First-in-class neuroprotective Nanodrug
Glutamatergic cytotoxicity mediated by overactivation of NMDA receptors (NMDARs) is implicated in numerous neurological disorders, from acute hypoxic-ischemic brain injury to chronic neurodegenerative diseases such as Huntington's, Parkinson's, and Alzheimer’s diseases, HIV-associated neurocognitive disorders, and amyotrophic lateral sclerosis. Therefore, NMDARs are considered important therapeutic targets.
However, NMDARs also play a critical role in numerous physiological processes, including developmental plasticity, learning, and memory. Therefore, there is a two-prong requirement for clinically tolerable and pharmacologically efficient NMDAR antagonists: they must preserve the physiological role of glutamate-mediated synaptic transmission, and block only excessive pathological activation of NMDARs.
Recent studies strongly suggest that the spatial separation of physiological and pathological NMDAR-mediated signaling cascades takes place with synaptic NMDARs (sNMDARs) mediating pro-survival pathways and extrasynaptic NMDARs (eNMDARs) triggering various apoptotic pathways. In this case, selective eNMDAR antagonists will be expected to act as pathology-specific drugs. Moreover, focusing efforts on exclusive antagonists of eNMDARs may avoid serious psychomimetic side effects that drug discovery programs have previously encountered while working with various NMDAR antagonists.