Small-Molecule Inhibitors at the PSD-95/nNOS Interface have Antidepressant-Like Properties in Mice

Abstract

Previous studies have demonstrated that nitric oxide (NO) synthase inhibitors are as efficacious as tricyclic antidepressants in preclinical antidepressant screening procedures and in attenuating behavioural deficits associated with animal models of depression. The N-methyl-D-aspartate receptor (NMDA-R) complex gates Ca 2 þ , which interacts with calmodulin to subsequently activate NO synthase. We hypothesised that uncoupling neuronal nitric oxide synthase (nNOS) from the NMDA-R through the scaffolding protein postsynaptic density protein 95 (PSD-95) would produce behavioural antidepressant effects similar to NO synthase inhibitors. Small-molecule inhibitors of the PSD-95/nNOS interaction, IC87201 (0.01-2 mg/kg) and ZL006 (10 mg/kg) were tested for antidepressant properties in tests of antidepressant activity namely the tail suspension and forced swim tests in mice. We now report that IC87201 and ZL006 produce antidepressant-like responses in the forced swimming test (FST) and tail suspension test (TST) following a single administration in mice. By contrast to the tricyclic antidepressant imipramine (25 mg/kg), the effects are not observed 1 h following drug administration but are apparent 24 and 72 h later. Furthermore prior exposure to the TST or FST is required in order to observe the antidepressantrelated activity. Similar delayed and sustained antidepressant-like effects were observed following TRIM (50 mg/kg) and ketamine (30 mg/kg) in the TST. The antidepressant-like effects of ZL006 also generalise to IC87201 in the TST. IC87201 was devoid of effects on locomotor activity and step-through latency in the passive avoidance cognition test. These data support the hypothesis that targeting the PSD-95/nNOS interaction downstream of NMDA-R produces antidepressant effects and may represent a novel class of therapeutics for major depressive disorders.

The genetic contribution of the NO system at the glutamatergic post-synapse to schizophrenia: Further evidence and meta-analysis

“…Blocking the PDZ-domain of NOS-I with small molecule inhibitors has been suggested as a possible therapeutic approach in the treatment of depression, a hypothesis that is supported by preclinical evidence (Doucet et al, 2013). Since we show that expression levels of NOS-I are reduced in rs41279104 risk allele carriers, and since elevated expression of NOS1AP interfering with post-synaptic targeting of NOS-I (Jaffrey et al, 2002;Jaffrey et al, 1998) is elevated in schizophrenic patients (Xu et al, 2005), a comparable approach (i.e., blocking NOS-I -NOS1AP interaction with small molecules) might provide a feasible strategy for treatment at least in patients carrying this risk allele.…”

The role of α-amino-3-hydroxy-5-methyl-4-isoxazolepropionic acid (AMPA) receptors in depression: Central mediators of pathophysiology and antidepressant activity?

“…Evidence for this strategy, using e.g. small molecules or blocking peptides, is sparse but so far very promising (Doucet et al, 2013). This figure has in part been adapted from Sanacora et al (2012) and Covington et al (2010).…”

“…One possibility is to target PDZ-interactions, which are often very specific, and also fairly easy to target (reviewed in Dev, 2004). This approach has already successfully been used in the mouse FST and TST to target the PDZ-interaction of neuronal nitric oxide using small molecules (Doucet et al, 2013), suggesting that targeting of specific PDZ-interactions in the glutamatergic synapse might indeed provide a promising approach in the treatment of depression.…”

Small molecule inhibitors of PSD95-nNOS protein–protein interactions as novel analgesics

“…IC87201 (see Figure 1), the first small molecule disruptor of PSD95-nNOS interaction, produces antinociceptive efficacy following intrathecal administration in a manner mimicked by the fusion protein TAT-nNOS (Florio et al, 2009). ZL006 (see Figure 1) is a second small molecule disruptor of PSD95-nNOS interaction that shows therapeutic efficacy in models of stroke and depression (Doucet et al, 2013; Zhou et al, 2010). Whether ZL006 produces antinociceptive efficacy in models of pathological pain remains unknown.…”