Eva Kudova
Academy of Sciences of the Czech Republic, Czech Republic
Title: S.M.A.R.T: Steroids-NMDA receptors modulators acting as CNS therapeutics
Biography
Biography: Eva Kudova
Abstract
N-Methyl-D-aspartate receptors (NMDARs) play an important role in development, synaptic plasticity, learning and memory; however, abnormal activation of NMDA receptors has been shown to mediate neuronal degeneration/cell death. The NMDA receptor activity can be modulated by various ligands, including neurosteroids. To find novel potentially beneficial drugs to treat neurological damage/neurodegeneration is one of the most investigated areas in contemporary pharmacology and neuroscience. Therefore, we designed and synthesized SMART Steroids– Steroidal Molecules As Rapid-acting Therapeutics. SMART Steroids are neuroactive molecules, targeting primarily the NMDA receptors and show neuroprotective properties and minimal side effects in animal models. Our screening pipeline covers physicochemical and biological properties like: (i) Solubility (DLS); (ii) lipophilicity (logP, logD, ΔGsolv); (iii) patch-clamp recordings from HEK293 cells assessing NMDAR inhibition rates and IC50 values; (iv) Caco-2 assay, (v) treatment of glutamate and NMDA-induced neurotoxicity (survival rate, caspase-3, intracellular calcium levels, ROS); (vi) in vitro growth of postnatal neurons after neurosteroid administration, (vii) models of animal behavior (open field, elevated plus maze, forced swim test, etc.); (viii) PTZ-induced seizures; (ix) paclitaxel-induced peripheral neuropathy; and (x) pharmacokinetic properties. Our results indicate that these compounds may be beneficial in treatment of several neurological diseases like epilepsy, neuropathic pain, AD, PD and others.