Allosteric modulation of M1 or M4 muscarinic receptors restores eNOS expression and L-arginine metabolism in dementia models and synergizes with NO releasers

Abstract

Background

Positive allosteric modulators (PAMs) of muscarinic receptors (M) have been shown to effectively prevent cognitive dysfunctions associated with dementias, but little is known about their impact on NO֗-dependent pathways, in particular eNOS expression, L-arginine metabolism and its derivatives (ADMA/SDMA/NMMA) production.

Methods

Biochemical studies were performed in frontal cortices, hippocampi and plasma samples from mice that were administered with MK-801 (schizophrenia-related dementa) or scopolamine (Alzheimer's disease model) for 14 days alone or together with muscarinic receptors modulators: VU0357017 (M₁) and VU0152100 (M₄). Western blot was used to measure eNOS, DDAH1 and PRMT5, while mass spectrometry was used to measure the levels of L-arginine derivatives. Behavioral studies aimed to investigate the procognitive effects of the combined administration of PAMs with NO^• releasers, spermineNONOate or DETANONOate were performed in novel object recognition (NOR) test, in scopolamine- or MK-801- induced amnesia.

Results

Our results indicate that MK-801 or scopolamine disturb eNOS, DDAH1, PRMT5 expression, and L-arginine bioavailability. VU0357017 or VU0152100 prevented scopolamine or MK-801-induced eNOS dysfunction, but L-arginine derivatives synthesis was inhibited only in MK-801 model. Synergistic effect with NO֗ releasers was observed in NOR.

Conclusions

eNOS expression and L-arginine bioavailability may contribute to antipsychotic action of VU0357017 or VU0152100. The antialzheimer's effect to a lesser extend involves normalization of L-arginine metabolism. The joint administration of the compounds with NO֗ releaser could be proposed as synergistic treatment for both schizophrenia and Alzheimer's disease.