Rhy regulates various molecular pathways in APP/PS1 mouse brains associated with amyloid metabolism and inflammation, specifically the ubiquitin proteasome system, angiogenesis, and microglial functional states. These results show that Rhy, which is blood-brain barrier permeable, is beneficial to amyloid pathology and regulates multiple molecular pathways.

Topics: Alzheimer Disease; Amyloid beta-Peptides; Amyloid beta-Protein Precursor; Animals; Disease Models, Animal; Inflammation; Mice; Mice, Inbred C57BL; Mice, Transgenic; Neurodegenerative Diseases; Oxindoles; Plaque, Amyloid; Presenilin-1