Neurochemical profiling and brain imaging of a novel neuroprotective compound class, positive allosteric modulators of Sigma-1 receptor

Summary

The overall aim of the project is pharmacological and neurochemical profiling of a novel class of compounds, positive allosteric modulators (PAM) of Sigma-1 receptor (Sig-1R), in pre-clinical models of spatial and neurodegenerative cognition impairment and investigate possibilities to regulate the interactions of Sigma-1 and NMDA receptors to discover novel treatment means for Alzheimer’s disease.

This aim will be achieved by the implementation of the following objectives:

1. Assessment of the role of PAMs of Sig-1R in the process of Sig-1 and NMDA receptor interactions, and Sig-1R-related changes in the functioning of presynaptic NMDA receptors;
2. Analysis of effectiveness of Sig-1R ligands as novel modulators of presynaptic NMDA receptors and dependence of Sig-1R effects on cholesterol content of the plasma membrane of nerve terminals;
3. Identification of unspecific and toxic effects of known Sig-1R agonists and new Sig-1R positive allosteric modulators in vitro;
4. Identify the role of PAM of Sig-1R in spatial and neurodegenerative amnesia models in vivo and analyse changes in the expression of Sig-1 and NMDA receptors in brain tissue in amnesic models;
5. Development of brain imaging methodology (in vivo 3D mice brain tissue images) with polymer-based nanocarriers with unique synthesized near-infrared polymethine/ cyanine dyes and study CNS processes after treatment with the positive allosteric modulators of Sig-1R.

Implementation of this project will lead to discovery of novel pharmaceutical applications of the compounds as well as strengthen the position of Sig-1R as a valuable drug target in CNS pharmacology.