FIGURE 2.

NitroSynapsin ameliorates aberrant S-nitrosylation that contributes to the pathophysiology of hyperexcitability and synaptic dysfunction in Alzheimer’s disease (AD). Oligomerized amyloid-β peptide (Aβ), neuronal hyperexcitability, aggregated proteins, and neuroinflammation can each trigger excessive NO production via inducible or neuronal NO synthase (glial iNOS or neuronal nNOS – the latter is physically tethered to the NMDA receptor), resulting in aberrant protein S-nitrosylation. The ensuing abnormal signaling mediated by protein S-nitrosylation and transnitrosylation results in mitochondrial fragmentation, bioenergetic compromise, and consequent synaptic impairment (Nakamura et al., 2021a,b). NitroSynapsin is a unique drug candidate that manifests dual actions to inhibit excessive (mainly extrasynaptic) NMDA receptor activity, thereby limiting subsequent NO production and its consequent downstream damage to synapses. Mechanistically, NitroSynapsin blocks the receptor’s ion channel when it is excessively open through its aminoadamantane moeity, and then delivers a nitro (–NO₂) group specifically to the NMDA receptor at sites of S-nitrosylation to further decrease excessive receptor activity. SNO, S-nitrosylation or S-nitrosothiol; PSD-95, postsynaptic density protein 95.