Spermidine trihydrochloride is an agonist of the N-methyl-D-aspartate (NMDA) receptor. The NMDA receptor is a ligand-gated ion channel complex with multiple regulatory sites in addition to the glutamate recognition site. Spermidine binds to the polyamine modulatory site of the NMDA receptor, and has been classified as agonists at this site based on their ability to enhance the binding of MK801 (a noncompetitive antagonist of the NMDA receptor). Thus, spermidine potentially enhances the neuroprotective effect of NMDA antagonists.

References:

1. Munir M, Subramaniam S, McGonigle P. Polyamines modulate the neurotoxic effects of NMDA in vivo. Brain Research, 1993, 616(1-2): 163-170.

2. Carvalho FB, Mello CF, Marisco PC, et al. Spermidine decreases Na⁺, K⁺-ATPase activity through NMDA receptor and protein kinase G activation in the hippocampus of rats. European Journal of Pharmacology, 2012, 684(1-3): 79-86.

3. Rao TS, Cler JA, Oei EJ, et al. The polyamines, spermine and spermidine, negatively modulate N-methyl-d-aspartate (NMDA) and quisqualate receptor mediated responses in vivo: Cerebellar cyclic GMP measurements. Neurochemistry International, 1990, 16(2): 199-206.